Research Paper Volume 12, Issue 19 pp 19293—19315
Modification of Mcl-1 alternative splicing induces apoptosis and suppresses tumor proliferation in gastric cancer
- 1 Key Laboratory of Preclinical Study for New Drug of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China
- 2 NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou 730000, China
- 3 The Second Department of General Surgery, Lanzhou University First Hospital, Lanzhou 730000, China
- 4 Key Lab of Stomatology of State Ethnic Affairs Commission, Northwest Minzu University, Lanzhou 730030, China
- 5 Pathology Department, Lanzhou University First Hospital, Lanzhou 730000, China
- 6 Oncology Department, The First Hospital of Lanzhou, Lanzhou 730050, China
Received: April 16, 2020 Accepted: July 7, 2020 Published: October 14, 2020https://doi.org/10.18632/aging.103766
How to Cite
Copyright © 2020 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Splicing dysregulation, which leads to apoptosis resistance, has been recognized as a major hallmark for tumorigenesis and cancer progression. Targeting alternative splicing by either increasing pro-apoptotic proteins or inhibiting anti-apoptotic proteins in tumor cells may be an effective approach for gastric cancer (GC) therapy. However, the role of modulation of alternative splicing in GC remains poorly understood. In this study, to the best of our knowledge, the unbalanced expression of the myeloid cell leukemia-1 (Mcl-1) splicing variants, Mcl-1L and Mcl-1S, was identified in GC patients for the first time. Increasing anti-apoptotic Mcl-1L and decreasing pro-apoptotic Mcl-1S expression levels were correlated with tumor proliferation and poor survival. In vitro data showed that a shift in splicing from Mcl-1L to Mcl-1S induced by treatment with Mcl-1-specific steric-blocking oligonucleotides (SBOs) efficiently decreased Mcl-1L expression, increased Mcl-1S expression, and accelerated tumor cell apoptosis in a dose-dependent manner. Additionally, mouse xenotransplant models confirmed that modification of Mcl-1 alternative splicing increased tumor cell death and suppressed tumor proliferation. This study demonstrated that the modification of Mcl-1 splicing might stimulate the pro-apoptotic factor and inhibit the anti-apoptotic protein to induce significant apoptosis. Thus, this finding provided a strategy for cancer therapy, according to which SBOs could be used to change the Mcl-1 splicing pattern, thereby inducing apoptosis.