Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
Introduction
Replicative senescence is irreversible cell proliferation arrest. Senescent cells stop their divisions, grow in size and start specific secretory activity. This process often results from somatic cells aging and telomeres shortening. The same state may be provoked by DNA damage, oncogenesis etc. Activity of oncogenes and pro-proliferative genes may promote expression of TP53 gene, well known as a tumor suppressor, and induce cellular senescence and/or apoptosis. Most senescent cells also express another tumor suppressor gene, p16INK4a. Thus, oncogene-induced senescence is a natural barrier for tumorigenesis. On the other side, senescent cells produce growth factors, proteases and cytokines which are necessary for the tissue renewal. Deregulated secretion of these factors can provoke malignant transformation after different premalignant damages and in benign tumors. There is a group of genes, which are necessary for both cellular senescence and carcinogenesis. The majority of these genes are regulated by microRNAs. These miRNAs regulating cellular senescence may act as tumor suppressors or stimulators. This review is focused on the role playing by senescence-associated miRNAs (SA-miRs) in development of pancreatic cancer, which is one of the most aggressive oncogenic diseases.
Cellular Senescence and Cancer
Almost 60 years ago, Hayflick described cellular senescence as a process blocking replicative potential and growth of human diploid fibroblasts in culture. As was found, human fibroblasts change their morphology and stop to divide after 50–60 rounds of cell divisions. This phenomenon is known as replicative senescence, or the Hayflick limit [1]. In contrast with the normal somatic cells, cancer and embryonic stem cells can escape the cellular senescence [2–4]. Senescent cells undergo some morphological changes, for example, they increase in size, more than twofold and form heterochromatin foci inside their nucleus. Besides, these cells start specific secretory activity (senescence-associated secretory phenotype, SASP) [5, 6].
Senescence can be also a cellular response to different damaging agents, chemical or physical. Many factors may trigger cellular senescence. The telomere shortening during replication is particularly important. Extremely short telomeres as well as DNA damages result in DNA damage response (DDR), a chain of events starting cellular senescence in G1 phase [6–9]. The molecular basis of this G1 arrest is thought to be due to a DNA damage response, resulting in accumulation of the cyclin dependent kinase (CDK) inhibitors p21 and p16 that block the inactivating phosphorylation of the retinoblastoma tumor suppressor pRb, thereby preventing DNA replication. Protein p21 acts downstream of p53 whereas p16 acts upstream of pRB. As was shown, p21 also mediates permanent DNA damage-induced cell cycle arrest in G2 (G2 exit) by inhibiting mitotic CDK complexes and pRb inactivation [10, 11].
Loss of tumor suppressors (ARF, TP53, and PTEN) or active expression of oncogenes (KRAS, BRAF and MYC) in normal cells also promotes cellular senescence. This phenomenon is known as oncogene induced senescence (OIS) [5, 6, 9]. It was first observed when an oncogenic form of RAS, a cytoplasmic transducer of mitogenic signals, was expressed in normal human fibroblasts [12].
Both DDR and OIS activate one of the main pathways for cellular senescence, INK4a/ARF cascade [9, 13]. INK4a locus expresses two small proteins: p16INK4a and p19ARF (alternative reading frame). Cyclin-dependent kinase inhibitor (CDKI) p16INK4a prevents pRB (retinoblastoma protein) phosphorylation and inactivation, which leads to cellular senescence. Another protein, p19ARF, cooperates with p53 bringing about cell cycle arrest and subsequent senescence [9, 13, 14]. All genes of ARF cascade are well known tumor suppressors blocking cell cycle progression during malignant transformation. Products of these genes produce a barrier that prevents carcinogenesis. Accordingly, these genes are often inactivated by mutations or promoter methylation in different tumors, such as breast, colon, liver and pancreatic cancer [15–18].
There are several pathways triggering or regulating cellular senescence, but their deregulation results in tumor development. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway constitutes an additional route to the establishment of OIS since it promotes mTOR-regulated translation and stabilization of p53 [19, 20]. Loss of tumor suppressor PTEN, negative regulator of PI3K/Akt pathway, may promote cancer progression. It is estimated that in at least 50% of all cancer patients PI3K/Akt signaling pathway is deregulated [20]. Another pathway, which involves transforming growth factor beta (TGF-β), blocks cell cycle progress through G1 phase. TGF-β causes senescence stimulating synthesis of p15 and p21 proteins and prevents Rb phosphorylation. On the other hand, constant TGF-β expression is necessary for cancer cell migration and invasion [6, 21, 22]. Nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) participates in a senescence-associated cytokine response and control of SASP components secretion which suggests a tumor restraining role of NF-κB. On the other hand, constitutive aberrant activation of NF-κB has been observed in different kinds of cancer, including lymphoma, leukemia, breast, colon, liver, pancreas, prostate, and ovarian cancers [4, 23]. Notch signaling pathway is involved in cell-contact-dependent juxtacrine senescence, where cells are characterized by distinct SASP components [24, 25]. In cancers aberrant NOTCH activation correlates with activation of NF-κB and PI3K/Akt pathways which enhances tumor growth and resistance chemotherapy [26].
NF-κB [23, 27], mTOR [6, 28], and Notch [24, 29] pathways are involved in SASP regulation. Senescent cells secrete up to 80 specific substances including collagen and fibronectin, interleukins (in particular IL-1, IL-6 and IL-8), growth factors and metalloproteases. These factors are necessary for tissue renewal [6, 30, 31]. Cellular senescence can be transmitted to neighboring cells through secreted SASP factors (including IL-1 and Notch ligands) thus it prevents the malignant transformation. IL-6 and IL-8 promote inflammation leading to the recruitment of lymphocytes and macrophages to eliminate senescent and premalignant cells [32–34]. On the other hand, deregulated persistent SASP factors secretion produces a chronic inflammatory microenvironment in tissues and can induce malignant transformation in neighboring cells. Pro-inflammatory cytokines IL-6 and IL-8 can stimulate epithelial-mesenchymal transition (EMT), cell migration and invasion [8, 34]. SASP turns senescent fibroblasts into pro-inflammatory cells with the ability to promote EMT and tumor progression [35]. Additionally, senescent fibroblasts and mesothelial cells secrete vascular endothelial growth factor (VEGF) inducing neovascularization as well as matrix metalloproteinases which facilitate tumor cell migration and invasion [8, 36, 37]. Thus, SASP acts in a context dependent manner and has either pro- or anti- tumorigenic effect.
Therefore, cellular senescence is a process, which may act in two opposite directions. On the one hand, senescence is a natural mechanism of somatic cells protection against unlimited proliferation and malignant transformation. The main genes, controlling the senescence pathways, are also well known as the tumor suppressors. Their loss or aberrant expression helps malignant cells to bypass senescence and promotes cancer progression. Besides, senescent cells produce secretory factors, which are necessary for cancer cells elimination and the tissue renewal. On the other hand, aberrant SASP secretion can stimulate inflammation and carcinogenesis.
Cellular Senescence in Pancreatic Cancer
Senescent pancreatic cells have first been detected in low grade pancreatic intraepithelial neoplasias (PanINs) in the mouse models expressing oncogene KRAS from its endogenous promoter [38]. More than 90% of pancreatic ductal adenocarcinomas (PDACs) harbor KRAS activating mutations [39, 40]. Active KRAS in the pancreas leads to development of premalignant lesions which display low proliferative activity and contain cells expressing markers of cellular senescence [41, 42]. Caldwell et al. found that about 10% of cells in mouse PanIN-1 are senescent and express the standard senescence marker SA-β-gal (senescence-associated β-galactosidase). These cells were negative for proliferative marker Ki67. The number of senescent cells in mouse PanINs was decreasing during the PanIN progression from grade 1 to 3. Senescent cells were also detected in human PanINs and PDACs but the number of these cells was much less than in the mouse models [41, 43]. High-grade mouse PanIN2/3 lesions as well as PDAC were negative for senescence markers including endogenous senescence-associated β-galactosidase and expression of the p16INK4a [41, 43]. Moreover, another cell subpopulation (about 10%) expressing both Ki67 and SA-β-gal was detected in murine PanINs [41]. Deschênes‐Simard et al. found that mouse PDAC-derived cell lines exhibit stem cells properties, while PanIN‐derived cell lines do not. These findings indicate that cancer cells can escape senescence and reentry in the cell cycle and proliferation through the reprogramming from senescent to “stem” cell status [42].
Senescence may also be bypassed by a number of mutations inactivating most important genes of senescence pathways. Tumor suppressors TP53 and CDKN2A/INK4 harbor mutations in 80% and 85% of PDACs correspondently [18]. Deletion of Rb accelerates pancreatic carcinogenesis driven by oncogenic KRAS expression and impairs senescence in premalignant lesions [44]. SMAD4, a member of TGF-β pathway, is deleted in 50% PDACs [18]. In almost 60% of all PDAC patients the PI3K/Akt signaling pathway is deregulated [20, 45]. Loss of PTEN (PI3K inhibitor) expression in 25–70% of PDAC cases correlate with the short-term overall survival [20].
Some of tumor suppressors can also be inactivated by epigenetic alterations. Altered gene methylation, regulated by DNA methyltransferases (DNMT) 1, 3a and 3b, contributes to PDAC development [46]. DNMT1, 3a and 3b were expressed in 46.6%, 23.9%, and 77.3% of PDAC tissues, respectively, but not in normal pancreas [47]. CDKN2A (INK4a) locus may be inactivated by hypermethylation in 18% of PDACs [48]. Overexpression of DNMT1 was believed to be responsible for silencing key tumor suppressor genes including p16 [49]. Histone deacetylase SIRT1 has been shown to be involved in the deacetylation of non-histone proteins such as p53, Rb, and Smad7, allowing cells to bypass senescence and survive DNA damage [3].
