DJ-1 promotes development of DEN-induced hepatocellular carcinoma and proliferation of liver cancer cells.

Bijun Qiu,Wenjun Liu,Qiang Xia,Yankai Wen,Chao Zhen,Junqi Wang,Xiaoni Kong,Yingxue Yu,Yueqiu Gao,Jinyang Gu,Lili Chen

doi:10.18632/oncotarget.14293

Abstract

Chronic liver inflammation and injuries play a critical role in development of hepatocellular carcinoma (HCC). Parkinson disease (autosomal recessive, early onset) 7, encoding PARK7 protein (also called DJ-1), plays important roles in many carcinogenesis processes and is essential in modulating inflammation. However, whether DJ-1 is involved in HCC development remains largely unknown. To determine the effect of DJ-1 on HCC development, we accessed the correlation of hepatic DJ-1 expression with overall survival (OS) and TNM stage in 96 HCC patients and found a significant inverse correlation between DJ-1 expression and OS. By adopting a classic diethylnitrosamine (DEN)-induced murine HCC model, DJ-1 knockout (KO) mice displayed reduced tumorigenesis and cell proliferation, accompanied by decreased hepatic inflammation and IL-6/STAT3 activation. Furthermore, after an acute DEN challenge, DJ-1 KO mice showed significant decreases in liver injury, hepatocyte proliferation and DNA damage. In a human HCC cell line (MHCC-97L), cancer cell proliferation was induced by overexpression of DJ-1 and is related to oncogenic signaling of MAPKs and AKT. Induction of DJ-1 may serve as a novel regulator for HCC cell proliferation and HCC development possibly through enhanced MAPK signaling and inflammation.

Highlights

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide and the major global health problem currently [1, 2]
To determine whether DJ-1 is associated to hepatocellular carcinoma (HCC) development, we first examined the DJ-1 levels in tumors of 96 HCC patients by immunohistochemistry (IHC)
We further evaluated the correlation between DJ-1 expression and clinicopathologic variables and found that DJ-1 expression was negatively correlated with overall survival (OS) in HCC patients (Figure 1C)

Summary

Introduction

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide and the major global health problem currently [1, 2]. Due to lack of effective diagnostic and therapeutic approaches, the mortality rate of HCC in most developing countries almost equals the incidence rate [3, 4]. The studies about the underlying mechanisms of HCC are urgent. There are abundant studies supporting the notion that amplification of DJ-1 plays a cytoprotective role by eliminating oxidative stress via oxidizing itself and/or stabilizing Nrf, a master regulator of antioxidant transcriptional responses [14, 15]. Whether DJ-1 contributes to HCC development is largely unknown

Methods

Results

Conclusion