Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors

Abstract

Hepatocellular carcinoma (HCC) accounts for a large proportion of liver cancer cases and has an extremely poor prognosis. Therefore, novel innovative therapies for HCC are strongly desired. As gene therapy tools for HCC, 2 hepatic transcription factors (TF), HNF4A and HNF1A, have been used to suppress proliferation and to extinguish cancer‐specific characteristics of target cells. However, our present data demonstrated that single transduction of HNF4A or HNF1A had only a limited effect on suppression of HCC cell proliferation. Thus, in this study, we examined whether combinations of TF could show more effective antitumor activity, and found that combinatorial transduction of 3 hepatic TF, HNF4A, HNF1A and FOXA3, suppressed HCC cell proliferation more stably than single transduction of these TF. The combinatorial transduction also suppressed cancer‐specific phenotypes, such as anchorage‐independent growth in culture and tumorigenicity after transplantation into mice. HCC cell lines transduced with the 3 TF did not recover their proliferative property after withdrawal of anticancer drugs, indicating that combinatorial expression of the 3 TF suppressed the growth of all cell subtypes within the HCC cell lines, including cancer stem‐like cells. Transcriptome analyses revealed that the expression levels of a specific gene set involved in cell proliferation were only decreased in HCC cells overexpressing all 3 TF. Moreover, combined transduction of the 3 TF could facilitate hepatic differentiation of HCC cell lines. Our strategy for inducing stable inhibition and functional differentiation of tumor cells using a defined set of TF will become an effective therapeutic strategy for various types of cancers.

Opposing Roles of FoxA1 and FoxA3 in Intrahepatic Cholangiocarcinoma Progression

“…FoxA3 protein expression is age-dependent and may be relevant in diminishment of the thermogenic capacity of fat tissues during the aging process [31]. Transfections of HNF4A, HNF1A and FoxA3 suppressed hepatocellular carcinoma (HCC) cell proliferation, suggesting tumor suppressive roles of FoxA3 in HCC [32]. High expression of FoxA3 was correlated with poor prognosis in lung cancer [16].…”

Direct reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells

“…Functional enrichment analyses of the DEGs were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) (v6.8) 40 , 41 . GSEA for cross-platform comparison of the gene expression was performed using “data sets” and “gene sets” calculated from the present CEL-seq2 data sets or previously reported microarray and RNA-seq data sets as described previously 42 . Briefly, for preparation of the “data sets”, transcriptome-wide ranking lists of the gene expression fold change between sample pairs were calculated with GEO2R program in the Gene Expression Omnibus (GEO) for publicized microarray data (Accession Numbers: GEO: GSE42643 , GSE63859 , and GSE98324 ) 6 , 13 , 14 and edgeR package 38 , 39 on R software for the present CEL-seq2 data (Accession Number: GEO: GSE120732 ) and publicized RNA-seq data (Accession Number: GEO: GSE54066 ) 5 .…”

Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover

“…Although there is a ceramide increase during NAFLD development at all the stages [76,77,89], ceramide content has been reported to be reduced in HCC leading to a decrease in apoptosis [116] that correlates with the highly proliferative capacity of the disease [117]. Such reduction is caused by the metabolism of ceramide into other bioactive compounds.…”