miR-6126 modulates GRP78 to suppress the Warburg effect and mitochondrial dynamics in triple-negative breast cancer

Sep 24, 2026

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Cancer cells often shift metabolism toward aerobic glycolysis, the Warburg effect, producing excess energy that supports tumorigenesis, including in breast cancer. This study evaluates how non-coding microRNA miR-6126 regulates metabolic reprogramming in triple-negative breast cancer (TNBC). miR-6126 is highly expressed in TNBC and suppresses TNBC growth while inducing apoptosis by targeting GRP78. Functional assays link GRP78 to increased glucose metabolism and mitochondrial dysfunction through mitochondrial fission.

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Ivyspring International Publisher InternationalJournal of Medical Sciences 2025; 22(14): 3598-3616. doi: 10.7150/ijms.107240 Research Paper miR-6126 modulates GRP78 to suppress the Warburg effect and mitochondrial dynamics in triple-negative breast cancer Wei-Jan Wang1,2, Jian-Sheng Liu1,3, Nguyen Hoang Anh Kha1, Wan-Jou Shen4, Chih-Jung Chen5, Shuan-Chu Chen1, Pin-Chen Liao1, Chih-Yang Huang4,6,7,8,9,􀀍, and Wei-Wen Kuo1,10,􀀍 1. Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan ROC. 2. Cancer Biology and Precision Therapeutics Center and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan ROC. 3. Thoracic Department, China Medical University Beigang Hospital, Yunlin, Taiwan ROC. 4. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan ROC. 5. Surgical Department, China Medical University Hospital, Taichung, Taiwan ROC. 6. Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan ROC. 7. Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan ROC. 8. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan ROC. 9. Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan ROC. 10. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan ROC. 􀀍 Corresponding authors: Wei-Wen Kuo ([wwkuo@mail.cmu.edu.tw](wwkuo@mail.cmu.edu.tw)); Chih-Yang Huang ([cyhuang@mail.cmu.edu.tw](cyhuang@mail.cmu.edu.tw)) . © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2024.11.19; Accepted: 2025.07.10; Published: 2025.07.28 Abstract Cancer cells often exhibit a metabolic shift towards aerobic glycolysis, known as the Warburg effect, leading to excessive energy production that facilitates tumorigenesis, including in breast cancer. Recently, non-coding RNAs, including microRNAs (miRNAs), have been identified as playing crucial roles in various human cancers. However, their roles in regulating metabolic reprogramming in breast cancer remain largely unexplored. Here, we identified the novel miRNA miR-6126, which is highly expressed in TNBC cells by using a miRNA microarray analysis. Overexpression of miR-6126 reduced the growth of TNBC cells and induced apoptosis by targeting GRP78 in vitro and in vivo. In addition, a luciferase reporter assay confirmed that GRP78 is a direct target of miR-6126. Elevated glucose metabolism, indicated by increased levels of LDHA and glucose transporter-1, was observed in TNBC following GRP78 overexpression. Treatment with miR-6126 mimics or GRP78 siRNA not only reduced LDHA and GLUT1 expression but also decreased glucose uptake and lactate release in TNBC cells. Moreover, miR-6126 impaired mitochondrial function by inducing mitochondrial fission through the downregulation of phospho-Drp1 (Ser616) and FIS1. Furthermore, we demonstrated that the expression of miR-6126 is negatively correlated with GRP78 in human tumor tissues. Our findings revealed that miR-6126 is implicated in tumorigenesis via the Warburg effect by targeting GRP78 and restoring mitochondrial function in TNBC. Keywords: Warburg effect; miR-6126; GRP78; triple-negative breast cancer; mitochondria dynamics Introduction Breast cancer is the most frequently diagnosed malignancy among women worldwide, and it is the second leading cause of cancer-related death in women [1] . Breast cancer is classified into different subtypes, which have varying therapeutic sens

FAQs

What does miR-6126 do in triple-negative breast cancer cells?

miR-6126 overexpression reduces TNBC cell growth and induces apoptosis in vitro and in vivo.

How does miR-6126 exert its effects mechanistically?

The study shows miR-6126 directly targets GRP78, confirmed by a luciferase reporter assay.

What metabolic and mitochondrial changes are associated with the miR-6126/GRP78 axis?

GRP78 upregulation elevates glucose metabolism markers and increases glucose uptake and lactate release; miR-6126 mimics or GRP78 knockdown reduce these effects and impair mitochondrial function via mitochondrial fission.

Sep 24, 2026

Uploaded by Bulrr