Conversion of hepatoma cells to hepatocyte-like cells by defined hepatocyte nuclear factors

Abstract

Normal cells become cancer cells after a malignant transformation, but whether cancer cells can be reversed to normal status remains elusive. Here, we report that the combination of hepatocyte nuclear factor 1A (HNF1A), HNF4A and forkhead box protein A3 (FOXA3) synergistically reprograms hepatocellular carcinoma (HCC) cells to hepatocyte-like cells (reprogrammed hepatocytes, rHeps). Our results show that rHeps lose the malignant phenotypes of cancer cells and retrieve hepatocyte-specific characteristics including hepatocyte-like morphology; global expression pattern of genes and specific biomarkers of hepatocytes; and the unique hepatic functions of albumin (ALB) secretion, glycogen synthesis, low-density lipoprotein (LDL) uptake, urea production, cytochrome P450 enzymes induction and drug metabolism. Intratumoral injection of these three factors efficiently shrank patientderived tumor xenografts and reprogrammed HCC cells in vivo. Most importantly, transplantation of rHeps in the liver of fumarylacetoacetate hydrolase-deficient (Fah −/− ) mice led to the reconstruction of hepatic lobules and the restoration of hepatic function. Mechanistically, exogenous expression of HNF1A, HNF4A and FOXA3 in HCC cells initiated the endogenous expression of numerous hepatocyte nuclear factors, which promoted the conversion of HCC cells to hepatocyte-like cells. Collectively, our results indicate the successful conversion of hepatoma cells to hepatocyte-like cells, not only extending our current knowledge of cell reprogramming but also providing a route towards a novel therapeutic strategy for cancer.

Unveiling prognostics biomarkers of tyrosine metabolism reprogramming in liver cancer by cross-platform gene expression analyses

“…A metabolomics study on esophageal cancer (EC) showed that tyrosine decreased in serum of patients with EC compared with healthy control [59,60]. There has been little evidence on how tyrosine metabolism might contribute to cancer development even though changes in expression of some tyrosine metabolic genes have been reported in HCC patients [23,61]. Our interesting findings add to existing body of knowledge in tyrosine catabolism in HCC.…”

Over a century of cancer research: Inconvenient truths and promising leads

“…For decades, the management of clinical cancers has been based on the premises of the SMT that, in short, meant to kill the allegedly immortalized, mutated "cancer cells." This approach ignores evidence that the carcinogenic process is reversible, as repeatedly proven both experimentally [92][93][94][95] and clinically [14,16,38,96]. Regardless of these damning conclusions, the SMT and its variants have maintained their hegemony in academic circles, in the hospital ward, in BigPharma, in the specialized and lay media at large, and, equally important, in study sections of funding agencies, in which short-and long-term future trends in cancer research are decided.…”

Integrated Analyses of Mouse Stem Cell Transcriptomes Provide Clues for Stem Cell Maintenance and Transdifferentiation

“…Studies focusing on liver regeneration have suggested endogenous reprogramming as a therapeutic strategy for cell repair. Ectopic expression of Foxa3, Gata4, Hnf1a, and Hnf4a can convert murine myofibroblasts into hepatocyte-like cells in vivo (Song et al, 2016;Cheng et al, 2019). Ectopic expression of Sox2 is sufficient to convert astrocytes into ASCL1-positive neural progenitors (Niu et al, 2013).…”