Analysis of all exons and selected introns of 410 cancer-associated genes was performed in tumor samples from 336 PDAC patients demonstrated frequent gene alterations of several pathways, including TGF-β, Notch and NF-κB signaling, which are associated with cellular senescence and SASP regulation but can stimulate cancer aggressiveness, chemoresistance and metastasis in PDACs [37, 50]. NF-κB, a major transcription factor involved in these inflammatory responses, is found to be activated in KRAS-transformed epithelial cells. In mouse models it also has been shown that interaction between NF-κB and Notch signaling pathways is needed to drive a sustained inflammatory response [51, 52].
Certain pathological stimuli, such as inflammation, also seem appear to promote tumorigenesis in PDAC by means of a senescence bypass [4, 43]. Senescent cells secrete interleukins (in particular IL-1 and IL-6), growth factors and metalloproteases that stimulate inflammation leading to the recruitment of lymphocytes and macrophages for elimination of premalignant cells [3, 4, 53]. On the other hand, persistent or deregulated SASP activation can promote chronic inflammation and therefore drive cancer progression [4, 54]. In chronic pancreatitis, the number of senescent cells significantly correlates with the severity of inflammation and fibrosis. Both the fibrotic region and senescence-associated SA-β-gal positive region overlap with the region densely infiltrated by immune cells [55]. Senescent cells are also accumulated in tumor microenvironment, including carcinoma-associated fibroblasts and activated pancreatic stellate cells [55–57]. Both these cell subpopulations produce SASP factors which may contribute to cancer development and metastasis [57, 58]. The role that senescent cells play in formation of the inflammatory PDAC microenvironment remains for the most part unknown [3, 4, 56].
Therefore, in chronic pancreatitis or PanIN of low grade cellular senescence may prevent malignant transformation. Under conditions of chronic inflammation pancreatic cells may accumulate mutations inactivating key senescence pathways and thus start tumor development. However, the mechanism of senescence bypass in tumors that spontaneously arise from premalignant lesions remains mostly unclear. SASP possibly may play a dual role in pancreatic carcinogenesis: at the beginning it recruits immune cells for elimination of the malignant cells, but later it provokes persistent inflammation and supports tumor progression.
SA-miRs in Pancreatic Cancer
According to the data Tacutu et al., more than 262 human genes are associated with cellular senescence. More than a half of the senescence-associated genes (138 genes) participate in both cellular senescence and cancer pathways [59]. Almost two thirds of these genes (64%) are regulated by microRNAs. MicroRNAs (miRNAs) are a class of single-stranded RNA molecules of 15–27 nucleotides in length that regulate gene expression at the post-transcriptional level. Initially, miRNAs are transcribed as thousand-base-long primary transcripts by RNA polymerase II and are called precursor miRNAs. Precursor miRNAs are exported to the cytoplasm via exportin 5, where they are integrated into DICER and RNA-induced silencing complex (RISC). MicroRNAs use the RISC complex on their mRNA targets for translational repression or degradation [60].
Tacutu et al. detected approximately 40 miRNAs regulating expression of both senescence-associated and cancer-related genes [59]. The senescence-associated miRNAs (SA-miRs) control cell transition during cell cycle, mainly through the G1/S or G2/M checkpoints by targeting cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs) [61].
More than 25 senescence-associated miRs (SA-miRs) were identified in pancreatic cancer. Pancreatic tumors demonstrate very low number of senescent cells, but PDAC cells produce SA-miRs stimulating processes of carcinogenesis, tumor growth and survival as well as cancer microenvironment formation [59]. These miRNAs are often packed into exosomes which can deliver functional SA-miRs to recipient cells. Exosomes are membrane-bound extracellular vesicles (EV) containing biological materials (proteins and nucleic acids) and play an important role in communication among cells. This kind of EVs originates by the release of intraluminal vesicles (ILVs) after fusion of multivesicular bodies (MVBs) with plasma membrane. MVBs move toward the plasma membrane to fuse and release ILVs that, in extracellular space, become exosomes. Target cells uptake these miRNAs by endocytosis or pinocytosis then release them from microvesicles [62, 63]. Exosomal miR-155 and miR-210 can increase PDAC resistance to chemotherapy. SA-miRs of miR-200 family stimulate cancer cells migration and invasion. Highly elevated levels of miR-17-5p and miR-21 stimulating cancer cells proliferation were detected in serum samples of pancreatic cancer patients [62, 64].
Cancer cells release extra-cellular miRNAs to recruit macrophages for the tumor microenvironment formation. One more function of these EVs is to “educate” the immune system to spare PDAC cells from active killing [64]. Moreover, exosomes released by cancer cells can travel to distant organs, such as the liver and brain, and can modulate the microenvironment to establish a metastatic niche and subsequent metastasis [65].
EVs are implicated in the transformation of various precancerous lesions into PDAC and in the progression of cancer toward more invasive and metastasizing forms. Inside these lesions cells produce exosomes containing miR-21, miR-155 and 210 which promote inflammation as well as pancreatic stellate cells activation [62, 66]. Vicentini et al. located by in situ hybridization that exosomal SA-miRNAs including miR17-5p were derived from the epithelial components of the lesions [67].
In contrast with PDAC, anti-oncogenic SA-miRs are constantly expressed in normal pancreatic tissues. These miRNAs, such as miR-146a and miR-217, demonstrate high expression levels not only in the senescent cells [68, 69]. As a component of SASP, exosomes of the senescent cells can include two opposite sets of SA-miRs, both senescence-inducing (let-7a, miR-34 and miR-217) and pro-oncogenic (miR-21, miR-155 and miR-221) [70, 71].
Accumulating evidences showed that pancreatic tumor cells communicate with stromal cells in the local environment or even in the remote organs via secretion of extracellular vesicles packed with SA-miRs. Stromal cells that lack genomic instabilities uptake these miRNAs then release from microvesicles into the target cells as messengers to dictate them so as to facilitate tumor progression and metastasis [72, 73]. Pancreatic cancer-secreted SA-miRs, such as miR-21, miR-155 or miR-210 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts (CAF) [74, 75]. Also, exosomes containing SA-miRs can promote EMT as well as convert pancreatic stellate cells and bone marrow-derived stem cells into the CAF [76]. In turn, CAF release a variety of circulating SA-microRNAs including miR-21, miR-210 etc. which stimulate cancer cells proliferation, migration and invasion as well as support angiogenesis, and recruit monocytes/macrophages [74]. Senescent CAFs, like other senescent cells, present a SASP composed of pro-tumorigenic factors. Senescent cells produce exosomal miR-21, miR-146, miR-155a, miR-210 and miR-221 stimulating inflammation process aa well as cancer cells proliferation, migration and invasion [77]. In addition, the existence of a senescent CAF population in PDAC endowed with invasion- and metastasis-promoting properties as well as poor patient prognosis [78].
SA-miRs often display aberrant expression levels in tumors. Abnormal expression of miRNAs is one of important clinical markers for PDACs diagnostics and treatment. A list of SA-miRs [37, 59, 79], deregulated in pancreatic cancers, are presented in Tables 1, 2.
TABLE 1
| Oncomirs (upregulated) | miRNA targets | SA-miR enhances | References |
|---|---|---|---|
| miR-10b | TIP30 | Invasion | [80, 89] |
| miR-15b | SMURF2 | Metastasis | [90] |
| mir-17-5p | RBL2 and up to 20 cell cycle regulators | Proliferation, invasion | [91–94] |
| miR-21 | CDK2AP1, Pdcd, BCL2, PTEN and almost 30 genes | Proliferation, invasion, chemoresistance, tumor survival | [81–83] |
| miR-155 | TP53INP1, FOXO3a, and SOCS1 | Proliferation, transformation, migration and invasion | [95–97] |
| miR-181a | PTEN | Proliferation | [84] |
| miR-210 | Ephrin-A3, MNT | Proliferation, angiogenesis, tumor growth and survival | [98–101] |
| miR-221 | TIMP2, PTEN, p27(kip1), p57(kip2), and PUMA | Proliferation, invasion | [82, 83] |
| miR-222 | TIMP2 | Proliferation, invasion | [82] |
Senescence-associated oncomirs in pancreatic tumors.
TABLE 2
| Tumor suppressors (downregulated) | miRNA targets | SA-miR inhibits | References |
|---|---|---|---|
| let-7 family | KRAS, HMGA2, CDC25a, CDC34, CDK6, BCL2 | Proliferation, aEMT, metastasis, chemoresistance | [104–106] |
| miR-24-3p | LAMB | Migration, invasion | [115] |
| mir-26b | CDK14 | Proliferation | [116] |
| miR-29a | MUC1 and LOXL2 | Proliferation, migration, chemoresistance | [117–119] |
| miR-30a | SNAI1 | Proliferation, tumor survival, chemoresistance | [120] |
| miR-34a | NOTCH, BCL2, VEGFA, CCND1, and CDK6 | Proliferation, angiogenesis, EMT, metastasis | [107–112] |
| miR-107 | CDK6, PI3K/AKT | Proliferation, metastasis | [113, 114] |
| mir-124 | IL6R, STAT3, MCT1 | Proliferation, tumor growth | [110, 111, 124] |
| miR-126 | ADAM9 | Invasion, EMT | [133] |
| miR-137 | KDM4A | Proliferation | [122, 123] |
| miR-141 | MAP4K4 | EMT, metastasis | [125–127] |
| miR-145 | MUC13, NEDD9 | Invasion, EMT | [134] |
| miR-146a | IRAK-1 | Migration, invasion | [135, 170] |
| miR-148a | PHLDA2, LPCAT2, and AP1S3 | Proliferation, migration, invasion | [122] |
| miR-200 family | ZEB1, ZEB2 | EMT, migration, invasion | [69, 128, 136] |
| miR-217 | KRAS, SIRT1 | Proliferation | [132] |
| miR-335 | OCT4 | Proliferation | [129] |
| miR-494 | SDC1 | EMT, metastasis |
Tumor-suppressing SA-miRs in pancreatic cancer.
