Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression

Abstract

Background: A significant desmoplastic response, particularly in the fibroblasts, is a characteristic of pancreatic ductal adenocarcinoma (PDAC). Increasing evidence has shown that cancer-associated fibroblasts (CAFs) assist tumor development, invasion, and metastasis in PDAC. However, CAFs-derived molecular determinants that regulate the molecular mechanisms of PDAC have not been fully characterized. Methods:The expression of microRNA 125b-5p (miR-125b-5p) in Pancreas Cancer (PC) tissue and para-cancerous normal tissue was examined using Polymerase Chain Reaction (PCR). Cell counting kit-8 (CCK8), wound healing, and transwell experiments were utilized to assess the effect of miR-125b-5p. Using a cell luciferase activity test and bioinformatics, it was demonstrated that miR-125b-5p may bind to the 3'-untranslated region (3'-UTR) of the adenomatous polyposis coli (APC), thereby limiting the progression of pancreatic cancer.Results: PDAC cells are prompted to proliferate, undergo the epithelial-mesenchymal transition (EMT), and spread. Importantly, CAFs release exosomes into PDAC cells, which significantly increase the level of miR-125b-5p in those cells. Meanwhile, pancreatic cancer cell lines and PDAC tissues have considerably higher miR-125b-5p expression. MiR-125b-5p's elevated expression mechanically suppresses the expression of APC and accelerates the spread of pancreatic cancer.Conclusions: Exosomes released by CAFs promote PDAC growth, invasion, and metastasis. Exosomal miR-125b-5p inhibition offers an alternate strategy for combating the basic malady of PDAC.

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

“…Experimental studies have demonstrated that reducing the levels of miR-421 leads to a decrease in tumor growth that was initially stimulated by CAF-derived exosomes. Further emphasizing the role of CAFs in cancer progression, exosomal miR-125b-5p facilitates pancreatic cancer cell growth, migration, and invasion by suppressing the expression of the adenomatous polyposis coli (APC) gene, a known tumor suppressor [ 29 ]. This suppression leads to the activation of the Wnt signaling pathway.…”

Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-β pathway

“…Cancer-associated fibroblasts (CAFs) are the main cell type in the tumor stroma which play pivotal roles in ECM remodeling ( 14 - 17 ). Various bioactive molecules derived from CAFs such as growth factors, cytokines, and ECM-modifying enzymes, remodel the ECM environment, which not only provides mechanical support for tumor cells but also promotes tumor cell proliferation, metastasis, and drug resistance ( 15 , 17 - 19 ). However, the molecular mechanisms by which cancer cells influence pro-metastatic matrix remodeling are still not fully understood.…”