title: SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas.
abstract: The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.
authors.affiliation: Department of Pathology, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Jeonju, Republic of Korea.
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Sang Jae
authors.initials: SJ
authors.lastname: Noh
authors.forename: Nadja
authors.initials: N
authors.lastname: Lehwald
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: David I
authors.initials: DI
authors.lastname: Bellovin
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Park
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
authors.forename: Dean W
authors.initials: DW
authors.lastname: Felsher
authors.forename: Karl G
authors.initials: KG
authors.lastname: Sylvester
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D056564:Sirtuin 1 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019394:Ki-67 Antigen; D016159:Tumor Suppressor Protein p53; D056564:Sirtuin 1