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The miR-27a/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells
- Source :
- Cancers, Volume 13, Issue 19, Cancers, Vol 13, Iss 4994, p 4994 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
Abstract
- Simple Summary Cellular and mitochondrial metabolism can be dysregulated during tumorigenesis. miR-27a plays a central role in redirecting cell metabolism in colorectal cancer. In this study, we searched for new miR-27a targets that could influence mitochondria and identified FOXJ3 a master regulator of mitochondrial biogenesis. We validated FOXJ3 as an miR-27a target in an in vitro cell model system that was genetically modified for miR-27a expression and showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and regulates other members of the pathway. The miR-27a/FOXJ3 axis also influences mitochondrial dynamics, superoxide production, respiration capacity, and membrane potential. A mouse xenograft model confirmed that miR-27a downregulates FOXJ3 in vivo and a survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and the impact on mitochondrial biogenesis. The miR-27a/FOXJ3 axis is a major actor in regulating mitochondrial homeostasis, and its discovery may contribute to therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities. Abstract miR-27a plays a driver role in rewiring tumor cell metabolism. We searched for new miR-27a targets that could affect mitochondria and identified FOXJ3, an apical factor of mitochondrial biogenesis. We analyzed FOXJ3 levels in an in vitro cell model system that was genetically modified for miR-27a expression and validated it as an miR-27a target. We showed that the miR-27a/FOXJ3 axis down-modulates mitochondrial biogenesis and other key members of the pathway, implying multiple levels of control. As assessed by specific markers, the miR-27a/FOXJ3 axis also dysregulates mitochondrial dynamics, resulting in fewer, short, and punctate organelles. Consistently, in high miR-27a-/low FOXJ3-expressing cells, mitochondria are functionally characterized by lower superoxide production, respiration capacity, and membrane potential, as evaluated by OCR assays and confocal microscopy. The analysis of a mouse xenograft model confirmed FOXJ3 as a target and suggested that the miR-27a/FOXJ3 axis affects mitochondrial abundance in vivo. A survey of the TCGA-COADREAD dataset supported the inverse relationship of FOXJ3 with miR-27a and reinforced cellular component organization or biogenesis as the most affected pathway. The miR-27a/FOXJ3 axis acts as a central hub in regulating mitochondrial homeostasis. Its discovery paves the way for new therapeutic strategies aimed at restraining tumor growth by targeting mitochondrial activities.
- Subjects :
- Cancer Research
FOXJ3
Superoxide
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
colorectal cancer
Mitochondrion
Biology
Article
Cell biology
mitochondria
Cellular component organization
chemistry.chemical_compound
Oncology
chemistry
Mitochondrial biogenesis
In vivo
microRNA
Organelle
miRNA
tumor metabolism
Biogenesis
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....fe33fcb1e787bfa9d276928c5d820017
- Full Text :
- https://doi.org/10.3390/cancers13194994