Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Matrix Biol. 2020 Jul;89:43-58. doi: 10.1016/j.matbio.2020.01.001. Epub 2020 Jan 23.
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.
转录事件促进肾细胞癌（RCC）的侵袭和转移表型仍知之甚少。在这里，我们报告过氧化物酶体增殖物激活受体γ、共激活因子 1 阿尔法（PGC1α）的表达下调和编码胶原家族成员的几个基因的表达增加与 RCC 肿瘤进展有关。PGC1α 恢复减弱了侵袭表型，并抑制了体内肿瘤的进展。相比之下，RCC 细胞产生的胶原促进侵袭和迁移表型。PGC1α 通过诱导 miR-29a 恢复抑制胶原基因的表达和肿瘤表型。此外，通过 PGC1α/miR-29a 轴降低胶原抑制了盘状结构域受体 1（DDR1）/ERK 信号的胶原介导的激活。反过来，PGC1α 对胶原/DDR1 信号的抑制导致 EMT 调节剂 SNAIL1 和 2 的水平降低。总之，我们的研究结果表明 PGC1α 在调节促侵袭性 SNAIL 蛋白方面发挥了新的作用。
