Abstract:Syndecan 2 (SDC2) belongs to a four-member family of evolutionary conserved small type I transmembrane proteoglycans consisting of a protein core to which glycosaminoglycan chains are covalently attached. SDC2 is a cell surface heparan sulfate proteoglycan, which is increasingly drawing attention for its distinct characteristics and its participation in numerous cell functions, including those related to carcinogenesis. Increasing evidence suggests that the role of SDC2 in cancer pathogenesis is dependent on c… Show more
“…Syndecan-2 protein, encoded by the SDC2 gene, is a type I transmembrane proteoglycan. The role of SDC2 depends on the type of tumor: it acts as an oncogene and contributes to disease progression in colon cancer, breast cancer and melanoma, while it serves as a metastasis suppressor in Lewis lung carcinoma [39][40][41]. Moreover, SDC2 has been found to be positively associated with the differentiation level and prognosis of neuroendocrine tumors, which is consistent with our ndings [42].…”
Background: Patients with well-differentiated thyroid carcinoma can achieve long-term survival after reasonable treatments, but there is no standard treatment mode for poorly or undifferentiated thyroid carcinoma and its prognosis is very poor. Immune cells, especially tumor-associated macrophages, account for a large proportion of the tumor microenvironment of anaplastic thyroid carcinomas (ATCs). However, whether immune-related genes can mediate the dedifferentiation of thyroid cells is unclear.Methods: We initially compared the differences of thyroid differentiation score, infitration of immune cells and enriched pathways between ATCs and papillary thyroid carcionma (PTCs) or normal thyroid tissues in Gene Expression Omnibus database. Then, The Cancer Genome Atlas database was used to screen out the prognosis associated IRGs. A risk score was constructed and we next investigated its predictive value for differentiation by applying receiver operating characteristic (ROC) curves and correlation analyses. Kaplan-Meier curves were used to evaluated its prognostic value. We further explored the associations of the risk score with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy.Results: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower thyroid differentiation scores, higher infiltration of most immune cells and higher activation of inflammatory response. The risk score composed of MMP9 and SDC2 was significantly increased in ATCs and low differentiated PTCs. Moreover, it showed favorable predictive value for differentiation and survival. Higher risk score displayed dedifferentiation status and a worse prognosis. Additionly, the risk score was positively correlated with immune checkpoint molecules PDL1, CTLA4, IDO1, HAVCR2 and infiltration of multiple immune cells. Importantly, we found that samples with higher risk score tend to have a better response to immune checkpoint agents than lower ones.Conclusion: Our findings indicate that the risk score may not only contribute to the judgement of differentiation and prognosis of thyroid cancer, but also help to the prediction of immune cell infiltration and immune checkpoint inhibitor response.
“…Syndecan-2 protein, encoded by the SDC2 gene, is a type I transmembrane proteoglycan. The role of SDC2 depends on the type of tumor: it acts as an oncogene and contributes to disease progression in colon cancer, breast cancer and melanoma, while it serves as a metastasis suppressor in Lewis lung carcinoma [39][40][41]. Moreover, SDC2 has been found to be positively associated with the differentiation level and prognosis of neuroendocrine tumors, which is consistent with our ndings [42].…”
Background: Patients with well-differentiated thyroid carcinoma can achieve long-term survival after reasonable treatments, but there is no standard treatment mode for poorly or undifferentiated thyroid carcinoma and its prognosis is very poor. Immune cells, especially tumor-associated macrophages, account for a large proportion of the tumor microenvironment of anaplastic thyroid carcinomas (ATCs). However, whether immune-related genes can mediate the dedifferentiation of thyroid cells is unclear.Methods: We initially compared the differences of thyroid differentiation score, infitration of immune cells and enriched pathways between ATCs and papillary thyroid carcionma (PTCs) or normal thyroid tissues in Gene Expression Omnibus database. Then, The Cancer Genome Atlas database was used to screen out the prognosis associated IRGs. A risk score was constructed and we next investigated its predictive value for differentiation by applying receiver operating characteristic (ROC) curves and correlation analyses. Kaplan-Meier curves were used to evaluated its prognostic value. We further explored the associations of the risk score with important immune checkpoint molecules, infiltrating immune cells and response to immunotherapy.Results: Compared with PTCs or normal thyroid tissues, ATCs exhibited lower thyroid differentiation scores, higher infiltration of most immune cells and higher activation of inflammatory response. The risk score composed of MMP9 and SDC2 was significantly increased in ATCs and low differentiated PTCs. Moreover, it showed favorable predictive value for differentiation and survival. Higher risk score displayed dedifferentiation status and a worse prognosis. Additionly, the risk score was positively correlated with immune checkpoint molecules PDL1, CTLA4, IDO1, HAVCR2 and infiltration of multiple immune cells. Importantly, we found that samples with higher risk score tend to have a better response to immune checkpoint agents than lower ones.Conclusion: Our findings indicate that the risk score may not only contribute to the judgement of differentiation and prognosis of thyroid cancer, but also help to the prediction of immune cell infiltration and immune checkpoint inhibitor response.
