Cyclin G1 expands liver tumor-initiating cells by Sox2 induction via Akt/mTOR signaling

• Published in: Molecular cancer therapeutics Vol. 12; no. 9; pp. 1796 - 1804
• Main Authors: Wen, Wen, Han, Tao, Chen, Cheng, Huang, Lei, Sun, Wen, Wang, Xue, Chen, Shu-Zhen, Xiang, Dai-Min, Tang, Liang, Cao, Dan, Feng, Gen-Sheng, Wu, Meng-Chao, Ding, Jin, Wang, Hong-Yang
• Format: Journal Article
• Language: English
• Published: United States 01.09.2013
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cisplatin - therapeutic use; Cyclin G1 - genetics; Cyclin G1 - metabolism; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Niacinamide - analogs & derivatives; Niacinamide - therapeutic use; Phenylurea Compounds - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-13-0099

Recurrence and chemoresistance of liver cancer has been attributed to the existence of liver tumor-initiating cells (T-ICs). It is important to decipher the molecular mechanism for acquisition of drug resistance and to design combinatorial therapeutic strategies. Cyclin G1 has been shown to play a pivotal role in initiation and metastasis of hepatocellular carcinoma. In this study, we found that enhanced cyclin G1 expression was associated with drug resistance of hepatoma cells and higher recurrence rate in hepatocellular carcinoma patients. Expression of cyclin G1 was elevated in liver T-ICs and closely correlated with the expression of liver T-IC markers. Forced cyclin G1 expression remarkably enhanced self-renewal and tumorigenicity of hepatoma cells. Cyclin G1 overexpression dramatically upregulated the expression of Sox2 both in vitro and in vivo, which was impaired by chemical inhibitors of Akt/mTOR signaling. Furthermore, blockade of Akt/mTOR signaling or interference of Sox2 expression suppressed cyclin G1-enhanced self-renewal, chemoresistance, and tumorigenicity of hepatoma cells, indicating that cyclin G1 expands liver T-ICs through Sox2 induction via Akt/mTOR signaling pathway. These results suggest that cyclin G1-induced liver T-IC expansion contributes to the recurrence and chemoresistance of hepatoma, and cyclin G1 may be a promising biomarker for individualized therapy of hepatocellular carcinoma patients.