下调和上调
癌症研究
血管内皮生长因子A
舒尼替尼
医学
血管生成
酪氨酸激酶
活力测定
阿西替尼
小RNA
肾透明细胞癌
肾细胞癌
细胞
生物
内科学
血管内皮生长因子
受体
基因
血管内皮生长因子受体
生物化学
遗传学
作者
Markus Krebs,Mischa J. Kotlyar,Julian Fahl,Sudha Janaki Raman,Florian Roehrig,André Marquardt,Hubert Kübler,Burkhard Kneitz,Almut Schulze,Charis Kalogirou
出处
期刊:Urologia Internationalis
[S. Karger AG]
日期:2023-11-30
摘要
Metformin (MF) intake could be associated with a favorable outcome in Sunitinib (SUT)- and Axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers.qRT-PCR, viability assays and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. HUVEC (Human Umbilical Vein Endothelial Cell) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt re-expressing RCC4 and 786-O cells.Viability assays confirmed a sensitizing effect of MF towards SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression - as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt expressing RCC4, and 786-O cells displayed higher miR-205 and lower VEGFA levels.Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors (TKI).
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