IDDF2019-ABS-0160 Cathepsin C promotes tumor growth and metastasis through activating TNF-α/MAPK (p38) pathway in hepatocellular carcinoma. (7th June 2019) - Zhang, Guo-Pei
Abstract : Background: Although cathepsin C (CTSC), a multifunctional molecule, has been reported to maintain various malignant biological properties in several types of cancers, the potential function of CTSC in HCC remains obscure. We aimed to investigate the potential role of cathepsin C (CTSC) in the tumorigenesis of HCC. Methods: One hundred and twenty-two HCC specimens upon tissue microarrays were employed to analyze the correlation between CTSC expression and clinicopathological characteristics through immunohistochemistry staining. qRT-PCR, western blot assay, CCK-8 assay, colony formation, cell migration and invasion assays, xenograft mice model were adopted to validate what had been indicated by the bioinformatic web tools. Results: In our study, by the bioinformatic tools and tissue microarrays, CTSC was found upregulated in HCC compared with normal liver tissues, and its higher expression was correlated with poor prognosis of HCC patients. By gain-of-function and loss-of-function studies, we implicated that CTSC functioned as an oncogene to promote the proliferation, migration and invasion of HCC cells. Mechanistically, we revealed that CTSC was involved in several cancer-related signaling pathways by Gene Set Enrichment Analysis (GSEA), among which TNF-α/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-α could activate CTSC expression in a concentration-dependent manner. Ralimetinib, an oral MAPK (p38) inhibitor could inhibit CTSC expression. These indicated a potential positive feedback loop between CTSC and TNF-α/MAPK (p38) signaling. Conclusions: Taken together, CTSC plays an important role in the growth and metastasis of HCC and may be a promising therapeutic target upon HCC.