HMGB3 inhibition by miR-142-3p/sh-RNA modulates autophagy and induces apoptosis via ROS accumulation and mitochondrial dysfunction and reduces the tumorigenic potential of human breast cancer cells.

Autor: Sharma P; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India., Yadav P; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India., Sundaram S; Department of Pathology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra University, Porur, Chennai 600116, India., Venkatraman G; Department of Human Genetics, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India., Bera AK; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India., Karunagaran D; Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India. Electronic address: karuna@iitm.ac.in.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2022 Sep 01; Vol. 304, pp. 120727. Date of Electronic Publication: 2022 Jun 23.
DOI: 10.1016/j.lfs.2022.120727
Abstrakt: Aims: High mobility group box (HMGB) family proteins, HMGB1, HMGB2, HMGB3, and HMGB4 are oncogenic. The oncogenic nature of HMGB1 is characterized by its association with autophagy, ROS, and MMP. Since HMGB3 is its paralog, we hypothesized that it might also modulate autophagy, ROS, and MMP. Hence, we targeted HMGB3 using its shRNA or miR-142-3p and assessed the changes in autophagy, ROS, MMP, and tumorigenic properties of human breast cancer cells.
Main Methods: Cell viability was assessed by resazurin staining and annexin-V/PI dual staining was used for confirming apoptosis. Colony formation, transwell migration, invasion and luciferase reporter (for miRNA-target validation) assays were also performed. ROS and MMP were detected using DHE and MitoTracker dyes, respectively. A zebrafish xenograft model was used to assess the role of miR-142-3p on in vivo metastatic potential of breast cancer cells.
Key Findings: Breast cancer tissues from Indian patients and TCGA samples exhibit overexpression of HMGB3. miR-142-3p binds to 3' UTR of HMGB3, leading to its downregulation that subsequently inhibits colony formation and induces apoptosis involving increased ROS accumulation and decreased MMP, phospho-mTOR and STAT3. Our findings show that HMGB3 is directly involved in the miR-142-3p-mediated disruption of autophagy and induction of apoptotic cell death via modulation of LC3, cleaved PARP and Bcl-xL. In addition, miR-142-3p inhibited migration, invasion and metastatic potential of breast cancer cells.
Significance: Our findings highlighted the role of HMGB3, for the first time, in the modulation of autophagy and apoptosis in human breast cancer cells, and these results have therapeutic implications.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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