SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway
Xiao-Tong Wang,
Lei Li,
Zhou Zhu,
Yu-Liang Huang,
Huan-Huan Chen,
Zheng-Yi Shi,
Qiao-Ming Deng,
Kun Wu,
Long-Jie Xia,
Wei Mai,
Jian-Rong Yang,
Fan-Biao Kong
Affiliations
Xiao-Tong Wang
Departments of Gastrointestinal, Hernia and Enterofistula Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Lei Li
Departments of Gastrointestinal, Hernia and Enterofistula Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Zhou Zhu
Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Yu-Liang Huang
Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Huan-Huan Chen
Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Zheng-Yi Shi
Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
Qiao-Ming Deng
Department of Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, 530023, People’s Republic of China
Kun Wu
Department of Surgery, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi Zhuang Autonomous Region, 530001, People’s Republic of China
Long-Jie Xia
Department of Cosmetology and Plastic Surgery Center, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, 530021, People’s Republic of China; Corresponding author.
Wei Mai
Departments of Gastrointestinal, Hernia and Enterofistula Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; Corresponding author.
Jian-Rong Yang
Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region & Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences & Guangxi Key Laboratory of Eye Health, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; Jinan University, Guangzhou, Guangdong Province, 510362, People’s Republic of China; Corresponding authors. Department of Hepatobiliary, Pancreas and Spleen Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region & Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences & Guangxi Key Laboratory of Eye Health, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China.
Fan-Biao Kong
Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; Jinan University, Guangzhou, Guangdong Province, 510362, People’s Republic of China; Corresponding author. Department of Colorectal and Anal Surgery, Guangxi Academy of Medical Sciences, People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Minimally Invasive Technology and Applications Guangxi Academy of Medical Sciences, 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China.
SIVA-1 has been shown to affect apoptotic processes in various different cell lines, and SIVA-1 significantly contributes to the decreased responsiveness of cancer cells to some chemotherapy agents. However, whether SIVA-1 has potential application in gastric cancer remains unknown. Therefore, the objective of this investigation was to clarify the distinct function of SIVA-1 in chemotherapeutic drug resistance within a living murine model with gastric malignancy, and initially elucidate the underlying mechanisms. In an established multidrug-resistant gastric cancer xenograft mouse model, lentivirus, named Lv-SIVA-1, was injected into xenograft tumors, and increased the mRNA and protein expression of endogenous SIVA-1 in tumors. Immunohistochemical assays of xenograft tumor showed that SIVA-1 was significantly upregulated, and the protein expression levels of SIVA-1 were highly increased, as detected by Western blotting. In addition, we detected the role of SIVA-1 in cell proliferation and cell apoptosis in gastric cancer cells by TUNEL and found that SIVA-1 decreased tumor cell apoptosis and promoted tumor growth in vivo. Using a TMT assay between tumor tissues of experimental and control groups, differentially expressed proteins were examined and three potential biomarkers of multidrug resistance (ARF, MDM2, and p53) were screened. We further investigated the molecular mechanism by which SIVA-1 played an efficient role against chemotherapies and found that overexpressed SIVA-1 leads to increased ARF and MDM2 expression and suppressed expression of p53 in tumor tissue. In conclusion, SIVA-1 plays a significant role in the multidrug resistance of gastric tumors. In addition, overexpressed SIVA-1 positively regulates cell proliferation, adjusts cycle progression, and reduces the response to drug treatment for gastric cancer in an ARF/MDM2/p53-dependent manner. This novel research provides a basis for chemical management of gastric cancer through regulation of SIVA-1 expression.
