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MiR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

ABSTRACT: In clear cell renal cell carcinoma (ccRCC), dysregulated lipid metabolism plays a pivotal role in tumor initiation and progression. This study delves into the unexplored landscape of Dysregulated Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) in ccRCC. Using a combination of "fatty acid metabolism" dataset analysis and differentially expressed genes (DEGs) derived from Gene Expression Omnibus (GEO) database, potential metabolic regulators in ccRCC were identified. Subsequent investigations utilizing public databases, clinical samples, and in vitro experiments revealed that ALDH3A2 was down-regulated in ccRCC, mediated by miR-1182, highlighting its role as an independent prognostic factor for patient survival. Functionally, ALDH3A2 exhibited tumor-suppressive properties, impacting ccRCC cell phenotypes and influencing epithelial-mesenchymal transition. Mechanistically, silencing ALDH3A2 promoted lipid accumulation in ccRCC cells by activating the PI3K-AKT pathway, thereby promoting tumor progression. These findings shed light on the critical role of the miR-1182/ALDH3A2 axis in ccRCC tumorigenesis, emphasizing the potential for targeting lipid metabolism as a promising anti-cancer strategy.

SUBMITTER: Lv Q

PROVIDER: S-EPMC10730858 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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miR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

Lv Qingyang Q Shi Jian J Miao Daojia D Tan Diaoyi D Zhao Chuanyi C Xiong Zhiyong Z Zhang Xiaoping X

Translational oncology 20231130

In clear cell renal cell carcinoma (ccRCC), dysregulated lipid metabolism plays a pivotal role in tumor initiation and progression. This study delves into the unexplored landscape of Dysregulated Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) in ccRCC. Using a combination of "fatty acid metabolism" dataset analysis and differentially expressed genes (DEGs) derived from Gene Expression Omnibus (GEO) database, potential metabolic regulators in ccRCC were identified. Subsequent investigations ...[more]

PMID: 38039946

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Project description:BackgroundBone metastasis is a leading cause of morbidity and mortality in advanced prostate cancer (PCa). Downexpression of miR-133a-3p has been found to contribute to the progression, recurrence and distant metastasis in PCa. However, clinical significance of miR-133a-3p in bone metastasis of PCa, and the biological role of miR-133a-3p and its molecular mechanisms underlying bone metastasis of PCa remain unclear.MethodsmiR-133a-3p expression was evaluated in 245 clinical PCa tissues by real-time PCR. Statistical analysis was performed to evaluate the clinical correlation between miR-133a-3p expression and clinicopathological features, and overall and bone metastasis-free survival in PCa patients. The biological roles of miR-133a-3p in the bone metastasis of PCa were investigated both in vitro and in vivo. Bioinformatics analysis, real-time PCR, western blot and luciferase reporter analysis were applied to demonstrate the relationship between miR-133a-3p and its potential targets. Western blotting and luciferase assays were examined to identify the underlying pathway involved in the anti-tumor role of miR-133a-3p. Clinical correlation of miR-133a-3p with its targets was verified in human PCa tissues.ResultsmiR-133a-3p expression is reduced in PCa tissues compared with the adjacent normal tissues and benign prostate lesion tissues, particularly in bone metastatic PCa tissues. Low expression of miR-133a-3p is significantly correlated with advanced clinicopathological characteristics and shorter bone metastasis-free survival in PCa patients by statistical analysis. Moreover, upregulating miR-133a-3p inhibits cancer stem cell-like phenotypes in vitro and in vivo, as well as attenuates anoikis resistance in vitro in PCa cells. Importantly, administration of agomir-133a-3p greatly suppresses the incidence of PCa bone metastasis in vivo. Our results further demonstrate that miR-133a-3p suppresses bone metastasis of PCa via inhibiting PI3K/AKT signaling by directly targeting multiple cytokine receptors, including EGFR, FGFR1, IGF1R and MET. The negative clinical correlation of miR-133a-3p with EGFR, FGFR1, IGF1R, MET and PI3K/AKT signaling activity is determined in clinical PCa tissues.ConclusionOur results unveil a novel mechanism by which miR-133a-3p inhibits bone metastasis of PCa, providing the evidence that miR-133a-3p may serve as a potential bone metastasis marker in PCa, and delivery of agomir-133a-3p may be an effective anti-bone metastasis therapeutic strategy in PCa.

Dataset Information

MiR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

Publications

miR-1182-mediated ALDH3A2 inhibition affects lipid metabolism and progression in ccRCC by activating the PI3K-AKT pathway.

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