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PGC1α suppresses kidney cancer progression by inhibiting collagen-induced SNAIL expression
Hyeyoung Nam1, Anirban Kundu1, Garrett J Brinkley1
1Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Abstract:
The transcriptional events that promote invasive and metastatic phenotypes in renal cell carcinoma (RCC) remain poorly understood. Here we report that the decreased expression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) and the increased expression of several genes encoding collagen family members are associated with RCC tumor progression. PGC1α restoration attenuates invasive phenotypes and suppresses tumor progression in vivo. In contrast, collagens produced by RCC cells promote invasive and migratory phenotypes. PGC1α restoration suppresses the expression of collagens and tumor phenotypes via the induction of miR-29a. Furthermore, decreased collagens via the PGC1α/miR-29a axis suppresses collagen-mediated activation of discoidin domain receptor 1 (DDR1)/ERK signaling. In turn, the suppression of collagen/DDR1 signaling by PGC1α leads to decreased levels of the known EMT regulators SNAIL1 and 2. Collectively, our results demonstrate a novel role for PGC1α in the regulation of proinvasive SNAIL proteins.
Insights
Decreased peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) promotes renal cell carcinoma (RCC) invasion. Restoring PGC1α suppresses tumor progression by downregulating collagens and SNAIL proteins via miR-29a.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The molecular mechanisms driving renal cell carcinoma (RCC) invasion and metastasis are not fully elucidated.
- Understanding transcriptional regulation is key to identifying therapeutic targets for RCC progression.
Purpose of the Study:
- To investigate the role of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α) in RCC progression.
- To identify key molecular pathways and regulators involved in RCC invasiveness.
Main Methods:
- Analysis of PGC1α and collagen expression in RCC.
- In vivo studies to assess the effect of PGC1α restoration on tumor progression.
- Investigation of the miR-29a, discoidin domain receptor 1 (DDR1)/ERK, and SNAIL signaling pathways.
Main Results:
- Decreased PGC1α expression and increased collagen gene expression correlate with RCC tumor progression.
- PGC1α restoration inhibits RCC cell invasion and tumor growth in vivo.
- PGC1α suppresses collagen expression and tumor phenotypes through miR-29a induction.
- The PGC1α/miR-29a axis inhibits DDR1/ERK signaling, leading to reduced SNAIL1/2 levels.
Conclusions:
- PGC1α plays a critical role in suppressing RCC invasion and metastasis.
- The PGC1α/miR-29a pathway regulates collagen production and downstream signaling, impacting EMT regulators.
- This study reveals a novel mechanism by which PGC1α controls proinvasive SNAIL proteins in RCC.
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