Circular RNA Hsa_circRNA_101996 promotes the development of Gastric Cancer via Upregulating Matrix Metalloproteinases-2/Matrix Metalloproteinases-9 through MicroRNA-143/Ten-eleven translocation-2 Pathway

Feng Huang; Jiajia Jiang; Yongliang Yao; Shiyue Hu; He Wang; Ma Zhu; Liya Yu; Qingqian Liu; Haoyuan Jia; Wenrong Xu

doi:10.7150/jca.62121

Circular RNA Hsa_circRNA_101996 promotes the development of Gastric Cancer via Upregulating Matrix Metalloproteinases-2/Matrix Metalloproteinases-9 through MicroRNA-143/Ten-eleven translocation-2 Pathway

J Cancer. 2021 Sep 21;12(22):6665-6675. doi: 10.7150/jca.62121. eCollection 2021.

Authors

Feng Huang^{1

2}, Jiajia Jiang^{1

3}, Yongliang Yao², Shiyue Hu², He Wang², Ma Zhu⁴, Liya Yu², Qingqian Liu², Haoyuan Jia⁵, Wenrong Xu^{1

3}

Affiliations

¹ Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu 212013, China.
² Department of Clinical Laboratory, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Kunshan, 215300, China.
³ Aoyang Institute of Cancer, Jiangsu University, 279 Jingang Road, Suzhou, 215600, Jiangsu, China.
⁴ Cancer Research Institute of Wuhan, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
⁵ Department of Clinical Laboratory, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.

Abstract

Background: The long-term survival rate of gastric cancer (GC) patients at advanced stages remains low worldwide. Circular RNAs (circRNAs) a newly studied type of non-coding RNA that play an important role in the pathogenesis and diagnosis of various diseases. In this research, we aimed to explore the functions of hsa_circRNA_101996 in GC cells and an animal model of GC. Methods: The expression of hsa_circRNA_101996, microRNA (miR)-143, and ten-eleven translocation (TET)-2 in GC tissues, the adjacent tissues, and cell lines were determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Transwell assays were used to analyze the knockdown effects of hsa_circRNA_101996, miR-143, and overexpression of TET2 on cell proliferation, migration, and invasion abilities. Western blotting was used to analyze the expression of matrix metalloproteinases (MMP)2/MMP9. Binding interactions between, hsa_circRNA_101996 and miR-143 and between, miR-143 and TET2 were detected by Dual-luciferase reporter assays. Levels of protein expression were analyzed by Western blotting. Tumor models were established by subcutaneous injection of tumor cells in Bl6/Rag2/GammaC double knockout mice. Results: The result showed that hsa_circRNA_101996 expression was significantly upregulated in GC tissues compared to that in the adjacent tissues, and its level in cancer tissue was correlated with tumor size, lymphatic metastasis, and distant metastasis. Compared with the low hsa_circRNA_101996 expression group, the three-year survival rate of patients in the high hsa_circRNA_101996 expression group was significantly lower. The knockdown of hsa_circRNA_101996 dramatically suppressed the cell migration, invasion, and proliferation of GC cells by sponging to absorb miR-143 and elevated the expression of TET2. In vivo studies showed that the knockdown of hsa_circRNA_101996 delayed tumor growth. Furthermore, we revealed that TET2 regulates MMP2/MMP9 expression through the DNA demethylation pathway. Conclusion: Our findings indicate that hsa_circRNA_101996 promotes GC development by upregulating MMP2/MMP9 through miR-143/TET2 pathway, which may provide a novel target for GC.

Keywords: gastric cancer; hsa_circRNA_101996; matrix metalloproteinases; microRNA143; ten-eleven translocation-2.