CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling

Abstract

<b>Rationale:</b> Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. <b>Methods:</b> The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated <i>in vitro</i> and <i>in vivo</i>. A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. <b>Results:</b> CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities <i>in vitro</i>, and suppressed tumorigenicity <i>in vivo</i>, whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. <b>Conclusions:</b> In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients.