Research Paper|Volume 14, Issue 16|pp 6668—6688

MicroRNA-148a induces apoptosis and prevents angiogenesis with bevacizumab in colon cancer through direct inhibition of ROCK1/c-Met via HIF-1α under hypoxia

Hsiang-Lin Tsai^1,², Yueh-Chiao Tsai¹, Yen-Cheng Chen^1,³, Ching-Wen Huang^1,², Po-Jung Chen^1,³, Ching-Chun Li¹, Wei-Chih Su^1,³, Tsung-Kun Chang^1,^2,³, Yung-Sung Yeh^2,^4,^5,⁶, Tzu-Chieh Yin^1,^7,⁸, Jaw-Yuan Wang^1,^2,^3,^9,^10,¹¹

¹Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
²Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
³Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
⁴Division of Trauma and Surgical Critical Care, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
⁵Department of Emergency Medicine, Faculty of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
⁶Graduate Institute of Injury Prevention and Control, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan
⁷Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
⁸Department of Surgery, Kaohsiung Municipal Tatung Hospital, Kaohsiung Medical University, Kaohsiung 80145, Taiwan
⁹Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
¹⁰Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
¹¹Pingtung Hospital, Ministry of Health and Welfare, Pingtung 90054, Taiwan

Received: March 15, 2022Accepted: August 9, 2022Published: August 22, 2022

https://doi.org/10.18632/aging.204243

Copyright: © 2022 Tsai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Angiogenesis and antiapoptosis effects are the major factors influencing malignancy progression. Hypoxia induces multiple mechanisms involving microRNA (miRNA) activity. Vascular endothelial growth factor (VEGF) is correlated with angiogenesis. An antiapoptotic factor, myeloid leukemia 1 (Mcl-1) is the main regulator of cell death. This study examined the role of miR-148a in inhibiting VEGF and Mcl-1 secretion by directly targeting ROCK1/c-Met by downregulating HIF-1α under hypoxia. The protein expression of ROCK1 or Met/HIF-1α/Mcl-1 in HCT116 and HT29 cells (all P < 0.05) was significantly reduced by miR-148a. The tube-formation assay revealed that miR-148a significantly suppressed angiogenesis and synergistically enhanced the effects of bevacizumab (both P < 0.05). The MTT assay revealed the inhibitory ability of miR-148a in HCT116 and HT29 cells (both P < 0.05). miR-148a and bevacizumab exerted synergistic antitumorigenic effects (P < 0.05) in an animal model. Serum miR-148a expression of metastatic colorectal cancer (mCRC) patients with a partial response was higher than that of mCRC patients with disease progression (P = 0.026). This result revealed that miR-148a downregulated HIF-1α/VEGF and Mcl-1 by directly targeting ROCK1/c-Met to decrease angiogenesis and increase the apoptosis of colon cancer cells. Furthermore, serum miR-148a levels have prognostic/predictive value in patients with mCRC receiving bevacizumab.