EMT, epithelial-mesenchymal transitions.
SA-miRs playing an important role in pancreatic tumors formation and development can be classified into two major groups: oncomirs and cancer suppressors. The first group of SA-miRs stimulates proliferation and migration of cells, chemotherapy resistance and metastasis (Table 1). The second group of miRNAs activates genes of cellular senescence and apoptosis pathways; thereby functioning as tumor suppressors (Table 2).
Oncogenic SA-miRs Promote Pancreatic Cancer
A large number of SA-miRNAs are overexpressed in pancreatic cancer. Nakata et al and Eun et al. reported that miR-10b, miR-155, miR-21, miR-221 and miR-222, were aberrantly expressed in PDAC [80, 81]. MiR-21 is one of the first identified cancer-promoting oncomirs, which targets almost 30 genes, including tumor suppressors, such as CDK2AP1, Pdcd4 and BCL2 [82]. PTEN, which suppresses PI3K-AKT-mTOR senescence pathway, is also a target for miR-21 as well as miR-181a and miR-221 [83, 84]. High expression levels of miR-21 were detected in early pancreatic ductal adenocarcinoma precursor lesions [85]. MiR-21 stimulates PDAC cell proliferation, invasion, chemoresistance and prevents apoptosis [83, 85–88]. MiRNA-10b enhances pancreatic cancer cell invasiveness by suppressing TIP30 expression and promoting EGF and TGF-β effects [80, 89]. MiR-15b degrades SMURF2 transcripts, which is also participant of TGF-β pathway, and this miRNA expression was associated with enhanced metastasis in PDACs [90]. MiRNA-17-5p negatively regulates more than 20 genes involved in the G1/S-phase transition [91, 92]. Overexpression of this miRNA in pancreatic cancer is associated with intensive cancer cell proliferation and invasion as well as poor prognosis [93, 94]. MiR-155 is inhibitor of tumor protein 53-induced nuclear protein 1 (TP53INP1) and FOXO3a expression, leading to cell proliferation and malignant transformation [95, 96]. Also miR-155 is associated with the JAK/STAT pathway, it negatively regulates SOCS1 and accelerates migration and invasion of PDAC cells [97]. Mir-210 is necessary for tumor angiogenesis, cell cycle regulation and cancer survival in hypoxia conditions [98–101]. MiR-221 and 222 genes are placed in tandem on the X chromosome. Activity of these miRNAs stimulates cancer cells proliferation and invasion [102, 103].
The cited works show that SA-miRNAs may control expression of several groups of tumor-suppressor genes from various pathways. Most of them act like the inhibitors of main senescence or apoptosis pathways, such as p53-p16-pRB or PTEN-PI3K-AKT-mTOR. Thus, SA-oncomirs are necessary for successful PDAC cell proliferation, chemoresistance, survival and tumor progression.
SA-miRNAs May Act as Tumor Suppressors in Pancreatic Ductal Adenocarcinomas
Another group of the SA-miRs are often downregulated in PDACs by DNA methylation or gene loss. These miRNAs may inhibit cell proliferation; prevent cancer cells chemoresistance, migration and invasions besides they induce cellular senescence and apoptosis. For example, miRNA family let-7 inhibits cancer cell proliferation, metastasis and chemoresistance [104–106]. MicroRNA-34a is a tumor suppressor, like let-7, and a promising candidate for pancreatic cancer therapy [107]. There are multiple target genes for miR-34a, such as NOTCH, BCL2, VEGFA, CCND1 and CDK6, regulating cell cycle, p53/p38-MAPK, Notch and PI3K/Akt pathways [108–112]. Tumor suppressing miR-107 also inhibits CDK6 and stimulates PTEN expression [113, 114]. MiR-24-3p downregulates laminin subunit beta 3 (LAMB), inhibits processes of cancer cells attachment and migration, modifies their interaction with other extracellular matrix components [115]. MiR-26b directly inactivates cyclin-dependent kinase CDK14 in cancers. Expression of CDK14 promotes cancer cell aggressiveness [116]. The data about miR-29a are controversial. MiR-29a, targeting MUC1 and LOXL2, inhibits cell proliferation, migration, invasion and sensitize pancreatic cancer cells to gemcitabine [117, 118]. On the other hand, miR-29a may stimulate pancreatic cancer growth by inhibiting the expression of tristetraprolin [119]. MiR-30a regulates cancer cell response to chemotherapy through SNAI1/IRS1/Akt pathway, which is fundamental in mediating multiple processes, including cell proliferation and survival, angiogenesis and glucose metabolism [120]. There is a group of SA-miRs, involved in pancreatic cancer stem cells regulation, inhibition of epithelial-mesenchymal transitions (EMT) as well as prevention of cancer cells migration and invasion [121]. This group includes two miRNA families: let-7 [104, 105] and miR-200 (including miR-141) [122, 123] as well as miR-34a [111, 121] miR-126 [124], miR-145 [125–127], mir-217 [128] and miR-494 [129]. Overexpression of miR-124 downregulates IL6-JAK2-STAT3 pathway and inhibits PDAC cells proliferation [130]. Mir-124 also may suppress PDAC growth by regulation of cancer lactate metabolism [131]. MiR-137 and miR-335 triggers p53, p16 and KRAS-induced cellular senescence in PDACs [132, 133] MiR-146a inhibits the invasive capacity of pancreatic cancer cells with concomitant downregulation of EGFR and the NF-κB regulatory kinase, interleukin 1 receptor–associated kinase 1 (IRAK-1) [134]. MiR-148a targets may affect cell cycle and apoptosis [135]. MiR-217 is significantly downregulated in PDAC tissues and cell lines. Dual-luciferase reporter assay revealed that KRAS mRNA is the direct target of miR-217. Overexpression of miR-217 in a PDAC cell line decreases KRAS mRNA levels, and inhibits cell proliferation [136]. On the other hand, miR-217 is usually expressed in normal pancreas [69], and can induce cellular senescence in fibroblasts [137].
Thus, there are two groups of SA-miRs with opposite functions: the first one promotes cells proliferation, tumor growth and metastasis, the second one stimulates cellular senescence and apoptosis in PDACs. In PDACs the oncomirs are overexpressed but the tumor-suppressing SA-miRs are downregulated.
SA-miRs and Pancreatic Cancer Diagnostics and Patient Prognosis
For the last 20 years aberrant expression was detected in a great number of SA-miRs. Differential expression of SA-miR profiles has been well described in PDAC, with miRNAs isolated from various patient-derived specimens, including the peripheral blood, pancreatic tissue, and digestive juices [138, 139]. Oncomirs, such as miR-21, may be upregulated up to 6888-fold in PDACs in comparison with normal tissue. About up to 52-fold increase for miR-155 was described in PDACs [140]. On the other hand, tumor-suppressing miR-217, was downregulated up to 62.5-fold in diagnostic needle aspirates from surgical pancreatic cancer specimens [141]. Lee et al. have selected a set of four miRNAs including miR-10b, miR-210, miR-202-3p and miR-375, and these miRNAs differentiated mucinous cystic lesions from intraductal papillary mucinous neoplasms and PDAC with sensitivity of 100% and specificity of 100% [142]. Diagnostic kit detecting aberrant expression of miRNAs was developed to discriminate malignant tissues from pancreatic lesions. This kit, miRInform Pancreas (Asuragen, Inc. Austin, TX), uses miR-217 and miR-196a to differentiate PDAC from other benign conditions with sensitivity and specificity of 95% [143]. The clinical trials of this kit have not been completed yet.
Circulating SA-miRs are attractive objects of study because of their abundance, stability, and easiness of isolation and amplification with inexpensive and non-invasive techniques [138, 139]. These miRNAs expression levels are also deregulated in the blood samples of PDAC patients’. Vila-Navarro et al. described significant overexpression of let-7, miR-21, miR-155, miR-181a and miR-210 in PDAC patients plasma samples [144]. Wei et al. analyzed 27 published studies involving more than 2000 PDAC patients and found that miR-10b, miR-21, miR34a, miR-221 and miR-155 were often upregulated in serum- or plasma samples. Among them, miR-21 was the most frequently identified dysregulated miRNA [145]. Meta-analysis of 46 studies involving 4326 pancreatic cancer patients demonstrated that utilization of circulating SA-miRs such as miR-10b, miR-181a and let-7a distinguished PDAC patients from non-PDAC controls with sensitivity of more than 90%. The serum levels of miR-200a identify patients with PDAC from healthy controls with a sensitivity and specificity of >80% [146]. A significant difference between PDAC and healthy groups was observed for the expression of miR-21 and miR-34a in serum samples [147]. Serum miR-124 levels were significantly decreased in patients with PDAC. Serum levels of miR-124 distinguished PDAC from chronic pancreatitis and healthy control subjects [148].
SA-miRs, whether circulating or isolated from tissue samples may serve as predictors of PDAC patient outcome. High expression levels of SA-miRs, including miR-21 [88, 149, 150], miR-155 [151, 152] and also miR-210 [153, 154] may be used as predictors for the cancer chemoresistance as well as poor prognosis. Greither et al. have proposed a prognostic panel consisting of miR-155, -203, -210, and -222, where their elevated expression is a predictor of poor outcome [154]. Low serum levels of miR-124 were significantly associated with lymph node metastasis, tumor node metastasis (TNM) stage and shorter survival time after surgery [148]. Yu et al. analyzed plasma levels of miR-210 with RT-qPCR in a cohort of 31 PDAC patients. High miR-210 expression was significantly associated with improved survival [153].
