title: The RNA-binding protein Sam68 regulates tumor cell viability and hepatic carcinogenesis by inhibiting the transcriptional activity of FOXOs.
abstract: Src associated in mitosis (Sam68; 68 kDa) is a KH domain RNA-binding protein that belongs to the signal transduction and activation of RNA family, and has been implicated in the oncogenesis and progression of several human cancers. Our study aimed to investigated the clinicopathologic significance of Sam68 expression and its role in cell proliferation and the underlying molecular mechanism in hepatocellular carcinoma (HCC). We demonstrated that Sam68 expression was significantly increased in HCC and high expression of Sam68 was significantly associated with Edmondson grade, tumor size, tumor nodule number, HBsAg status and Ki-67 expression. The Kaplan-Meier survival curves showed that increased expression of Sam68 was correlated with poor prognosis in HCC patients and served as an independent prognostic marker of overall survival in a multivariable analysis. In addition, through serum starvation and refeeding assay, we demonstrated that Sam68 was lowly expressed in serum-starved HCC cells, and was progressively increased after serum-additioning. Furthermore, siRNA knockdown of endogenous Sam68 inhibited cell proliferation and tumourigenicity of HCC cells in vitro, through blocking the G1 to S phase transition. Moreover, we reported that the anti-proliferative effect of silencing Sam68 was accompanied with up-regulated expression of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1), enhanced transactivation of FOXO factors (FOXO4), and dysreuglation of Akt/GSK-3β signaling. Taken together, these findings provide a rational framework for the progression of HCC and thereby indicated that Sam68 might be a novel and useful prognostic marker and a potential target for human HCC treatment.
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Medical College, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Nantong, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Nantong, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Nantong, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Digestion, Affiliated Hospital of Nantong University, Medical College of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China. nirz1133@163.com.
authors.forename: Runzhou
authors.initials: R
authors.lastname: Ni
authors.affiliation: Department of Oncology, The Second Peoples Hospital of Nantong, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Xiubing
authors.initials: X
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C489559:KHDRBS1 protein, human; D019394:Ki-67 Antigen; D016601:RNA-Binding Proteins; D051057:Proto-Oncogene Proteins c-akt
keywords: FOXOs; Hepatocellular carcinoma; RNA binding protein; Sam68; p27kip1