Sp1‐regulated transcription of Ras GRP 1 promotes hepatocellular carcinoma ( HCC ) proliferation

Background and Aims The role of Ras guanine nucleotide‐releasing protein 1 (Ras GRP 1) 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 Ras GRP 1 in HCC and determined how it contributes to HCC cell proliferation. Methods Ras GRP 1 expression was measured by quantitative polymerase chain reaction ( qPCR ) and Western blotting of 24 paired HCC tissues and para‐tumour tissues. Ras GRP 1 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 Ras GRP 1 was examined by small interfering RNA s and an exogenous plasmid construct. Chromatin immunoprecipitation assays were performed to examine the binding of Sp1 to the Ras GRP 1 promoter. Results Increased Ras GRP 1 expression was associated with tumour size ( P  =   .004), tumour‐node‐metastasis stage ( P  =   .032), and Barcelona Clinic Liver Cancer stage ( P  =   .002). Ras GRP 1 overexpression was an independent prognostic factor in HCC patients. Ras GRP 1 downregulation inhibited cell proliferation, whereas Ras GRP 1 overexpression promoted cell proliferation. Moreover, specificity protein 1 bound to the Ras GRP 1 promoter and promoted Ras GRP 1 transcription. In addition, Ras GRP 1 overexpression enhanced activation of the c‐Raf pathway. Conclusions Ras GRP 1 is upregulated in HCC and promotes HCC cell proliferation. Thus, Ras GRP 1 may be a novel therapeutic target for HCC .