On the other hand, there is still no clinically approved miRNAs-based PDAC diagnostic system. The possible reasons for this may be a great variability of PDAC cells as well as the gene variability within the human population. Expression levels of miRNAs may vary greatly (sometimes showing opposite results) among patients even in the same hospital as well as in the population of different regions or countries.
SA-miRs as Agents for Pancreatic Cancer Therapy
Therapy of PDAC by SA-miRs is based on assumption that oncomirs should be inhibited whereas tumor suppressors need to be restored to proper levels. As a result, cancer cells should enter the state of cellular senescence, stop proliferation and metastasis. Artificial SA-miRs (so called mimics) are two-stranded hairpin molecules imitating tumor-suppressor miRNAs [68, 155], whereas anti-miRs are chemically modified antisense strands [oligonucleotides with 2′-sugar modifications or locked nucleic acids (LNAs)], designed for elimination of oncomirs in cancer cells [156, 157]. Another possible way to eliminate oncomirs is miRNA sponge. This “sponge” is a small vector expressing miRNA target sequence “soaking” oncomirs and preventing them from association with their targets. These vectors may carry binding sequences for several different miRNAs. Expression levels of this vector need to be carefully calibrated for effective miRNAs elimination [158, 159]. A serious problem in the miRNAs-based cancer therapy is a proper miRNAs selection. Because of cancer cells heterogeneity in PDAC, single miRNA may not suffice for the tumor elimination [135]. Obviously, it is necessary to select a group of several miRNAs. On the other hand, each member of this group may control up to 30 target genes which may increase the probability of side-effects. Therefore, a lot of bioinformatics analyses are needed to predict and specify the whole network of selected miRNAs targets.
Efficient delivery of miRNA for therapeutic purposes is also highly problematic. Low cellular uptake of RNA, degradation in the bloodstream, and rapid renal clearance are significant obstacles on the way to the successful delivery of miRNA [160]. There are three methods for miRNAs delivery into tumors. The first one is based on lipid nanoparticles. Liposomes are spherical lipid bilayers that mimic biological membranes. Cationic liposome is positively charged and the negatively charged DNA binds to it by electrostatic interaction. Cells uptake lipid nanoparticles by endocytosis [161, 162]. The second approach make use of different viruses as the delivery agents [163]. The third method uses cationic polymers or dendrimers. Cationic polymers such as poly-L-lysine (PLL), polyethyleneimine (PEI), and oligopeptides can form polyplexes with miRNAs by means of electrostatic interactions. They can exist as linear or branched polymers of varying length. Dendrimers are a type of highly branched synthetic polymers with a spherical shape [160]. All of these methods have a lack of tissue and tumor-specific selectivity. SA-miRs delivery into normal tissues may have destructive consequences. Perhaps using of tissue specific and tumor specific (telomerase) promoters will help to solve this problem [164, 165]. Another possible way is to bind lipid particles or polymers with different ligands for tumor-specific receptors [160].
The first-ever miRNA therapeutic drug called miravirsen for the treatment of hepatitis C virus (HCV) infection is in phase II of clinical trials. Miravirsen is a short locked nucleic acid (LNA) antisense sequence for miR-122 [166]. MiR-34a mimicking drug MRX34 based on a lipid nanoparticle delivery system was used in a Phase I clinical trial to treat solid tumors and hematologic malignancies. This study was terminated because of the drug’s side effects [155, 167]. The study of two SA-miRs-based systems for PDAC therapy was started as preclinical trials. The first system is based on using lipid particles and mir-34a and miR-143/miR-145 cluster carrying nanovector [161, 168]. The second one employs miR-34a nanovector with special delivery nanocomplexes [169]. Nevertheless, there has not been developed any clinically approved miRNAs delivery system yet.
Thus, a lot of obstacles should be overcome to use SA-miRs for both PDAC diagnostics and miRNAs-based therapy.
Conclusion
The SA-miRs may play two opposing roles in PDAC formation: some of these miRNAs block cellular senescence pathways and promote pancreatic cancer, whereas other acts like tumor-suppressors inducing senescence and apoptosis. Both these groups demonstrate abnormal expression levels which may be useful for PDAC diagnostics and patients prognosis. SA-miRs seem to have a great therapeutic potential as an instrument of decreasing chemoresistance of PDACs and preventing cancer cells proliferation, migration and invasion. But for the present there has not been established any clinically approved SA-miRs-based systems for diagnostics or therapy. Thus, future investigations are needed to resolve these problems.
Statements
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This work was supported by the Charles University research program PROGRES Q 28 (Oncology).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that cousld be construed as a potential conflict of interest.
Abbreviations
EMT, epithelial-mesenchymal transitions; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; SA-miRs, senescence-associated microRNAs; SASP, senescence-associated secretory phenotype.
References
1
Hayflick L . The Limited In Vitro Lifetime of Human Diploid Cell Strains. Exp Cel Res (1965) 37:614–36. 10.1016/0014-4827(65)90211-9
2
Miura T Mattson MP Rao MS . Cellular Lifespan and Senescence Signaling in Embryonic Stem Cells. Aging Cell (2004) 3:333–43. 10.1111/j.1474-9728.2004.00134.x
3
Ag Moir J A White S Mann J . Arrested Development and the Great Escape - the Role of Cellular Senescence in Pancreatic Cancer. Int J Biochem Cel Biol (2014) 57:142–8. 10.1016/j.biocel.2014.10.018
4
Porciuncula A Hajdu C David G . The Dual Role of Senescence in Pancreatic Ductal Adenocarcinoma. Adv Cancer Res (2016) 131:1–20. 10.1016/bs.acr.2016.05.006
5
Rodier F Campisi J . Four Faces of Cellular Senescence. J Cel Biol (2011) 192:547–56. 10.1083/jcb.201009094
6
Ou HL Hoffmann R González‐López C Doherty GJ Korkola JE Muñoz‐Espín D . Cellular Senescence in Cancer: from Mechanisms to Detection. Mol Oncol (2021) 15:2634–71. 10.1002/1878-0261.12807
7
Nakamura AJ Chiang YJ Hathcock KS Horikawa I Sedelnikova OA Hodes RJ et al Both telomeric and Non-telomeric DNA Damage Are Determinants of Mammalian Cellular Senescence. Epigenetics Chromatin (2008) 1:6. 10.1186/1756-8935-1-6
8
Campisi J . Cellular Senescence: Putting the Paradoxes in Perspective. Curr Opin Genet Develop (2011) 21:107–12. 10.1016/j.gde.2010.10.005
9
Collado M Blasco MA Serrano M . Cellular Senescence in Cancer and Aging. Cell (2007) 130:223–33. 10.1016/j.cell.2007.07.003
10
Gire V Dulić V . Senescence from G2 Arrest, Revisited. Cell Cycle (2015) 14:297–304. 10.1080/15384101.2014.1000134
11
Kumari R Jat P . Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cel Dev Biol (2021) 9:645593. 10.3389/fcell.2021.645593
12
Serrano M Lin AW McCurrach ME Beach D Lowe SW . Oncogenic Ras Provokes Premature Cell Senescence Associated with Accumulation of P53 and p16INK4a. Cell (1997) 88:593–602. 10.1016/s0092-8674(00)81902-9
13
Ko A Han SY Song J . Dynamics of ARF Regulation that Control Senescence and Cancer. BMB Rep (2016) 49:598–606. 10.5483/BMBRep.2016.49.11.120
14
Dimri GP . What Has Senescence Got to Do with Cancer?Cancer Cell (2005) 7:505–12. 10.1016/j.ccr.2005.05.025
15
Silva J Silva JM Domínguez G García JM Cantos B Rodríguez R et al Concomitant Expression ofp16INK4aandp14ARFin Primary Breast Cancer and Analysis of Inactivation Mechanisms. J Pathol (2003) 199:289–97. 10.1002/path.1297
16
Dominguez G Silva J Garcia JM Silva JM Rodriguez R Muñoz C et al Prevalence of Aberrant Methylation of p14ARF over p16INK4a in Some Human Primary Tumors. Mutat Res Fundam Mol Mech Mutagenesis (2003) 530:9–17. 10.1016/s0027-5107(03)00133-7
17
Tannapfel A Busse C Geissler F Witzigmann H Hauss J Wittekind C . INK4a-ARF Alterations in Liver Cell Adenoma. Gut (2002) 51:253–8. 10.1136/gut.51.2.253
18
