Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice

Abstract

Hepatocyte nuclear factor-1alpha (HNF1a) is one of the key transcription factors of the HNF family, which plays a critical role in hepatocyte differentiation. Substantial evidence has suggested that down-regulation of HNF1a may contribute to the development of hepatocellular carcinoma (HCC). Herein, human cancer cells and tumor-associated fibroblasts (TAFs) were isolated from human HCC tissues, respectively. A recombinant adenovirus carrying the HNF1a gene (AdHNF1a) was constructed to determine its effect on HCC in vitro and in vivo. Our results demonstrated that HCC cells and HCC tissues revealed reduced expression of HNF1a. Forced reexpression of HNF1a significantly suppressed the proliferation of HCC cells and TAFs and inhibited the clonogenic growth of hepatoma cells in vitro. In parallel, HNF1a overexpression reestablished the expression of certain liver-specific genes and microRNA 192 and 194 levels, with a resultant increase in p21 levels and induction of G 2 /M arrest. Additionally, AdHNF1a inhibited the expression of cluster of differentiation 133 and epithelial cell adhesion molecule and the signal pathways of the mammalian target of rapamycin and transforming growth factor beta/Smads. Furthermore, HNF1a abolished the tumorigenicity of hepatoma cells in vivo. Most interestingly, intratumoral injection of AdHNF1a significantly inhibited the growth of subcutaneous HCC xenografts in nude mice. Systemic delivery of AdHNF1a could eradicate the orthotopic liver HCC nodules in nonobese diabetic/severe combined immunodeficiency mice. Conclusion: These results suggest that the potent inhibitive effect of HNF1a on HCC is attained by inducing the differentiation of hepatoma cells into mature hepatocytes and G 2 /M arrest. HNF1a might represent a novel, promising therapeutic agent for human HCC treatment. Our findings also encourage the evaluation of differentiation therapy for tumors of organs other than liver using their corresponding differentiation-determining transcription factor.

RYBP Expression Is Regulated by KLF4 and Sp1 and Is Related to Hepatocellular Carcinoma Prognosis

“…After predicting the putative transcription factor binding sites on the two fragments by ALGGEN, TFSEARCH, and JASPAR program analyses in combination with a review of the biological functions, six putative transcription factors, Ets-1, KLF4, Mzf-1, Nkx2-5 (including two protein isoforms, 112 and 324 aa), YY-1, and Sp1, were selected for further study. We also included HNF1A because it had previ-ously been reported to show significantly different expression between liver cancer tissues and adjacent normal tissues and to play a critical role in hepatocarcinogenesis (21).…”

Regulation of hepatocyte identity and quiescence

“…FOXA2, which is required for normal bile acid homeostasis, was later found reduced in the liver of patients with cholestatic syndromes and shown to contribute to disease progression [68]. HNF1a expression is also reduced in experimental liver cirrhosis and hepatocarcinogenesis, as well as in human HCC tissues [152,[176][177][178]. Moreover, adenoviral delivery of HNF1a in human HCC cell lines resulted in partial restoration of the liver-specific gene expression profile, reduced cell proliferation and in vivo tumorigenicity [178].…”

Quantitative implementation of the endogenous molecular–cellular network hypothesis in hepatocellular carcinoma

“…Proliferation and inflammation-related proteins have been approved by the US Food and Drug Administration to treat certain human cancers [58,62]. Liver-specific transcription factors that are overexpressed to induce HCC differentiation have shown anti-tumour effects [60,61]. However, the separate treatment strategies may result in dilemmas such as drug resistance [59] or just cannot obtain favourable results in clinical practice [61].…”