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

Abstract

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 effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR‐421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR‐421 attenuated CAF‐exo induced tumor growth. Exosomal miR‐421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF‐1α axis. This study provided insights into the molecular mechanism of PC.

Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma

“…The current study identified the reduced expression of ENTPD3-AS1 in LUAD patients, who have poor clinical outcomes, supporting that ENTPD3-AS1 could act as a promising prognostic predictor in LUAD. miR-421, which is an oncomir associated with various cancers, including pancreatic cancer, cholangiocarcinoma, and LUAD [22][23][24], is sponged by ENTPD3-AS1. Indeed, the knockdown of ENTPD3-AS1 or miR-421 inhibitors decreased cell proliferation, enhanced cell migration and epithelial phenotype transition in A549 cells, supporting the findings that ENTPD3-AS1 inhibited the oncogenic function of miR-421 in LUAD.…”

The hidden messengers: cancer associated fibroblasts—derived exosomal miRNAs as key regulators of cancer malignancy

“…In HCC, miR-20a-5p has been demonstrated to have a comparable impact ( Qi et al, 2022 ). Other studies about CAF-derived exosomal miRNAs’ role in invasion and migration are shown in Table 1 ( Xu et al, 2019 ; Yang F. et al, 2020 ; Guo et al, 2020 ; Shi et al, 2020 ; Liu et al, 2021 ; Zhou et al, 2022 ; Wu et al, 2023 ).…”

Pancreatic cancer cell- and cancer-associated fibroblast-derived exosomes in disease progression, metastasis, and therapy

“…Studies have revealed that the miRNAs, proteins, and other biomarkers within exosomes derived from CAFs can influence crucial biological processes in pancreatic cancer cells [ 8 – 10 ]. The exosomes in the pancreatic tumor microenvironment contain RNA molecules, including but not limited to miR-10a-5p [ 11 ], miR-21 [ 12 ], miR-22 [ 8 ], miR-106b [ 13 ], miR-125b [ 8 ], miR-331-3p [ 14 ], miR-421 [ 15 ], miR616-3p [ 16 ], miR-1246 [ 17 ], miR-1290 [ 17 ], miR-3173-5p (Acyl-CoA Synthetase long chain family member 4 (ACSL4)-targeting miRNAs) [ 18 ], miR-4456 [ 16 ], miR-5703 [ 19 ], ANXA6/LRP1/TSP1 [ 8 , 20 ], Hyaluronic Acid (HA) [ 21 ], tRF-19-PNR8YPJZ [ 22 ], as well as long non-coding RNA UCA1 [ 23 ] (Table 1 ). They promote the growth and dissemination of pancreatic cancer cells by modulating signaling pathways in the tumor microenvironment, especially those related to tumor proliferation, cell cycle control, and apoptosis.…”