Hansel DE Kern SE Hruban RH . Molecular Pathogenesis of Pancreatic Cancer. Annu Rev Genom Hum Genet (2003) 4:237–56. 10.1146/annurev.genom.4.070802.110341
19
Astle MV Hannan KM Ng PY Lee RS George AJ Hsu AK et al AKT Induces Senescence in Human Cells via mTORC1 and P53 in the Absence of DNA Damage: Implications for Targeting mTOR during Malignancy. Oncogene (2012) 31:1949–62. 10.1038/onc.2011.394
20
Murthy D Attri KS Singh PK . Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics. Front Physiol (2018) 9:335. 10.3389/fphys.2018.00335
21
Lin S Yang J Elkahloun AG Bandyopadhyay A Wang L Cornell JE et al Attenuation of TGF-β Signaling Suppresses Premature Senescence in a P21-dependent Manner and Promotes Oncogenic Ras-Mediated Metastatic Transformation in Human Mammary Epithelial Cells. MBoC (2012) 23:1569–81. 10.1091/mbc.E11-10-0849
22
Roupakia E Markopoulos GS Kolettas E . Genes and Pathways Involved in Senescence Bypass Identified by Functional Genetic Screens. Mech Ageing Develop (2021) 194:111432. 10.1016/j.mad.2021.111432
23
Jing H Lee S . NF-κB in Cellular Senescence and Cancer Treatment. Mol Cell (2014) 37:189–95. 10.14348/molcells.2014.2353
24
Hoare M Ito Y Kang T-W Weekes MP Matheson NJ Patten DA et al NOTCH1 Mediates a Switch between Two Distinct Secretomes during Senescence. Nat Cel Biol (2016) 18:979–92. 10.1038/ncb3397
25
Parry AJ Hoare M Bihary D Hänsel-Hertsch R Smith S Tomimatsu K et al NOTCH-mediated Non-cell Autonomous Regulation of Chromatin Structure during Senescence. Nat Commun (2018) 9:1840. 10.1038/s41467-018-04283-9
26
Aster JC Pear WS Blacklow SC . The Varied Roles of Notch in Cancer. Annu Rev Pathol Mech Dis (2017) 12:245–75. 10.1146/annurev-pathol-052016-100127
27
Chien Y Scuoppo C Wang X Fang X Balgley B Bolden JE et al Control of the Senescence-Associated Secretory Phenotype by NF-κB Promotes Senescence and Enhances Chemosensitivity. Genes Dev (2011) 25:2125–36. 10.1101/gad.17276711
28
Laberge R-M Sun Y Orjalo AV Patil CK Freund A Zhou L et al MTOR Regulates the Pro-tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation. Nat Cel Biol (2015) 17:1049–61. 10.1038/ncb3195
29
Teo YV Rattanavirotkul N Olova N Salzano A Quintanilla A Tarrats N et al Notch Signaling Mediates Secondary Senescence. Cel Rep (2019) 27:997–1007. 10.1016/j.celrep.2019.03.104
30
Coppé J-P Desprez P-Y Krtolica A Campisi J . The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu Rev Pathol Mech Dis (2010) 5:99–118. 10.1146/annurev-pathol-121808-102144
31
Gorgoulis V Adams PD Alimonti A Bennett DC Bischof O Bishop C et al Cellular Senescence: Defining a Path Forward. Cell (2019) 179:813–27. 10.1016/j.cell.2019.10.005
32
Kuilman T Michaloglou C Vredeveld LCW Douma S van Doorn R Desmet CJ et al Oncogene-Induced Senescence Relayed by an Interleukin-dependent Inflammatory Network. Cell (2008) 133:1019–31. 10.1016/j.cell.2008.03.039
33
Acosta JC O'Loghlen A Banito A Guijarro MV Augert A Raguz S et al Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence. Cell (2008) 133:1006–18. 10.1016/j.cell.2008.03.038
34
Kojima H Inoue T Kunimoto H Nakajima K . IL-6-STAT3 Signaling and Premature Senescence. JAK-STAT (2013) 2:e25763. 10.4161/jkst.25763
35
Laberge R-M Awad P Campisi J Desprez P-Y . Epithelial-mesenchymal Transition Induced by Senescent Fibroblasts. Cancer Microenviron (2012) 5:39–44. 10.1007/s12307-011-0069-4
36
Kapoor P Deshmukh R . VEGF: A Critical Driver for Angiogenesis and Subsequent Tumor Growth: An IHC Study. J Oral Maxillofac Pathol (2012) 16:330–7. 10.4103/0973-029X.102478
37
Olivieri F Rippo MR Monsurrò V Salvioli S Capri M Procopio AD et al MicroRNAs Linking Inflamm-Aging, Cellular Senescence and Cancer. Ageing Res Rev (2013) 12:1056–68. 10.1016/j.arr.2013.05.001
38
Collado M Gil J Efeyan A Guerra C Schuhmacher AJ Barradas M et al Senescence in Premalignant Tumours. Nature (2005) 436:642. 10.1038/436642a
39
Biankin AV Waddell N Kassahn KS Gingras MC Muthuswamy LB Johns AL et al Pancreatic Cancer Genomes Reveal Aberrations in Axon Guidance Pathway Genes. Nature (2012) 491:399–405. 10.1038/nature11547
40
Waters AM Der CJ . KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med (2018) 8:a031435. 10.1101/cshperspect.a031435
41
Caldwell ME DeNicola GM Martins CP Jacobetz MA Maitra A Hruban RH et al Cellular Features of Senescence during the Evolution of Human and Murine Ductal Pancreatic Cancer. Oncogene (2012) 31:1599–608. 10.1038/onc.2011.350
42
Deschênes-Simard X Parisotto M Rowell M-C Le Calvé B Igelmann S Moineau-Vallée K et al Circumventing Senescence Is Associated with Stem Cell Properties and Metformin Sensitivity. Aging Cell (2019) 18:e12889. 10.1111/acel.12889
43
Guerra C Collado M Navas C Schuhmacher AJ Hernández-Porras I Cañamero M et al Pancreatitis-induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced Senescence. Cancer Cell (2011) 19:728–39. 10.1016/j.ccr.2011.05.011
44
Carrière C Gore AJ Norris AM Gunn JR Young AL Longnecker DS et al Deletion of Rb Accelerates Pancreatic Carcinogenesis by Oncogenic Kras and Impairs Senescence in Premalignant Lesions. Gastroenterology (2011) 141:1091–101. 10.1053/j.gastro.2011.05.041
45
Schild C Wirth M Reichert M Schmid RM Saur D Schneider G . PI3K Signaling Maintains C-Myc Expression to Regulate Transcription of E2F1 in Pancreatic Cancer Cells. Mol Carcinog (2009) 48:1149–58. 10.1002/mc.20569
46
Ciernikova S Earl J García Bermejo ML Stevurkova V Carrato A Smolkova B . Epigenetic Landscape in Pancreatic Ductal Adenocarcinoma: On the Way to Overcoming Drug Resistance?Int J Mol Sci (2020) 21:4091. 10.3390/ijms21114091
47
Gao J Wang L Xu J Zheng J Man X Wu H et al Aberrant DNA Methyltransferase Expression in Pancreatic Ductal Adenocarcinoma Development and Progression. J Exp Clin Cancer Res (2013) 32:86. 10.1186/1756-9966-32-86
48
Ueki T Toyota M Sohn T Yeo CJ Issa JP Hruban RH et al Hypermethylation of Multiple Genes in Pancreatic Adenocarcinoma. Cancer Res (2000) 60:1835–9.
49
Hong L Sun G Peng L Tu Y Wan Z Xiong H et al The Interaction between miR-148a and DNMT1 Suppresses Cell Migration and Invasion by Reactivating Tumor Suppressor Genes in Pancreatic Cancer. Oncol Rep (2018) 40:2916–25. 10.3892/or.2018.6700
50
Lowery MA Jordan EJ Basturk O Ptashkin RN Zehir A Berger MF et al Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype. Clin Cancer Res (2017) 23:6094–100. 10.1158/1078-0432.CCR-17-0899
51
Maniati E Bossard M Cook N Candido JB Emami-Shahri N Nedospasov SA et al Crosstalk between the Canonical NF-κB and Notch Signaling Pathways Inhibits Pparγ Expression and Promotes Pancreatic Cancer Progression in Mice. J Clin Invest (2011) 121:4685–99. 10.1172/JCI45797
52
Prabhu L Mundade R Korc M Loehrer PJ Lu T . Critical Role of NF-κB in Pancreatic Cancer. Oncotarget (2014) 5:10969–75. 10.18632/oncotarget.2624
53
Penfield JD Anderson M Lutzke L Wang KK . The Role of Cellular Senescence in the Gastrointestinal Mucosa. Gut Liver (2013) 7:270–7. 10.5009/gnl.2013.7.3.270
54
Fane M Weeraratna AT . How the Ageing Microenvironment Influences Tumour Progression. Nat Rev Cancer (2020) 20:89–106. 10.1038/s41568-019-0222-9
55
Xue R Jia K Wang J Yang L Wang Y Gao L et al A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. Front Physiol (2018) 9:754. 10.3389/fphys.2018.00754
56
Petroni G Galluzzi L . Senescence Inflames the Pancreatic Tumor Microenvironment. Cel Rep Med (2020) 1:100020. 10.1016/j.xcrm.2020.100020
57
Shao C Tu C Cheng X Xu Z Wang X Shen J et al Inflammatory and Senescent Phenotype of Pancreatic Stellate Cells Induced by Sqstm1 Downregulation Facilitates Pancreatic Cancer Progression. Int J Biol Sci (2019) 15:1020–9. 10.7150/ijbs.27825
58
Wang T Notta F Navab R Joseph J Ibrahimov E Xu J et al Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes. Mol Cancer Res (2017) 15:3–14. 10.1158/1541-7786.MCR-16-0192
59
Tacutu R Budovsky A Yanai H Fraifeld VE . Molecular Links between Cellular Senescence, Longevity and Age-Related Diseases - a Systems Biology Perspective. Aging (2011) 3:1178–91. 10.18632/aging.100413
60
Bayraktar R Van Roosbroeck K Calin GA . Cell‐to‐cell Communication: microRNAs as Hormones. Mol Oncol (2017) 11:1673–86. 10.1002/1878-0261.12144
61
Bueno MJ Malumbres M . MicroRNAs and the Cell Cycle. Biochim Biophys Acta Mol Basis Dis (2011) 1812:592–601. 10.1016/j.bbadis.2011.02.002
62
Romano R Picca A Eusebi LHU Marzetti E Calvani R Moro L et al Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression. Cells (2021) 10:1361. 10.3390/cells10061361
