TIP30 inhibits growth of HCC cell lines and inhibits HCC xenografts in mice in combination with 5-FU.
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The specific cellular gene alterations responsible for hepatocarcinogenesis are not well known. Previous works showed that loss of TIP30, also called CC3, a putative tumor suppressor, increased the incidence of hepatocellular carcinoma in mice, and some clinical samples of human HCC tissues had aberrant expression of TIP30. Here, we report that the introduction of TIP30 by an adenovirus vector into HCC cell lines that had decreased expressions of TIP30 inhibited cell proliferation, decreased anchorage-dependent growth, suppressed invasion through the extracellular matrix, and inhibited tumorigenesis in nude mice. Moreover, exogenous expression of Tip30 sensitized HCC cells to cytotoxic drugs and to apoptosis induced by tumor necrosis factor-related ligands in vitro. Ectopic expression of TIP30 in HCC cells enhanced p53 expression and decreased Bcl-2/Bcl-xL expression. Treatment of nude mice bearing subcutaneously established HCC tumors with a combination of an adenovirus expressing TIP30 and the cytotoxic drug 5-fluorouracil completely suppressed tumor growth and prolonged survival. In conclusion, TIP30 may play an important role in the suppression of hepatocarcinogenesis by acting as a tumor suppressor. Overexpression of TIP30 might be a promising candidate as a treatment for HCC that would increase sensitivity to chemotherapeutic drugs.
Zhao
Jian
J
International Joint Cancer Institute & Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, China.
Zhang
Xia
X
Shi
Mei
M
Xu
Hao
H
Jin
Jun
J
Ni
Haidong
H
Yang
Silei
S
Dai
Jianxin
J
Wu
Mengchao
M
Guo
Yajun
Y
D000123:Acetyltransferases / Q000235:genetics / Q000494:pharmacology*; D000256:Adenoviridae; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000235:genetics; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; D005472:Fluorouracil