Osteosarcoma (OS), as an aggressive tumor in skeletal system, is the most prevalent malignant primary bone tumor in children, young adults and the elders [1]. Generally, the OS mainly occurs in the metaphysis regions of long bones [2]. Over the past decades, the survival rates of non-metastatic OS patients have significantly increased to 65–75% [3], but the overall 5-years survival rate of patients with metastases and relapsed OS are approximately 30 and 15%, respectively [4, 5], implying an undesirable prognosis. Many OS patients have detectable metastases at presentation, and the most common sites of OS metastases include lung (85%) and bone [6, 7]. Moreover, the great heterogeneity in OS patients limits the improvement of diagnosis and prognosis, which makes it difficult to identify reliable biomarkers and the cell type causing OS [8]. Although the pathogenesis of OS is quite complicated, especially from a molecular aspect, some previous studies give us important inspiration [7]. Aberrant expressions of several genes show vital effects on OS, such as TP53 [9], Rb [10], c-myc [11], etc. Accordingly, further investigation in OS is urgently needed to better understand the molecular mechanisms of OS tumorigenesis and provide more alternatives for clinical therapeutic strategies, in order to improve the prognosis of OS patients.

Selectin P ligand gene (SELPLG), also known as CD162 and PSGL-1, encodes P-selectin glycoprotein ligand 1 (PSGL-1) [12], which is involved in immune cell trafficking and the regulation of myeloid cell immune responses [13]. As a member of the selectin family, SELPLG mostly expresses in some immune or inflammatory cells [14]. SELPLG deficiency has been documented to influence the myeloid cell differentiation and lymphocyte maturation, thus it is important in cell differentiation [15]. Additionally, SELPLG has been investigated in many human diseases. For instance, SELPLG is identified as a novel acute respiratory distress syndrome (ARDS) susceptibility gene and a promising therapeutic target in ARDS [12]. Recently, SELPLG has been demonstrated to act as an immune checkpoint regulator, which might be novel therapeutic target in cancer [13]. It has been reported to mediate the development and chemotherapy resistance of acute myeloid leukemia (AML), and blocking the binding of SELPLG to E-selectin is probably a new target [16]. Moreover, SELPLG has been studied in several kinds of cancers as potential diagnostic or prognostic biomarkers, such as colorectal cancer (CRC) [17], head and neck squamous cell carcinoma (HNSCC) [18], anaplastic large T-cell lymphoma (ALCL) [19], uveal melanoma [20], and so on. In The Human Protein Atlas database (https://www.proteinatlas.org/), SELPLG is a favorable factor in most recorded tumors (such as cervical cancer, thyroid cancer, and so on). Whereas, to the best of our knowledge, few reports have focused on SELPLG in OS. Consequently, we hope that our research would provide more insights in the potential role of SELPLG in OS patients.

Herein, the purpose of our study was to explore the potential role of SELPLG in the metastasis and prognosis of OS patients utilizing the effective bioinformatic tools, based on the publicly available data in TARGET and GEO databases. The final results might be meaningful to improve the prognosis of OS patients in future clinical cases.

Recently, the crucial role of SELPLG in tumor metastasis has been demonstrated [25]. In this work, we have explored the association between SELPLG and the metastasis, prognosis of OS patients using the powerful bioinformatic tools, basing on the data in TARGET and GEO databases. We found that low SELPLG expression was closely associated with the metastases of OS patients, and OS patients with low SELPLG expression had relatively worse prognosis.

Compared with non-metastatic OS patients, metastatic OS patients usually have relatively poorer outcome in most clinical cases [4, 5]. Firstly, we found that significantly lower SELPLG expression was observed in metastatic OS samples compared with non-metastatic OS samples, both in TARGET and in GSE21257 dataset, indicating low SELPLG expression might be related to the metastases of OS. In colorectal cancer (CRC), it has been evidenced that SELPLG deficiency could render intestinal tissue more vulnerable to grow colorectal tumors [14]. Moreover, SELPLG was indicated to be downregulated in primary human AML M2 t(8;21)+ leukemia cells, besides RUNX1/ETO-mediated SELPLG suppression would probably reduce the cell adhesion of t(8;21)+ acute myeloid leukemia cells [26]. Cell adhesion might have impact on the move of leukemia cells [27], while more direct details among SELPLG, cell adhesion, and metastasis remained to be unclear. Whereas, SELPLG showed strong expression in primary effusion lymphoma (PEL), and it was vital for cell migration and chemotaxis [28], the expression of which was converse in OS in our research. The above evidence suggests that the role of SELPLG in different tumors might be different, more details of which are still unclear. Moreover, based on the results of survival analyses and multivariate Cox regression analyses, low SELPLG expression was an independent undesirable prognostic factor for OS patients, in both TARGET database and GEO datasets. It has been documented that the copy number of SELPLG was reported as a biomarker to differentiate subtypes of AML [29]. SELPLG was also identified in HNSCC and ALCL as predictor or potential therapeutic target [18, 19]. We have firstly reported SELPLG as a prognostic biomarker for OS, which might serve as a reference factor for OS prognosis prediction in the future.

Additionally, there were 1730 DEGs between high and low SELPLG expression OS patients, and 209 DEGs between non-metastatic and metastatic OS samples. To further identify the DEGs affecting metastases and then influencing the prognosis, 62 DEG overlaps were found. The subsequent functional analyses showed they were significantly enriched in 40 GO terms and six KEGG pathways. Neuroactive ligand-receptor interaction pathway has been suggested to be implicated in tumorigenesis of OS, which might be affected by abnormal DNA methylation [30, 31]. The mesenchymal stem cells (MSCs) might provide an advantageous source of microenvironments for OS cells partly through Cytokine-cytokine receptor interaction pathway [32]. However, some metabolism and biosynthesis related pathways, such as Ether lipid metabolism pathway, Glycerophospholipid metabolism pathway, Primary bile acid biosynthesis pathway, and Pantothenate and CoA biosynthesis pathway, have not been concretely studied in OS, which should be further studied.

Furthermore, given to the important role of selectins in tumor metastatic spread [33, 34], the immune cell infiltration was also analyzed between high and low SELPLG expression OS patients. Five kinds of immune cells, including Monocytes, M0, M1, M2 Macrophages, and CD8 T cells, were significantly differentially infiltrated between high and low SELPLG expression OS patients. The endogenous PSGL-1 encoded by SELPLG would facilitate the recruitment of monocytes to metastasize tumor cells, then contributing to metastasis would result in decreased survival [35], which supported our findings indirectly. However, the causal connection between the monocyte recruitment and SELPLG expression remains unclear in OS samples, which needs to be clarified via deepening exploration. Various macrophages M0, M1 (inflammatory macrophages), and M2 (alternative macrophages) have been evidenced to have fundamental role in the pathogenesis of OS [36]. Tumor-infiltrating macrophages are documented to orchestrate many aspects of OS and increased infiltration of M2 is correlated with the metastasis of OS and poor prognosis [37]. The above evidences imply that these immune cells’ infiltration does directly or indirectly affect the metastasis and undesirable prognosis of OS, which deserves further exploration in our future researches.

To summarize, we have firstly investigated the possible role of SELPLG in OS patients. Our findings indicate that SELPLG is closely correlated with the metastases and prognosis of OS patients. The OS patients with low SELPLG expression have relatively poorer prognosis and SELPLG is a potential prognostic biomarker for OS.