63
Conti I Varano G Simioni C Laface I Milani D Rimondi E et al miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment. Cells (2020) 9:220. 10.3390/cells9010220
64
Uddin MH Al-Hallak MN Philip PA Mohammad RM Viola N Wagner K-U et al Exosomal microRNA in Pancreatic Cancer Diagnosis, Prognosis, and Treatment: From Bench to Bedside. Cancers (2021) 13:2777. 10.3390/cancers13112777
65
Costa-Silva B Aiello NM Ocean AJ Singh S Zhang H Thakur BK et al Pancreatic Cancer Exosomes Initiate Pre-metastatic Niche Formation in the Liver. Nat Cel Biol (2015) 17:816–26. 10.1038/ncb3169
66
Sun W Ren Y Lu Z Zhao X . The Potential Roles of Exosomes in Pancreatic Cancer Initiation and Metastasis. Mol Cancer (2020) 19:135. 10.1186/s12943-020-01255-w
67
Vicentini C Calore F Nigita G Fadda P Simbolo M Sperandio N et al Exosomal miRNA Signatures of Pancreatic Lesions. BMC Gastroenterol (2020) 20:137. 10.1186/s12876-020-01287-y
68
Ling H Fabbri M Calin GA . MicroRNAs and Other Non-coding RNAs as Targets for Anticancer Drug Development. Nat Rev Drug Discov (2013) 12:847–65. 10.1038/nrd4140
69
Chang X Yu C Li J Yu S Chen J . hsa-miR-96 and Hsa-miR-217 Expression Down-Regulates with Increasing Dysplasia in Pancreatic Intraepithelial Neoplasias and Intraductal Papillary Mucinous Neoplasms. Int J Med Sci (2017) 14:412–8. 10.7150/ijms.18641
70
Terlecki-Zaniewicz L Lämmermann I Latreille J Bobbili MR Pils V Schosserer M et al Small Extracellular Vesicles and their miRNA Cargo are Anti-apoptotic Members of the Senescence-Associated Secretory Phenotype. Aging (2018) 10:1103–32. 10.18632/aging.101452
71
Wallis R Mizen H Bishop CL . The Bright and Dark Side of Extracellular Vesicles in the Senescence-Associated Secretory Phenotype. Mech Ageing Develop (2020) 189:111263. 10.1016/j.mad.2020.111263
72
Wang Z Tan Y Yu W Zheng S Zhang S Sun L et al Small Role with Big Impact: miRNAs as Communicators in the Cross-Talk between Cancer-Associated Fibroblasts and Cancer Cells. Int J Biol Sci (2017) 13:339–48. 10.7150/ijbs.17680
73
Zhang Y Yang P Wang X-F . Microenvironmental Regulation of Cancer Metastasis by miRNAs. Trends Cel Biol (2014) 24:153–60. 10.1016/j.tcb.2013.09.007
74
Gascard P Tlsty TD . Carcinoma-associated Fibroblasts: Orchestrating the Composition of Malignancy. Genes Dev (2016) 30:1002–19. 10.1101/gad.279737.116
75
Pang W Su J Wang Y Feng H Dai X Yuan Y et al Pancreatic Cancer‐secreted miR‐155 Implicates in the Conversion from normal Fibroblasts to Cancer‐associated Fibroblasts. Cancer Sci (2015) 106:1362–9. 10.1111/cas.12747
76
Sun Q Zhang B Hu Q Qin Y Xu W Liu W et al The Impact of Cancer-Associated Fibroblasts on Major Hallmarks of Pancreatic Cancer. Theranostics (2018) 8:5072–87. 10.7150/thno.26546
77
Olivieri F Albertini MC Orciani M Ceka A Cricca M Procopio AD et al DNA Damage Response (DDR) and Senescence: Shuttled Inflamma-miRNAs on the Stage of Inflamm-Aging. Oncotarget (2015) 6:35509–21. 10.18632/oncotarget.5899
78
Cortesi M Zanoni M Pirini F Tumedei MM Ravaioli S Rapposelli IG et al Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight. Int J Mol Sci (2021) 23:254. 10.3390/ijms23010254
79
Feliciano A Sánchez-Sendra B Kondoh H Lleonart ME . MicroRNAs Regulate Key Effector Pathways of Senescence. J Aging Res (2011) 2011:1–11. 10.4061/2011/205378
80
Nakata K Ohuchida K Mizumoto K Kayashima T Ikenaga N Sakai H et al MicroRNA-10b Is Overexpressed in Pancreatic Cancer, Promotes its Invasiveness, and Correlates with a Poor Prognosis. Surgery (2011) 150:916–22. 10.1016/j.surg.2011.06.017
81
Lee EJ Gusev Y Jiang J Nuovo GJ Lerner MR Frankel WL et al Expression Profiling Identifies microRNA Signature in Pancreatic Cancer. Int J Cancer (2007) 120:1046–54. 10.1002/ijc.22394
82
Buscaglia LEB Li Y . Apoptosis and the Target Genes of microRNA-21. Chin J Cancer (2011) 30:371–80. 10.5732/cjc.011.10132
83
Park J-K Lee EJ Esau C Schmittgen TD . Antisense Inhibition of microRNA-21 or -221 Arrests Cell Cycle, Induces Apoptosis, and Sensitizes the Effects of Gemcitabine in Pancreatic Adenocarcinoma. Pancreas (2009) 38:e190–e199. 10.1097/MPA.0b013e3181ba82e1
84
Liu J Xu D Wang Q Zheng D Jiang X Xu L . LPS Induced miR-181a Promotes Pancreatic Cancer Cell Migration via Targeting PTEN and MAP2K4. Dig Dis Sci (2014) 59:1452–60. 10.1007/s10620-014-3049-y
85
Du Rieu MC Torrisani J Selves J Al Saati T Souque A Dufresne M et al MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions. Clin Chem (2010) 56:603–12. 10.1373/clinchem.2009.137364
86
Giovannetti E Funel N Peters GJ Del Chiaro M Erozenci LA Vasile E et al MicroRNA-21 in Pancreatic Cancer: Correlation with Clinical Outcome and Pharmacologic Aspects Underlying its Role in the Modulation of Gemcitabine Activity. Cancer Res (2010) 70:4528–38. 10.1158/0008-5472.CAN-09-4467
87
Moriyama T Ohuchida K Mizumoto K Yu J Sato N Nabae T et al MicroRNA-21 Modulates Biological Functions of Pancreatic Cancer Cells Including Their Proliferation, Invasion, and Chemoresistance. Mol Cancer Ther (2009) 8:1067–74. 10.1158/1535-7163.MCT-08-0592
88
Hu G-y. Tao F Wang W Ji K-w. Prognostic Value of microRNA-21 in Pancreatic Ductal Adenocarcinoma: a Meta-Analysis. World J Surg Onc (2016) 14:82. 10.1186/s12957-016-0842-4
89
Ouyang H Gore J Deitz S Korc M . microRNA-10b Enhances Pancreatic Cancer Cell Invasion by Suppressing TIP30 Expression and Promoting EGF and TGF-β Actions. Oncogene (2014) 33:4664–74. 10.1038/onc.2013.405
90
Zhang W-L Zhang J-H Wu X-Z Yan T Lv W . miR-15b Promotes Epithelial-Mesenchymal Transition by Inhibiting SMURF2 in Pancreatic Cancer. Int J Oncol (2015) 47:1043–53. 10.3892/ijo.2015.3076
91
Cloonan N Brown MK Steptoe AL Wani S Chan W Forrest AR et al The miR-17-5p microRNA Is a Key Regulator of the G1/S Phase Cell Cycle Transition. Genome Biol (2008) 9:R127. 10.1186/gb-2008-9-8-r127
92
Dellago H Bobbili MR Grillari J . MicroRNA-17-5p: At the Crossroads of Cancer and Aging - A Mini-Review. Gerontology (2017) 63:20–8. 10.1159/000447773
93
Yu J Ohuchida K Mizumoto K Fujita H Nakata K Tanaka M . MicroRNAmiR-17-5pis Overexpressed in Pancreatic Cancer, Associated with a Poor Prognosis, and Involved in Cancer Cell Proliferation and Invasion. Cancer Biol Ther (2010) 10:748–57. 10.4161/cbt.10.8.13083
94
Zhu Y Gu J Li Y Peng C Shi M Wang X et al MiR-17-5p Enhances Pancreatic Cancer Proliferation by Altering Cell Cycle Profiles via Disruption of RBL2/E2F4-Repressing Complexes. Cancer Lett (2018) 412:59–68. 10.1016/j.canlet.2017.09.044
95
Gironella M Seux M Xie M-J Cano C Tomasini R Gommeaux J et al Tumor Protein 53-induced Nuclear Protein 1 Expression is Repressed by miR-155, and its Restoration Inhibits Pancreatic Tumor Development. Proc Natl Acad Sci U.S.A (2007) 104:16170–5. 10.1073/pnas.0703942104
96
Wang P Zhu C-f. Ma M-z. Chen G Song M Zeng Z-l. et al Micro-RNA-155 is Induced by K-Ras Oncogenic Signal and Promotes ROS Stress in Pancreatic Cancer. Oncotarget (2015) 6:21148–58. 10.18632/oncotarget.4125
97
Huang C Li H Wu W Jiang T Qiu Z . Regulation of miR-155 Affects Pancreatic Cancer Cell Invasiveness and Migration by Modulating the STAT3 Signaling Pathway through SOCS1. Oncol Rep (2013) 30:1223–30. 10.3892/or.2013.2576
98
Fasanaro P D'Alessandra Y Di Stefano V Melchionna R Romani S Pompilio G et al MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3. J Biol Chem (2008) 283:15878–83. 10.1074/jbc.M800731200
99
Zhang Z Sun H Dai H Walsh R Imakura M Schelter J et al MicroRNA miR-210 Modulates Cellular Response to Hypoxia through the MYC Antagonist MNT. Cell Cycle (2009) 8:2756–68. 10.4161/cc.8.17.9387
100
Huang X Le Q-T Giaccia AJ . MiR-210 - Micromanager of the Hypoxia Pathway. Trends Mol Med (2010) 16:230–7. 10.1016/j.molmed.2010.03.004
101
Huang X Zuo J . Emerging Roles of miR-210 and Other Non-coding RNAs in the Hypoxic Response. Acta Biochim Biophys Sinica (2014) 46:220–32. 10.1093/abbs/gmt141
102
Xu Q Li P Chen X Zong L Jiang Z Nan L et al miR-221/222 Induces Pancreatic Cancer Progression through the Regulation of Matrix Metalloproteinases. Oncotarget (2015) 6:14153–64. 10.18632/oncotarget.3686
103
Sarkar S Dubaybo H Ali S Goncalves P Kollepara SL Sethi S et al Down-regulation of miR-221 Inhibits Proliferation of Pancreatic Cancer Cells through Up-Regulation of PTEN, P27(kip1), P57(kip2), and PUMA. Am J Cancer Res (2013) 3:465–77.
