Anlotinib Downregulates RGC32 Which Provoked by Bevacizumab

Frontiers in Oncology

Wei Shi¹  Jie Yang²  Xiaohan Yuan³  Zhujun Liu⁴  Tingting Qin⁴  Xiaoling Zhang⁴  Shaochuan Liu⁴  Yanan Jia⁴  Jing Wang⁴  Kai Li⁴ 

[1] 0Research and Development Department, Jiangsu Chia-Tai Tian Qing Pharmaceutical Co., Ltd., Nanjing, China;Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China;Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China;Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China;Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China;Key Laboratory of Cancer Prevention and Therapy, Tianjin, China;Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China;National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China;National Key Discipline of Pediatrics (Capital Medical University), Beijing, China;Tianjin’s Clinical Research Center for Cancer, Tianjin, China;

关键词: anlotinib abrogated bevacizumab resistance;    anlotinib;    bevacizumab;    MMP2;    N-cadherin;    RGC32;   

DOI  :  10.3389/fonc.2022.875888

来源: DOAJ

【 摘 要 】

BackgroundBevacizumab is the representative drug in antiangiogenic therapy for lung cancer. However, it induced resistance in some neoplasm. Anlotinib, a novel multi-target tyrosine kinase inhibitor which has an inhibitory action on both angiogenesis and malignancy, is possible to reverse the resistance.MethodsTranswell migration and invasion experiments of bevacizumab with or without anlotinib were conducted to verify the activated/inhibited ability of lung adenocarcinoma cells. We sequenced A549 cells with enhanced migration and invasion abilities after bevacizumab treatment, screened out the differentially expressed gene and further confirmed by western blot and q-PCR assays. We also investigated immunohistochemical staining of tumor tissue in mice and human lung adenocarcinoma.ResultsBevacizumab facilitated migration and invasion of lung adenocarcinoma cells. Differentially expressed gene RGC32 was screened out. Bevacizumab upregulated the expression of RGC32, N-cadherin, and MMP2 through ERK-MAPK and PI3K-AKT pathways. Anlotinib downregulated their expression and reversed the effect of bevacizumab on A549 cells. In vivo experiments confirmed that higher-dose bevacizumab facilitated metastasis in tumor-bearing nude mice and upregulated the expression of RGC32, N-cadherin, and MMP2, whereas anlotinib abrogated its effect. Expression of both RGC32 and N-cadherin positively correlated with lymph node metastasis and stage in lung adenocarcinoma was found. Survival analysis revealed that higher expressions of RGC32 and N-cadherin were associated with poor progression-free survival and overall survival.ConclusionsBevacizumab may promote invasion and metastasis of lung adenocarcinoma cells by upregulating RGC32 through ERK-MAPK and PI3K-AKT pathways to promote epithelial–mesenchymal transition, whereas anlotinib reverses the effect. RGC32 and N-cadherin are independent prognostic factors in lung adenocarcinoma.

【 授权许可】

Unknown