OncoTargets and Therapy (Sep 2019)
Downregulation of miR-21 inhibits the malignant phenotype of pancreatic cancer cells by targeting VHL
Abstract
Jinjin Sun*, Zhijia Jiang*, Yanxun Li, Kaiqiang Wang, Xing Chen, Geng Liu Department of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinjin SunDepartment of Hepatopancreatobiliary Surgery, The Second Hospital of Tianjin Medical University, No. 23 Ping-Jiang Road, Hexi District, Tianjin 300211, People’s Republic of ChinaTel +86 1 862 205 7820Fax +86 8 832 8331Email [email protected]: MicroRNA (miR)-21 is overexpressed in numerous types of malignancy and participates in the development of cancer. However, the basic mechanism of the influence of miR-21 on the malignant phenotype of pancreatic cancer remains unclear.Purpose: The present study aimed to investigate the role of miR-21 in pancreatic cancer development and explore its molecular mechanism.Patients and methods: The tissue samples were collected at the Second Hospital of Tianjin Medical University (Tianjin, China) between January 2013 and December 2015. The expression of VHL in tissue samples was evaluated by IHC staining. The expression of miR-21 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-21 target gene was detected by real-time PCR, Western blot and the luciferase reporter assay. Cell viability, cell proliferation, cell migration and invasion were evaluated by the MTT assays, the colony formation assays and the transwell assays. The nude mouse tumor xenograft model was performed to detect the effect of miR-21 on tumor growth in vivo.Results: Von Hippel-Lindau tumor suppressor (VHL) was downregulated in pancreatic cancer tissues compared with pancreatic non-tumor tissues. VHL was identified as a novel direct target of miR-21, by which it is negatively regulated. In PANC-1 cells, inhibition of miR-21 and upregulation of VHL significantly suppressed cell proliferation, migration and invasion. Knockdown of miR-21 inhibited the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway, while inhibiting the expression of matrix metallopeptidase (MMP)-2 and MMP-9. Silencing of miR-21 inhibited tumor growth in vivo.Conclusion: Knockdown miR-21 increased the expression of VHL, and thus modulated the HIF-1α/VEGF pathway and the expression of MMP-2 and MMP-9, which led to the inhibition of the proliferation, migration and invasion of pancreatic cancer cells. All of these results suggest that the miR-21/VHL interaction may be a novel potential target for pancreatic cancer prevention and therapy.Keywords: miR-21, pancreatic cancer, VHL, proliferation, migration, invasion
