Abstract 533: S100A10 as a novel biomarker in hepatocellular carcinoma

Abstract

Abstract Background and Objective: Hepatocellular carcinoma (HCC) is the dominant form of primary liver tumor and the second most lethal malignancy in worldwide. From transcriptome sequencing analysis, we observed that S100A10 was overexpressed in our cohort of 16 HCC patients. S100A10 is a calcium binding protein and accumulating studies have indicated that annexin A2- S100A10 heterotetramer on the cell surface is important for the conversion of plasminogen to plasmin, which promotes activation of matrix metalloproteinases and degradation of extracellular matrix. This enhances cancer invasion and migration. While annexin A2 overexpression has been documented in various malignancies and shows significant association with local invasion and metastasis, information regarding the expression of S100A10 in human cancers is scarce. Furthermore, how S100A10 was regulated remains unexplored. Hypoxia is a common phenomenon in HCC microenvironment and stabilizies transcription factors, hypoxia inducible factor (HIF)-1α and -2α, to initiate transcription of a wide repertoire of genes for cancer progression. The major aim of this study is to evaluate the possible clinical relevance and diagnostic value of S100A10 in HCC and study the molecular mechanism that drives S100A10 overexpression under the influence of hypoxia in HCC. Experimental Procedures: We evaluated S100A10 expression in human HCC and the corresponding non-tumorous liver (NT) tissues in a cohort of 67 HCC patients by RT-PCR. S100A10 expression was correlated with various HCC clinico-pathological features by Student's t-test and survival outcome of HCC patients by Kaplan-Meier plot followed by log rank test. Promoter of S100A10 was analyzed for potential hypoxia responsive elements -A/GCGTG- and confirmed by ChIP assay with HIF antibodies. To evaluate the impact of HIF on S100A10 expression, we knocked-down (shRNA) and knocked-out (TALEN) HIF-1/2α in a HCC cell line, MHCC97L and evaluated S100A10 mRNA and protein expression. Results: S100A10 was significantly upregulated (P = 0.001, Wilcoxon signed rank test) in HCC as compared to NT tissues. Overexpression of S100A10 (≥ 2 fold) was found in 50.746% (34/67) of HCC patients and was closely correlated with direct liver invasion (P = 0.038), tumor microsatellite formation (P = 0.050) and absence of tumor encapsulation (P = 0.048). More importantly, S100A10 overexpression was associated with poorer 5-year survival rate in HCC patients (P = 0.062). ROC analysis suggested that S100A10 could be a potential diagnostic marker for HCC detection (Area Under Curve = 0.685, P = 0.001). Hypoxia induced S100A10 mRNA and protein expression levels in multiple HCC cell lines and this was abolished in HIF-1/2α knockdown or knockout HCC cells. Conclusion: Our current data have presented evidence that S100A10 can be a potential diagnostic and prognostic marker in HCC and S100A10 is a transcriptional target of HIF. Citation Format: David Kung-Chun Chiu, Carmen Chak-Lui Wong, Irene Oi-Lin Ng, Aki Pui-Wah Tse. S100A10 as a novel biomarker in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 533. doi:10.1158/1538-7445.AM2015-533