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The miR-27a/FOXJ3 Axis Dysregulates Mitochondrial Homeostasis in Colorectal Cancer Cells.

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.

SUBMITTER: Barisciano G

PROVIDER: S-EPMC8507763 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Lack of association between miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 gene polymorphisms and colorectal cancer.

Project description:Colorectal cancer (CRC) is one of the most common cancers worldwide with high mortality rates. MicroRNAs (miRNAs) have an established role in the development of different cancers. Single nucleotide polymorphisms (SNPs) in miRNA related genes were linked with various gastrointestinal malignancies. However, the data on association between miRNA SNPs and CRC development are inconsistent. The aim of the present study was to evaluate the association between miRNA-related gene polymorphisms (miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608) and the presence of CRC in European population. Gene polymorphisms were analyzed in 621 subjects (controls: n = 428; CRC: n = 193). MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR. Overall, all genotypes and alleles of miRNA SNPs were distributed equally between control and CRC groups. We observed a tendency for miR-146a C allele to be associated with lower risk of CRC when compared to G allele, however, the difference did not reach the adjusted P-value (odds ratio (OR) = 0.68, 95% confidence interval (CI) 0.49-0.95, P = 0.025). In conclusion, gene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of CRC in European subjects.

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miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer.

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| S-EPMC7188668 | biostudies-literature

The association of miR-27a rs895819 polymorphism with colorectal cancer risk in Chinese population.

Project description:BackgroundBesides environment and living habits, such as a sedentary lifestyle, smoking and drinking, genetic variation also plays an important role in the development of colorectal cancer (CRC). This study was aimed to investigate the role of miR-27a rs895819 polymorphism on CRC risk in Chinese population.MethodsIn a case-control study including 208 CRC and 312 age- and gender-matched healthy control subjects, the rs895819 polymorphism was genotyped using the TaqMan allelic discrimination assay. Furthermore, a pooled analysis based on eligible studies was performed by using the STATA software.ResultsLogistic regression analysis showed that the rs895819 polymorphism was not associated with CRC risk. However, a pooled analysis based on five studies from Chinese population showed a statistically significant association between the rs895819 polymorphism and CRC risk (GG vs AA: OR = 1.56, 95% CI = 1.27-1.92, Pz < .01; (AG + GG) vs AA: OR = 1.14, 95% CI = 1.01-1.30, Pz = .04; GG vs (AG + AA): OR = 1.54, 95% CI = 1.27-1.88, Pz < .01; G vs A: OR = 1.20, 95% CI = 1.09-1.33, Pz < .01).ConclusionOur study suggests that miR-27a rs895819 polymorphism plays an important role in CRC risk in Chinese population and may serve as a valuable biomarker for predicting an individual's susceptibility to CRC.

| S-EPMC7676186 | biostudies-literature

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