Role of Hepatocyte Nuclear Factor 4α in Regulating Hepatic Differentiation and the Inflammatory Response in HCC

Abstract

Wen Li Zhou and Zhan Wang made an equal contribution to this paper. Corresponding authors: Wen Li Zhou, MD, PhD, Department of Medical Oncology, Changzheng Hospital, Navy Medical University, Shanghai 200070, China; Tel:+86 216 654 0109; Email: doctorwinly@126. com; Yuan sheng Zang, MD, PhD, Department of Medical Oncology, Changzheng Hospital, Navy Medical University, Shanghai 200070, China; Tel:+86 216 654 0109; Email: doctorzangys@163.com Introduction According to the cancer statistics released by the National Cancer Center in 2018, the annual incidence of primary hepatocellular carcinoma (HCC) in China was 466,000, accounting for about 55% of the global cases of the disease [1]. Surgical resection can be effective for the treatment of HCC, but most patients already have local dissemination or distant metastasis at the time of diagnosis, limiting the efficacy of surgery. Although there are several some other options for the treatment, they have limited benefit. For example, the overall survival (OS) in one study of patients treated with sorafenib for HCC compared with placebo was 10.7 vs 7.9 months [2]. In another phase 3 trial done at 152 sites in 21 countries, the median survival for patients treated with regorafenib following progression on sorafenib was increased by 2.8 months (10.6 vs 7.8) compared with the placebo control group [3]. The median OS of the commonly-used chemotherapy regimen, FOLFOX4, was only 6.4 months [4]. These studies demonstrate that the efficacy of targeted cancer therapies and chemotherapy for advanced HCC is relatively limited. In recent years, the research and application of immunological checkpoint therapy has been increasing exponentially, but more work is necessary to make these approaches more effective. These shed the light on hunting for alternative therapeutic strategies. Based on the biology of tumors, especially from the studies of pathways capable of controlling cell fate programs, induced differentiation strategies have been developed as a novel strategy. Poor differentiation is an important hallmark of cancer cells. It has been increasingly recognized that liver cancer stem cells (LCSCs) are responsible for the carcinogenesis, recurrence and metastasis in HCC. The induced differentiation of LCSCs represents a new idea for the treatment of HCC. In addition, based on an analysis of whole-gene expression, it has been reported that the activation of embryonic stem cell (ESC)-like transcription is involved in hepatocellular carcinoma and strongly predicts early recurrence and metastasis [5-7]. These stem cells and stem celllike patterns of gene expression represent new target for HCC therapy. Many studies have suggested that hepatocyte nuclear factor 4α (HNF 4α) is a promising target for inducing hepatic differentiation as a treatment for HCC. We herein review the roles of HNF 4α in regulating hepatic metabolism and the inflammatory response, aiming to provide some ideas on induced hepatic differentiation therapy.