Yi Lu1, Jiansheng Zhou2, Jie Zhang3, Zhengping Wang4, Yaying Yu5, Mingyong Miao6, Qinghua Yao7. 1. Department of Nutrition, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences/Cancer Hospital of University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Hanzhou 310022, China. 2. Department of Clinical Lab, the 92nd Hospital of the Chinese People's Liberation Army (PLA), Nanping, Fujian 35300, China. 3. Department of Respiratory Diseases, the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223002, China. 4. Institute of biopharmaceutical, Liaocheng University, Liaocheng 252000, China. 5. Department of Nutrition, the First Affiliated Hospital of Henan University, Kaifeng 475001, China. Electronic address: lovefish432@163.com. 6. The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China. Electronic address: miaomy@163.com. 7. Department of Integrated Traditional Chinese and Western Medicine, the Key Laboratory of Integration of Chinese and Western Medicine, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences/Cancer Hospital of University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Hanzhou 310022, China. Electronic address: danfer1001@163.com.
Abstract
PURPOSE: Reactive oxygen species (ROS) are implicated in carcinogenesis, and cellular antioxidant systems are important for detoxifying ROS and reversing oxidant-mediated modifications. Glutathione S-transferase mu (GSTM) belongs to a family of phase II detoxification enzymes that catalyze the conjugation of reduced glutathione (GSH) to a wide range of endogenous and exogenous electrophilic compounds. The genotype of GSTM1 was associated with the risk and prognosis of cancer in several meta-analyses. This study explored the function of GSTM1 in hepatocellular carcinoma (HCC). METHODS: Polymerase chain reaction (PCR) and western blotting (WB) were used to detect the levels of gene and protein expression. MTS assays, Transwell assays, and flow cytometry were used to explore the function of GSTM1 in vitro. The xenograft assay and tail vein injection model were used to explore the function of GSTM1 in vivo. RESULTS: The mRNA and protein expression of GSTM1 was downregulated in HCC, but the expression levels of GSTM1 were not correlated with patient survival time. In vitro, Transwell and doxorubicin (DOX)-induced apoptosis assays revealed that GSTM1 showed opposite functions in different HCC cell lines with varied TP53 genotype statuses. The overexpression of GSTM1 in the above cell lines led to a significant decrease in ROS and an increase in GSH concentration and TP53 levels, suggesting that the controversial role of GSTM1 resulted from the TP53 genotype of HCC cells. The overexpression of GSTM1 promoted cell migration and inhibited apoptosis in the MHCC-97H cell line (TP53, R249S), but inhibited cell migration and increased apoptosis in the SMMC-7721 cell line (TP53 wildtype). CONCLUSION: GSTM1 down-regulation may partially account for ROS-mediated oxidative damage and HCC carcinogenesis. GSTM1 also regulates tumor progression by disrupting the ROS-TP53 axis in HCC cells with different genetic backgrounds.
PURPOSE:Reactive oxygen species (ROS) are implicated in carcinogenesis, and cellular antioxidant systems are important for detoxifying ROS and reversing oxidant-mediated modifications. Glutathione S-transferase mu (GSTM) belongs to a family of phase II detoxification enzymes that catalyze the conjugation of reduced glutathione (GSH) to a wide range of endogenous and exogenous electrophilic compounds. The genotype of GSTM1 was associated with the risk and prognosis of cancer in several meta-analyses. This study explored the function of GSTM1 in hepatocellular carcinoma (HCC). METHODS: Polymerase chain reaction (PCR) and western blotting (WB) were used to detect the levels of gene and protein expression. MTS assays, Transwell assays, and flow cytometry were used to explore the function of GSTM1 in vitro. The xenograft assay and tail vein injection model were used to explore the function of GSTM1 in vivo. RESULTS: The mRNA and protein expression of GSTM1 was downregulated in HCC, but the expression levels of GSTM1 were not correlated with patient survival time. In vitro, Transwell and doxorubicin (DOX)-induced apoptosis assays revealed that GSTM1 showed opposite functions in different HCC cell lines with varied TP53 genotype statuses. The overexpression of GSTM1 in the above cell lines led to a significant decrease in ROS and an increase in GSH concentration and TP53 levels, suggesting that the controversial role of GSTM1 resulted from the TP53 genotype of HCC cells. The overexpression of GSTM1 promoted cell migration and inhibited apoptosis in the MHCC-97H cell line (TP53, R249S), but inhibited cell migration and increased apoptosis in the SMMC-7721 cell line (TP53 wildtype). CONCLUSION:GSTM1 down-regulation may partially account for ROS-mediated oxidative damage and HCC carcinogenesis. GSTM1 also regulates tumor progression by disrupting the ROS-TP53 axis in HCC cells with different genetic backgrounds.
Authors: Juan Zhang; Yan Li; Juan Zou; Chun-Tian Lai; Tian Zeng; Juan Peng; Wen-da Zou; Bei Cao; Dan Liu; Li-Yu Zhu; Hui Li; Yu-Kun Li Journal: Front Oncol Date: 2022-07-28 Impact factor: 5.738