“…HSPGs have also been shown to influence cancer exosome shedding and uptake, thereby modulating cell-to-cell communication between cancer and healthy fibroblasts, immune cells, and endothelial cells (150, 151). HSPGs can also influence actin cytoskeleton remodeling and cancer cell motility (95). The HSPG, SDC2 binds Ezrin, a cytoskeletal protein (152) and serves as adapter molecules for IGF1 mediated activation of ERK (95).…”
Section: Resultsmentioning
confidence: 99%
“…HSPGs can also influence actin cytoskeleton remodeling and cancer cell motility (95). The HSPG, SDC2 binds Ezrin, a cytoskeletal protein (152) and serves as adapter molecules for IGF1 mediated activation of ERK (95). Additionally, HSPGs are implicated in lipoprotein uptake and cellular stress signaling (153, 154).…”
Section: Resultsmentioning
confidence: 99%
“…Similarly, RKIP and HMGB2-dependent breast cancer survival and metastasis was shown to be regulated in SDC2 dependent manner (67). However, it is important to note that in addition to the pro-tumorigenic effects, some HSPGs, such as SDC2, exert tumor suppressive effects depending on the cancer type (95, 96). …”
Section: Cell-autonomous Role Of Hs and Hspgs In Cancer Initiation Anmentioning
Heparan sulfate (HS) are complex unbranched carbohydrate chains that are heavily modified by sulfate and exist either conjugated to proteins or as free, unconjugated chains. Proteins with covalently bound Heparan sulfate chains are termed Heparan Sulfate Proteoglycans (HSPGs). Both HS and HSPGs bind to various growth factors and act as co-receptors for different cell surface receptors. They also modulate the dynamics and kinetics of various ligand-receptor interactions, which in turn can influence the duration and potency of the signaling. HS and HSPGs have also been shown to exert a structural role as a component of the extracellular matrix, thereby altering processes such as cell adhesion, immune cell infiltration and angiogenesis. Previous studies have shown that HS are deregulated in a variety of solid tumors and hematological malignancies and regulate key aspects of cancer initiation and progression. HS deregulation in cancer can occur as a result of changes in the level of HSPGs or due to changes in the levels of HS biosynthesis and remodeling enzymes. Here, we describe the major cell-autonomous (proliferation, apoptosis/senescence and differentiation) and cell-non-autonomous (angiogenesis, immune evasion, and matrix remodeling) roles of HS and HSPGs in cancer. Finally, we discuss therapeutic opportunities for targeting deregulated HS biosynthesis and HSPGs as a strategy for cancer treatment.
“…Researchers have demonstrated that syndecan 2 is a conduit point for signals originating in extracellular matrix capable, through exquisitely regulated downstream mechanisms, to regulate cancer cell functions. Studies on syndecan 2 pinpoint this proteoglycan as a potential target for cancer treatment . …”
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