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Aryl hydrocarbon receptor nuclear translocator is associated with tumor growth and progression of hepatocellular carcinoma
Author(s) -
Liang Ying,
Li WeiWei,
Yang BiWei,
Tao ZhongHua,
Sun HuiChuan,
Wang Lu,
Xia JingLin,
Qin LunXiu,
Tang ZhaoYou,
Fan Jia,
Wu WeiZhong
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26166
Subject(s) - aryl hydrocarbon receptor nuclear translocator , aryl hydrocarbon receptor , cancer research , biology , cell growth , gene knockdown , hepatocellular carcinoma , microbiology and biotechnology , transcription factor , apoptosis , gene , biochemistry
Abstract bHLH/PAS proteins play important roles in tumor progression. Lost or reduced expression of single‐minded homolog 2 (SIM) as well as aryl hydrocarbon receptor repressor (AHRR) has been observed in cancerous human tissues. Here, we investigated the role of aryl hydrocarbon receptor nuclear translocator (ARNT), another bHLH/PAS protein, in hepatocellular carcinoma (HCC). Using tissue microarray and immunohistochemistry, we found that intratumoral ARNT was inversely correlated with time to recurrence and overall survival of HCC patients after resection. Knockdown of ARNT in HepG2, HCCLM3 and HCCLM6 cells significantly shortened cell doubling time, increased S‐phase cell populations and accelerated in vivo HCCLM6 growth and metastasis. After ARNT expression was rescued, prolonged cell doubling time and decreased S‐phase cell populations were observed in HepG2, HCCLM3 and HCCLM6 cells. And, HCCLM6 growth and metastasis in vivo were remarkably inhibited. Screening by quantitative reverse‐transcription PCR and PCR arrays revealed that cyclin E1 , CDK2 , Fos and Jun were negatively regulated by ARNT, whereas CDKN1C , CNKN2A , CDKN2B , MAPK11 and MAPK14 were positively regulated in HCC. According to the results of immunoprecipitation assay, both ARNT/ARNT and ARNT/AHRR complexes were clearly formed in HCCLM6 xenograft with increased ARNT expression. In summary, ARNT is an important regulator of HCC growth and metastasis and could be a promising prognostic candidate in HCC patients.