Background Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplification. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of patients with HCC, its chemoresistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment.
Methods The clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolisation treatment was assessed by clinical correlation and Kaplan–Meier analyses. A CHD1L-overexpressing cell model was generated and the mechanism of chemoresistance involving CHD1L was investigated. An adenovirus-mediated silencing method was used to knockdown CHD1L, and its effects on tumorigenicity and chemoresistance were investigated in vivo and in vitro.
Results Overexpression of CHD1L was significantly associated with tumour microsatellite formation (p=0.045), advanced tumour stage (p=0.018), overall survival time (p=0.002), overall survival time of patients who received transarterial chemoembolisation treatment (p=0.028) and chemoresistance (p=0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin. The mechanistic study revealed that the involvement of the Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, an adenoviral vector containing short hairpin RNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemoresistance to 5-FU. An in vivo study found that CHD1L-shRNAs could inhibit xenograft tumour growth and increase the sensitivity of tumour cells to 5-FU in nude mice.
Conclusions This study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC treatment.
- Cell biology
- hepatocellular carcinoma
Statistics from Altmetric.com
L C and Y-F Y contributed equally to this paper.
Funding This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), Hong Kong RGC Collaborative Research Grants (HKU5/CRF/08 and HKU 7/CRG09), the ‘Hundred Talents Program’ at Sun Yat-Sen University (85000-3171311) and grants from the National Natural Science Foundation of China (30772475) and the National Key Sci-Tech Special Project of Infectious Diseases (Grant 2008ZX10002-022).
Competing interests None.
Ethics approval The studies using human tissue were reviewed and approved by the Committees for Ethical Review of Research involving Human Subjects at the University of Hong Kong and the Cancer Center of Sun Yat-Sen University, China.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.