Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Dysregulation of S100A2 has recently been found in many cancers including HCC. However, its regulatory mechanism in HCC remains poorly understood, especially in hypoxia. In this study, we found that S100A2 is upregulated and correlated with the clinicopathological features of HCC patients. Moreover, the elevated S100A2 showed worse overall survival. Functionally, S100A2 inhibition decreased the proliferation and migration of HepG2 cells. Interestingly, we found that HIF‐1α directly binds to hypoxia response elements (HREs) of the S100A2 promoter region. S100A2 expression could be induced in an HIF‐1α‐dependent manner under hypoxia. Furthermore, S100A2 silencing significantly suppressed HCC cell proliferation and invasion under hypoxia. Mechanistically, pyrosequencing results showed that the hypomethylation status of CpG located in the HRE at the S100A2 promoter was correlated with S100A2 induction. Additionally, HIF‐1α‐ mediated S100A2 activation was associated with TET2‐related epigenetic inactivation. TET2 was enriched in the HRE of the S100A2 promoter in HepG2 cells. Finally, S100A2 methylation‐related genes and pathways were analyzed. We found that the methylation of S100A2 is correlated with ANXA2, PPP1R15A, and FOS, which include in a hypoxia‐related gene set from the GSEA database. Moreover, some EMT‐related genes are associated with the methylation of S100A2 in HCC. Conclusively, our study thus uncovered a novel mechanism showing that hypoxia/HIF‐1α signaling associated with DNA methylation enhances S100A2 expression in HCC. S100A2 may be useful as a target for facilitating novel diagnostic and therapeutic strategies in liver cancer.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors with high mortality worldwide. Spermatogenesis-associated serine-rich 2 (SPATS2) could be a novel diagnostic and prognostic biomarker in HCC. However, the regulatory mechanism of SPATS2 in HCC requires further elucidation. Therefore, the study’s objective was to investigate this process in HCC. In this study, we found that SPATS2 is significantly upregulated in HepG2 cells to promote cell growth and migration. SPATS2 is the target transcript of lncRNA SNHG5. SPATS2 positively affects the proliferation and migration of HepG2 cells caused by the higher expression of SNHG5. Mechanistically, we identified that the elevated of SPATS2 was attributed to SNHG5 related hypomethylation of SPATS2. SNHG5 reduced the expression of DNMT3a to suppress the methylation level of SPATS2. Taken together, our results uncover a novel epigenetic regulatory mechanism of lncRNA SNHG5-DNMT3a axis-related SPATS2 expression underlying HCC progression. This may serve as a novel prognostic marker and a promising therapeutic target for the treatment of HCC.
S100B has been found to be dysregulated in many cancers including hepatocellular carcinoma (HCC). However, the functions of S100B and its underlying mechanisms in HCC remain poorly understood, especially in the tumor microenvironment. In this study, functions enrichment analysis indicated that S100B expression was correlated with hypoxia and immune responses. We found that hypoxia could induce S100B expression in an HIF-1α-dependent manner in HepG2 cells. Luciferase reporter and ChIP-qRCR assays demonstrated that HIF-1α regulates S100B transcription by directly binding to hypoxia-response elements (HREs) of the S100B promoter. Functionally, knockdown of S100B reduces hypoxia-induced HepG2 cell invasion and migration. Furthermore, GSVA enrichment results displayed that S100B and its co-expressed genes were positively correlated with EMT pathway in HCC. Additionally, GO/KEGG cluster analysis results indicated that co-expressed genes of S100B were involved in biological processes of immune response and multiple tumor immune-related signaling pathways in HCC. S100B expression was positively correlated with multiple immune cells tumor infiltration and associated with chemokines/chemokine receptors and immune checkpoint genes. Moreover, S100B is predominantly expressed in immune cells, especially NK (Natural Killer) cell. In addition, the hub genes of S100B co-expression and hypoxia response in HepG2 cell were also associated with immune cells infiltration in HCC. Taken together, these findings provide a new insight into the complex networks between hypoxia response and immune cells infiltration in tumor microenvironment of liver cancer. S100B maybe serve as a novel target for future HCC therapies.
The spermatogenesis associated serine rich 2 (SPATS2) is a member of RNA-binding protein in which the abnormal expression is linked with carcinogenesis in serval types of cancer. However, there is no systematic study on the differential expression, prognostic significance, epigenetic regulation, immune infiltration of SPATS2 in hepatocellular carcinoma (HCC). In the present study, we investigated the expression, prognosis, epigenetic regulation, and immune cell infiltration of SPATS2 in HCC. We found that the elevated expression of SPATS2 was unfavorably associated with the clinical pathological stage and prognosis. Functional enrichment analysis revealed that SPATS2 is associated with cell cycle, apoptosis and cancer cell metastasis processes in HCC. Our results confirmed that knockdown of SPATS2 will affect cell cycle, apoptosis and invasion of HCC cell lines. Moreover, the expression of SPATS2 is upregulated by epigenetic regulation, including DNA methylation, m6A and histone modification in HCC. In addition, SPATS2 expression was positively correlated with immune cell infiltration or expression of immune related gene markers in HCC. Taken together, our data demonstrated that SPATS2 is associated with progression and immune infiltration, and could serve as a prognostic biomarker for HCC. In conclusion, these results highlight the potential of SPATS2 to be used as a therapeutic target for HCC.
HCC is one of the most common primary malignant liver tumours with high incidence and mortality. Although the targeted therapy and immunotherapy have achieved encouraging results, it still had a poor overall survival rate in patients with advanced HCC.Therefore, more reliable prognostic markers and novel regulatory mechanisms identification is crucial for to improve the survival rate of HCC. DDR pathway has become the target of antitumour drugs. 1 It has been reported that DDR is involved in prognosis, tumour initiation, metastasis and antitumor immune responses. 2,3 DDR status has been confirmed to serve as a potential biomarker to predict opposite clinical prognosis of immunotherapy. WHSC1 encodes a SET
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