lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis

Hailu Wu; Ming Wei; Xinglu Jiang; Jiacheng Tan; Wei Xu; Xiaobo Fan; Rui Zhang; Chenbo Ding; Fengfeng Zhao; Xiangyu Shao; Zhigang Zhang; Ruihua Shi; Weijia Zhang; Guoqiu Wu

doi:10.1016/j.omtn.2020.03.006

lncRNA PVT1 Promotes Tumorigenesis of Colorectal Cancer by Stabilizing miR-16-5p and Interacting with the VEGFA/VEGFR1/AKT Axis

Mol Ther Nucleic Acids. 2020 Jun 5:20:438-450. doi: 10.1016/j.omtn.2020.03.006. Epub 2020 Mar 19.

Authors

Hailu Wu¹, Ming Wei², Xinglu Jiang³, Jiacheng Tan², Wei Xu³, Xiaobo Fan³, Rui Zhang³, Chenbo Ding³, Fengfeng Zhao⁴, Xiangyu Shao⁵, Zhigang Zhang⁶, Ruihua Shi², Weijia Zhang⁷, Guoqiu Wu⁸

Affiliations

¹ Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
² Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
³ Medical School of Southeast University, Nanjing 210009, People's Republic of China.
⁴ Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
⁵ Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
⁶ Medical School of Southeast University, Nanjing 210009, People's Republic of China; Department of Gastrointestinal Surgery, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.
⁷ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: weijia.zhang@mssm.edu.
⁸ Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China. Electronic address: nationball@163.com.

Abstract

Recently, the long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was reported to be involved in the pathogenesis of several cancers, including human colorectal cancer (CRC). However, the molecular basis for cancer initiation, development, and progression remains unclear. In this study, we observe that upregulated PVT1 is associated with poor prognosis and bad clinicopathological features of CRC patients. In vitro means of PVT1 loss in a CRC cell line inhibit cell proliferation, migration, and invasion. Furthermore, dual-luciferase reporter and RNA pull-down assays indicated that PVT1 binds to miR-16-5p, which has been shown to play strong tumor suppressive roles in CRC. Targeted loss of miR-16-5p partially rescues the suppressive effect induced by PVT1 knockdown. Vascular endothelial growth factor A (VEGFA), a direct downstream target of miR-16-5p, was suppressed by PVT1 knockdown in CRC cells. Overexpression of VEGFA is known to modulate the AKT signaling cascade by activating vascular endothelial growth factor receptor 1 (VEGFR1). We, therefore, show that PVT1 loss combined with miR-16-5p overexpression reduces tumor volume maximally when propagated within a mouse xenograft model. We conclude that the PVT1-miR-16-5p/VEGFA/VEGFR1/AKT axis directly coordinates the response in CRC pathogenesis and suggest PVT1 as a novel target for potential CRC therapy.

Keywords: AKT; CRC; PVT1; VEGFA; miR-16-5p.