Sp1-regulated transcription of RasGRP1 promotes hepatocellular carcinoma (HCC) proliferation.

BACKGROUND AND AIMS:The role of Ras guanine nucleotide-releasing protein 1 (RasGRP1) in tumourigenesis has been a subject of debate, and its functions and clinical significance in hepatocellular carcinoma (HCC) remain unknown. Here, we evaluated the expression of RasGRP1 in HCC and determined how it contributes to HCC cell proliferation. METHODS:RasGRP1 expression was measured by quantitative polymerase chain reaction (qPCR) and Western blotting of 24 paired HCC tissues and para-tumour tissues. RasGRP1 expression was confirmed by immunohistochemical analysis of a tissue microarray from 1 independent cohort. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and risk factors that contributed to OS or DFS were identified using Cox regression analysis. The biologic relevance of RasGRP1 was examined by small interfering RNAs and an exogenous plasmid construct. Chromatin immunoprecipitation assays were performed to examine the binding of Sp1 to the RasGRP1 promoter. RESULTS:Increased RasGRP1 expression was associated with tumour size (P = .004), tumour-node-metastasis stage (P = .032), and Barcelona Clinic Liver Cancer stage (P = .002). RasGRP1 overexpression was an independent prognostic factor in HCC patients. RasGRP1 downregulation inhibited cell proliferation, whereas RasGRP1 overexpression promoted cell proliferation. Moreover, specificity protein 1 bound to the RasGRP1 promoter and promoted RasGRP1 transcription. In addition, RasGRP1 overexpression enhanced activation of the c-Raf pathway. CONCLUSIONS:RasGRP1 is upregulated in HCC and promotes HCC cell proliferation. Thus, RasGRP1 may be a novel therapeutic target for HCC.

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