Frontiers in Oncology (May 2022)
Anlotinib Downregulates RGC32 Which Provoked by Bevacizumab
- Zhujun Liu,
- Zhujun Liu,
- Zhujun Liu,
- Zhujun Liu,
- Tingting Qin,
- Tingting Qin,
- Tingting Qin,
- Tingting Qin,
- Xiaohan Yuan,
- Xiaohan Yuan,
- Xiaohan Yuan,
- Xiaohan Yuan,
- Xiaohan Yuan,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Jie Yang,
- Wei Shi,
- Xiaoling Zhang,
- Xiaoling Zhang,
- Xiaoling Zhang,
- Xiaoling Zhang,
- Yanan Jia,
- Yanan Jia,
- Yanan Jia,
- Yanan Jia,
- Shaochuan Liu,
- Shaochuan Liu,
- Shaochuan Liu,
- Shaochuan Liu,
- Jing Wang,
- Jing Wang,
- Jing Wang,
- Jing Wang,
- Kai Li,
- Kai Li,
- Kai Li,
- Kai Li
Affiliations
- Zhujun Liu
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Zhujun Liu
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Zhujun Liu
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Zhujun Liu
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Tingting Qin
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Tingting Qin
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Tingting Qin
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Tingting Qin
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Xiaohan Yuan
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Xiaohan Yuan
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Xiaohan Yuan
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Xiaohan Yuan
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Xiaohan Yuan
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Jie Yang
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Jie Yang
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Jie Yang
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Jie Yang
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Jie Yang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, Beijing, China
- Jie Yang
- National Key Discipline of Pediatrics (Capital Medical University), Beijing, China
- Jie Yang
- Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing, China
- Jie Yang
- Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
- Wei Shi
- 0Research and Development Department, Jiangsu Chia-Tai Tian Qing Pharmaceutical Co., Ltd., Nanjing, China
- Xiaoling Zhang
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Xiaoling Zhang
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Xiaoling Zhang
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Xiaoling Zhang
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Yanan Jia
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Yanan Jia
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Yanan Jia
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Yanan Jia
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Shaochuan Liu
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Shaochuan Liu
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Shaochuan Liu
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Shaochuan Liu
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Jing Wang
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Jing Wang
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Jing Wang
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Jing Wang
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Kai Li
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Kai Li
- Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Kai Li
- Tianjin’s Clinical Research Center for Cancer, Tianjin, China
- Kai Li
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- DOI
- https://doi.org/10.3389/fonc.2022.875888
- Journal volume & issue
-
Vol. 12
Abstract
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.
Keywords