104
Balzeau J Menezes MR Cao S Hagan JP . The LIN28/let-7 Pathway in Cancer. Front Genet (2017) 8:31. 10.3389/fgene.2017.00031
105
Wang H Chirshev E Hojo N Suzuki T Bertucci A Pierce M et al The Epithelial-Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA Let-7 in Cancer. Cancers (2021) 13:1469. 10.3390/cancers13061469
106
Bhutia YD Hung SW Krentz M Patel D Lovin D Manoharan R et al Differential Processing of Let-7a Precursors Influences RRM2 Expression and Chemosensitivity in Pancreatic Cancer: Role of LIN-28 and SET Oncoprotein. PLoS One (2013) 8:e53436. 10.1371/journal.pone.0053436
107
Li XJ Ren ZJ Tang JH . MicroRNA-34a: a Potential Therapeutic Target in Human Cancer. Cell Death Dis (2014) 5:e1327. 10.1038/cddis.2014.270
108
Iliopoulos D Drakaki A . MicroRNA-gene Signaling Pathways in Pancreatic Cancer. Biomed J (2013) 36:200–8. 10.4103/2319-4170.119690
109
Kong YW Ferland-McCollough D Jackson TJ Bushell M . microRNAs in Cancer Management. Lancet Oncol (2012) 13:e249–e258. 10.1016/S1470-2045(12)70073-6
110
Guo S Fesler A Wang H Ju J . microRNA Based Prognostic Biomarkers in Pancreatic Cancer. Biomark Res (2018) 6:18. 10.1186/s40364-018-0131-1
111
Tang Y Tang Y Cheng Y-s. miR-34a Inhibits Pancreatic Cancer Progression through Snail1-Mediated Epithelial-Mesenchymal Transition and the Notch Signaling Pathway. Sci Rep (2017) 7:38232. 10.1038/srep38232
112
Hidalgo-Sastre A Lubeseder-Martellato C Engleitner T Steiger K Zhong S Desztics J et al Mir34a Constrains Pancreatic Carcinogenesis. Sci Rep (2020) 10:9654. 10.1038/s41598-020-66561-1
113
Lee K-H Lotterman C Karikari C Omura N Feldmann G Habbe N et al Epigenetic Silencing of MicroRNA miR-107 Regulates Cyclin-dependent Kinase 6 Expression in Pancreatic Cancer. Pancreatology (2009) 9:293–301. 10.1159/000186051
114
Xiong J Wang D Wei A Lu H Tan C Li A et al Deregulated Expression of miR-107 Inhibits Metastasis of PDAC through Inhibition PI3K/Akt Signaling via Caveolin-1 and PTEN. Exp Cel Res (2017) 361:316–23. 10.1016/j.yexcr.2017.10.033
115
Huang W Gu J Tao T Zhang J Wang H Fan Y . MiR-24-3p Inhibits the Progression of Pancreatic Ductal Adenocarcinoma through LAMB3 Downregulation. Front Oncol (2020) 9:1499. 10.3389/fonc.2019.01499
116
Sun Y Wang P Zhang Q Wu H . CDK14/β‐catenin/TCF4/miR‐26b Positive Feedback Regulation Modulating Pancreatic Cancer Cell Phenotypes In Vitro and Tumor Growth in Mice Model In Vivo. J Gene Med (2021) 24:e3343. 10.1002/jgm.3343
117
Tréhoux S Lahdaoui F Delpu Y Renaud F Leteurtre E Torrisani J et al Micro-RNAs miR-29a and miR-330-5p Function as Tumor Suppressors by Targeting the MUC1 Mucin in Pancreatic Cancer Cells. Biochim Biophys Acta Mol Cel Res (2015) 1853:2392–403. 10.1016/j.bbamcr.2015.05.033
118
Dey S Kwon JJ Liu S Hodge GA Taleb S Zimmers TA et al miR-29a is Repressed by MYC in Pancreatic Cancer and its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2. Mol Cancer Res (2020) 18:311–23. 10.1158/1541-7786.MCR-19-0594
119
Sun X-J Liu B-Y Yan S Jiang T-H Cheng H-Q Jiang H-S et al MicroRNA-29a Promotes Pancreatic Cancer Growth by Inhibiting Tristetraprolin. Cell Physiol Biochem (2015) 37:707–18. 10.1159/000430389
120
Wang T Chen G Ma X Yang Y Chen Y Peng Y et al MiR-30a Regulates Cancer Cell Response to Chemotherapy through SNAI1/IRS1/AKT Pathway. Cel Death Dis (2019) 10:1–15. 10.1038/s41419-019-1326-6
121
Xu Y-F Hannafon BN Ding W-Q . microRNA Regulation of Human Pancreatic Cancer Stem Cells. Stem Cel Investig. (2017) 4:5. 10.21037/sci.2017.01.01
122
Lu Y Lu J Li X Zhu H Fan X Zhu S et al MiR-200a Inhibits Epithelial-Mesenchymal Transition of Pancreatic Cancer Stem Cell. BMC Cancer (2014) 14:85. 10.1186/1471-2407-14-85
123
Zhao G Wang B Liu Y Zhang J-g. Deng S-c. Qin Q et al miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4. Mol Cancer Ther (2013) 12:2569–80. 10.1158/1535-7163.MCT-13-0296
124
Hamada S Satoh K Fujibuchi W Hirota M Kanno A Unno J et al MiR-126 Acts as a Tumor Suppressor in Pancreatic Cancer Cells via the Regulation of ADAM9. Mol Cancer Res (2012) 10:3–10. 10.1158/1541-7786.MCR-11-0272
125
Xu WX Liu Z Deng F Wang DD Li XW Tian T et al MiR-145: a Potential Biomarker of Cancer Migration and Invasion. Am J Transl Res (2019) 11:6739–53.
