Junfa Yang

Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer. It is a malignant tumor of liver epithelial cells. There are many ways to treat HCC, but the survival rate for HCC patients remains low. Therefore, understanding the underlying mechanisms by which HCC occurs and develops is critical to explore new therapeutic targets. Aldehyde dehydrogenase 2 (ALDH2) is an important player in the redox reaction of ethanol with endogenous aldehyde products released by lipid peroxidation. Increasing evidence suggests that ALDH2 is a crucial regulator of human tumor development, including HCC. Therefore, clarifying the relationship between ALDH2 and HCC is helpful for formulating rational treatment strategies. This review highlighted the regulatory roles of ALDH2 in the development of HCC, elucidated the multiple potential mechanisms by which ALDH2 regulates the development of HCC, and summarized the progress of research on ALDH2 gene polymorphisms and HCC susceptibility. Meanwhile, we envisioned viable strategies for targeting ALDH2 in the treatment of HCC. Significance Statement Numerous studies have aimed to explore novel therapeutic targets for HCC, and ALDH2 has been reported to be a critical regulator of HCC progression. This review discusses the functions, molecular mechanisms, and clinical significance of ALDH2 in the development of HCC and examines the prospects of ALDH2-based therapy for HCC.

RNF2 (also known as ding, Ring1B or Ring2) is a member of the Ring finger protein family, which functions as E3 ubiquitin ligase for monoubiquitination of histone H2A at lysine 119 (H2AK119ub). RNF2 gene is located at the 1q25.3 site of human chromosome and the coding region is composed of 9 exons, encoding 336 amino acids in total. Many studies have demonstrated that overexpressed RNF2 was involved in the pathological progression of multiple cancers and has an impact on their clinical features. For instance, the upregulated expression level of RNF2 is positively correlated with the occurrence and progression of hepatocellular carcinoma, melanoma, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, and bladder urothelial carcinoma, as well as with the radioresistance of lung cancer and chemoresistance of ovarian cancer. This review provides an up‐to‐date perspective on the relationship between RNF2 and several cancers and highlights recent studies on RNF2 regulation. In particular, the relevant cellular signaling pathways and potential clinical value of RNF2 in cancers are also discussed, suggesting its potential as an epigenetic biomarker and therapeutic target for these cancers.

Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA‐145 (miR‐145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E‐box binding homeobox 2 (ZEB2). In addition, overexpression of miR‐145 and p53 led to upregulation of the number of senescence‐associated β‐galactosidase‐positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α‐smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR‐145 specifically targeted the 3′‐untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E‐box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR‐145‐ZEB2‐p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.