Cancer‐associated fibroblast‐secreted miR ‐421 promotes pancreatic cancer by regulating the SIRT3 / H3K9Ac / HIF ‐1α axis

作者：Bin Zhou, Jinghao Lei, Qiang Wang, Tengfei Qu, Lichao Cha, Hanxiang Zhan, Shanglong Liu, Xiao Hu, Chuandong Sun, Weidong Guo, Fabo Qiu, Jingyu Cao · 发表于：The Kaohsiung Journal of Medical Sciences · 年份：2022 · DOI：10.1002/kjm2.12590 · 被引用次数：30 · 研究领域：Extracellular vesicles in disease、Peptidase Inhibition and Analysis、MicroRNA in disease regulation

This study was designed to explore the effects of exosomal miR-421 secreted by cancer-associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF-derived exos (CAF-exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR-421, sirtuin-3 (SIRT3), and hypoxia duciblefactors-1 alpha (HIF-1α) levels. Cell counting kit-8 (CCK-8), wound-healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual-luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR-421 and SIRT3. Chromatin immunoprecipitation (f)-verified H3K9Ac enrichment in the HIF-1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR-421 from CAFs on PC. CAFs and exos were successfully isolated. CAF-exo-treated PC cells highly expressed miR-421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR-421 increased the expression of SIRT3. SIRT3 is a target of miR-421, and inhibiting the expression of SIRT3 reversed the negative effects of miR-421 knockdown on PC cell. Knocking down miR-421 in CAF-exo inhibited the expression of HIF-1α in PC cells. Moreover, SIRT3-mediated HIF-1α expression by regulating H3K9Ac. HIF-1α overexpression reversed the inhibiting effe...