Studies On The Roles And Mechanisms Of MUC15in Hepatocarcinogenesis

PartⅠ:Studies on the roles and mechanisms ofMUC15in HepatocarcinogenesisBackground&Aims: Mucins have been implicated in human carcinogenesis. Theaberrant expression of MUC15has been correlated with colorectal adenocarcinomasand may play a critical role in the negative regulation of trophoblast invasion inhuman placentas. However, the potential role of MUC15in HCC remains unknown.The authors therefore determined the expression profile, functions and underlyingmechanisms of MUC15in the pathogenesis of hepatocellular carcinoma.Methods: MUC15expression levels were evaluated by immunohistochemistry,real-time RT-PCR and Western blotting assays. Clinical impact of MUC15wasassessed in a cohort of313HCC patients. Functional effect of MUC15was examinedby in vitro and in vivo assays.Results: We demonstrated that expression of MUC15frequently decreases in HCC,which is significantly associated with tumor aggressive characteristics and poorprognosis. Functional studies showed that exogenous expression of MUC15ameliorates metastasis and local growth of HCC cells in vitro and in vivo, viadecreasing the transcription of MMP2, MMP7but upregulating TIMP2expressionwith a PI3K/Akt-depended manner. Importantly, the physical interaction of MUC15and EGFR resulting in EGFR relocation within early endosome is indispensible forMUC15-mediated PI3K/AKT signaling inactivation. Consistently, a significantinverse correlation between MUC15expression and p-Akt levels in clinical samplesindicated that combination of these two parameters shows incremental prognosticvalue.Conclusions: MUC15is an independent prognostic biomarker and novel dimerizationpartner of EGFR, which involves in the negative regulation ofEGFR/PI3K/AKT-induced cell migration and invasion during the metastasis andprogression of HCC. PartⅡ:CHKA Enhances Hepatocellular Carcinoma Progression andMetastasis via Phosphoinositol3-Kinase/AKT PathwayBackground&Aims: Choline kinase α (CHKA), the enzyme that converts choline tophosphocholine, has been implicated in human carcinogenesis. However, its potentialrole in HCC progression remains largely unexplored.Methods: Overexpression and gene silencing experiments were performed to evaluatethe potential oncogenic role of CHKAin HCC.Results: Here, we demonstrated that gene copy number of CHKA was elevated inhuman HCC genome and CHKAprotein was frequently overexpressed in HCC tissuesand cancer cell lines. Functional studies showed that ectopic expression of CHKAenhanced cell migration and invasion, whereas silencing CHKA expressioneffectively inhibited the migratory and invasive abilities of tumor cells. Further studyrevealed that Phosphoinositol3-Kinase (PI3K)/AKT pathway was mainly responsiblefor the oncogenic role of CHKA. Moreover, investigation of clinical HCC specimensshowed that increased expression of CHKA was closely correlated with advancedtumor stage and poor overall and disease-free survivals.Conclusions: Our results suggest that CHKA promotes HCC progression andmetastasis mainly through PI3K/Akt pathway, which may provide new insights intothe pathogenesis of HCC. These findings indicate that CHKA might be a new targetfor treatment of liver cancer.