126
Khan S Ebeling MC Zaman MS Sikander M Yallapu MM Chauhan N et al MicroRNA-145 Targets MUC13 and Suppresses Growth and Invasion of Pancreatic Cancer. Oncotarget (2014) 5:7599–609. 10.18632/oncotarget.2281
127
Han T Yi X-P Liu B Ke M-J Li Y-X . MicroRNA-145 Suppresses Cell Proliferation, Invasion and Migration in Pancreatic Cancer Cells by Targeting NEDD9. Mol Med Rep (2015) 11:4115–20. 10.3892/mmr.2015.3294
128
Deng S Zhu S Wang B Li X Liu Y Qin Q et al Chronic Pancreatitis and Pancreatic Cancer Demonstrate Active Epithelial-Mesenchymal Transition Profile, Regulated by miR-217-SIRT1 Pathway. Cancer Lett (2014) 355:184–91. 10.1016/j.canlet.2014.08.007
129
Yang Y Tao X Li C-B Wang C-M . MicroRNA-494 Acts as a Tumor Suppressor in Pancreatic Cancer, Inhibiting Epithelial-Mesenchymal Transition, Migration and Invasion by Binding to SDC1. Int J Oncol (2018) 53:1204–14. 10.3892/ijo.2018.4445
130
Chen G Shi Y Zhang Y Sun J . CircRNA_100782 Regulates Pancreatic Carcinoma Proliferation through the IL6-STAT3 Pathway. OncoTargets Ther (2017) 10:5783–94. 10.2147/OTT.S150678
131
Wu D-H Liang H Lu S-N Wang H Su Z-L Zhang L et al miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism. Cel Physiol Biochem (2018) 50:924–35. 10.1159/000494477
132
Gao L Yang Y Xu H Liu R Li D Hong H et al MiR-335 Functions as a Tumor Suppressor in Pancreatic Cancer by Targeting OCT4. Tumor Biol (2014) 35:8309–18. 10.1007/s13277-014-2092-9
133
Neault M Mallette FA Richard S . miR-137 Modulates a Tumor Suppressor Network-Inducing Senescence in Pancreatic Cancer Cells. Cel Rep (2016) 14:1966–78. 10.1016/j.celrep.2016.01.068
134
Li Y VandenBoom TG Wang Z Kong D Ali S Philip PA et al miR-146a Suppresses Invasion of Pancreatic Cancer Cells. Cancer Res (2010) 70:1486–95. 10.1158/0008-5472.CAN-09-2792
135
Delpu Y Lulka H Sicard F Saint-Laurent N Lopez F Hanoun N et al The rescue of miR-148a Expression in Pancreatic Cancer: an Inappropriate Therapeutic Tool. PLoS One (2013) 8:e55513. 10.1371/journal.pone.0055513
136
Zhao W-G Yu S-N Lu Z-H Ma Y-H Gu Y-M Chen J . The miR-217 microRNA Functions as a Potential Tumor Suppressor in Pancreatic Ductal Adenocarcinoma by Targeting KRAS. Carcinogenesis (2010) 31:1726–33. 10.1093/carcin/bgq160
137
Wang B Du R Xiao X Deng Z-L Jian D Xie H-F et al Microrna-217 Modulates Human Skin Fibroblast Senescence by Directly Targeting DNA Methyltransferase 1. Oncotarget (2017) 8:33475–86. 10.18632/oncotarget.16509
138
Tesfaye AA Azmi AS Philip PA . miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma. Am J Pathol (2019) 189:58–70. 10.1016/j.ajpath.2018.10.005
139
Friedman RC Farh KK-H Burge CB Bartel DP . Most Mammalian mRNAs Are Conserved Targets of microRNAs. Genome Res (2009) 19:92–105. 10.1101/gr.082701.108
140
Zhang Y Li M Wang H Fisher WE Lin PH Yao Q et al Profiling of 95 MicroRNAs in Pancreatic Cancer Cell Lines and Surgical Specimens by Real-Time PCR Analysis. World J Surg (2009) 33:698–709. 10.1007/s00268-008-9833-0
141
Hong TH Park IY . MicroRNA Expression Profiling of Diagnostic Needle Aspirates from Surgical Pancreatic Cancer Specimens. Ann Surg Treat Res (2014) 87:290. 10.4174/astr.2014.87.6.290
142
Lee LS Szafranska-Schwarzbach AE Wylie D Doyle LA Bellizzi AM Kadiyala V et al Investigating MicroRNA Expression Profiles in Pancreatic Cystic Neoplasms. Clin Transl Gastroenterol (2014) 5:e47. 10.1038/ctg.2013.18
143
Szafranska-Schwarzbach AE Adai AT Lee LS Conwell DL Andruss BF . Development of a miRNA-Based Diagnostic Assay for Pancreatic Ductal Adenocarcinoma. Expert Rev Mol Diagn (2011) 11:249–57. 10.1586/erm.11.10
144
Vila-Navarro E Duran-Sanchon S Vila-Casadesús M Moreira L Ginès À Cuatrecasas M et al Novel Circulating miRNA Signatures for Early Detection of Pancreatic Neoplasia. Clin Transl Gastroenterol (2019) 10:e00029. 10.14309/ctg.0000000000000029
145
Wei L Yao K Gan S Suo Z . Clinical Utilization of Serum- or Plasma-Based miRNAs as Early Detection Biomarkers for Pancreatic Cancer. Medicine (Baltimore) (2018) 97:e12132. 10.1097/MD.0000000000012132
146
Peng C Wang J Gao W Huang L Liu Y Li X et al Meta-analysis of the Diagnostic Performance of Circulating MicroRNAs for Pancreatic Cancer. Int J Med Sci (2021) 18:660–71. 10.7150/ijms.52706
147
Alemar B Izetti P Gregório C Macedo GS Castro MAA Osvaldt AB et al miRNA-21 and miRNA-34a Are Potential Minimally Invasive Biomarkers for the Diagnosis of Pancreatic Ductal Adenocarcinoma. Pancreas (2016) 45:84–92. 10.1097/MPA.0000000000000383
148
Sun B Liu X Gao Y Li L Dong Z . Downregulation of miR-124 Predicts Poor Prognosis in Pancreatic Ductal Adenocarcinoma Patients. Br J Biomed Sci (2016) 73:152–7. 10.1080/09674845.2016.1220706
149
Wald P Liu XS Pettit C Dillhoff M Manilchuk A Schmidt C et al Prognostic Value of microRNA Expression Levels in Pancreatic Adenocarcinoma: a Review of the Literature. Oncotarget (2017) 8:73345–61. 10.18632/oncotarget.20277
150
Frampton AE Krell J Jamieson NB Gall TMH Giovannetti E Funel N et al microRNAs with Prognostic Significance in Pancreatic Ductal Adenocarcinoma: A Meta-Analysis. Eur J Cancer (2015) 51:1389–404. 10.1016/j.ejca.2015.04.006
151
Papaconstantinou IG Manta A Gazouli M Lyberopoulou A Lykoudis PM Polymeneas G et al Expression of microRNAs in Patients with Pancreatic Cancer and its Prognostic Significance. Pancreas (2013) 42:67–71. 10.1097/MPA.0b013e3182592ba7
152
Mikamori M Yamada D Eguchi H Hasegawa S Kishimoto T Tomimaru Y et al MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma. Sci Rep (2017) 7:42339. 10.1038/srep42339
153
Yu Q Xu C Yuan W Wang C Zhao P Chen L et al Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively. Biomed Res Int (2017) 2017:1–10. 10.1155/2017/6495867
154
Greither T Grochola LF Udelnow A Lautenschläger C Würl P Taubert H . Elevated Expression of microRNAs 155, 203, 210 and 222 in Pancreatic Tumors is Associated with Poorer Survival. Int J Cancer (2010) 126:73–80. 10.1002/ijc.24687
155
Bader AG Brown D Stoudemire J Lammers P . Developing Therapeutic microRNAs for Cancer. Gene Ther (2011) 18:1121–6. 10.1038/gt.2011.79
156
Krützfeldt J Rajewsky N Braich R Rajeev KG Tuschl T Manoharan M et al Silencing of microRNAs In Vivo with 'antagomirs'. Nature (2005) 438:685–9. 10.1038/nature04303
157
Cheng CJ Bahal R Babar IA Pincus Z Barrera F Liu C et al MicroRNA Silencing for Cancer Therapy Targeted to the Tumour Microenvironment. Nature (2015) 518:107–10. 10.1038/nature13905
158
Ebert MS Sharp PA . MicroRNA Sponges: Progress and Possibilities. RNA (2010) 16:2043–50. 10.1261/rna.2414110
159
Tay FC Lim JK Zhu H Hin LC Wang S . Using Artificial microRNA Sponges to Achieve microRNA Loss-Of-Function in Cancer Cells. Adv Drug Deliv Rev (2015) 81:117–27. 10.1016/j.addr.2014.05.010
160
Ben-Shushan D Markovsky E Gibori H Tiram G Scomparin A Satchi-Fainaro R . Overcoming Obstacles in microRNA Delivery towards Improved Cancer Therapy. Drug Deliv Transl Res (2014) 4:38–49. 10.1007/s13346-013-0160-0
161
Pramanik D Campbell NR Karikari C Chivukula R Kent OA Mendell JT et al Restitution of Tumor Suppressor microRNAs Using a Systemic Nanovector Inhibits Pancreatic Cancer Growth in Mice. Mol Cancer Ther (2011) 10:1470–80. 10.1158/1535-7163.MCT-11-0152
162
Trang P Wiggins JF Daige CL Cho C Omotola M Brown D et al Systemic Delivery of Tumor Suppressor microRNA Mimics Using a Neutral Lipid Emulsion Inhibits Lung Tumors in Mice. Mol Ther (2011) 19:1116–22. 10.1038/mt.2011.48
163
Kota J Chivukula RR O'Donnell KA Wentzel EA Montgomery CL Hwang H-W et al Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model. Cell (2009) 137:1005–17. 10.1016/j.cell.2009.04.021
164
Li L Xie X Luo J Liu M Xi S Guo J et al Targeted Expression of miR-34a Using the T-VISA System Suppresses Breast Cancer Cell Growth and Invasion. Mol Ther (2012) 20:2326–34. 10.1038/mt.2012.201
165
Pai P Rachagani S Are C Batra S . Prospects of miRNA-Based Therapy for Pancreatic Cancer. Cdt (2013) 14:1101–9. 10.2174/13894501113149990181
166
Lindow M Kauppinen S . Discovering the First microRNA-Targeted Drug. J Cel Biol (2012) 199:407–12. 10.1083/jcb.201208082
167
Gurbuz N Ozpolat B . MicroRNA-based Targeted Therapeutics in Pancreatic Cancer. Anticancer Res (2019) 39:529–32. 10.21873/anticanres.13144
168
Passadouro M Faneca H . Managing Pancreatic Adenocarcinoma: A Special Focus in MicroRNA Gene Therapy. Int J Mol Sci (2016) 17:718. 10.3390/ijms17050718
169
Hu QL Jiang QY Jin X Shen J Wang K Li YB et al Cationic microRNA-Delivering Nanovectors with Bifunctional Peptides for Efficient Treatment of PANC-1 Xenograft Model. Biomaterials (2013) 34:2265–76. 10.1016/j.biomaterials.2012.12.016
170
Idichi T Seki N Kurahara H Fukuhisa H Toda H Shimonosono M et al Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of Passenger Strand of Pre-miR-148aon Gene Regulation. Cancer Sci (2018) 109:2013–26. 10.1111/cas.13610
Summary
Keywords
oncogene, pancreatic ductal adenocarcinoma, cellular senescence, senescence-associated miRNA, senescence bypass, tumor suppressor
Citation
Popov A and Mandys V (2022) Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol. Oncol. Res. 28:1610156. doi: 10.3389/pore.2022.1610156
Received
26 October 2021
Accepted
12 April 2022
Published
29 April 2022
Volume
28 - 2022
Edited by
Andrea Ladányi, National Institute of Oncology (NIO), Hungary
Updates
Copyright
© 2022 Popov and Mandys.
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*Correspondence: Alexey Popov, alexey.popov@lf3.cuni.cz
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