Cancer associated fibroblasts secreted exosomal miR-1290 contributes to prostate cancer cell growth and metastasis via targeting GSK3β

Abstract

Cancer-associated fibroblasts (CAFs) play crucial roles in mediating tumor growth and metastasis via transferring exosomes to neighboring cells, whereas the mechanisms by which CAFs regulate the tumorgenesis of prostate cancer (PC) remain largely unknown. In this study, CAFs and normal fibroblasts (NFs) were isolated from PC tissues and adjacent normal tissues, respectively. Exosomes (NFs-Exo and CAFs-Exo) were then isolated from the supernatant of NFs and CAFs. Next, the differentially expressed miRNAs (DEMs) between NFs-Exo and CAFs-Exo were identified using RNA-sequencing. Cell viability, migration and invasion were detected with CCK-8 and Transwell assays. Protein expression was measured with western blot. We found that CAFs-Exo remarkably enhanced PC cell migration, invasion, stemness, epithelial-mesenchymal transition (EMT) and metastasis. Significantly, miR-1290 level was upregulated in CAFs-Exo compared to NFs-Exo. In addition, CAFs could transfer exosomes to PC cells, resulting in a marked increase of miR-1290 level in cells. Moreover, exosomal miR-1290 could inhibit GSK3β/β-catenin signaling by binding with the downstream target GSK3β mRNA. Meanwhile, miR-1290 antagomir notably reversed the effects of CAFs-Exo on PC cells through activating GSK3β/β-catenin signaling. Collectively, exosomal miR-1290 from CAFs could promote PC cell growth and metastasis via inhibiting GSK3β/β-catenin signaling, suggesting that miR-1290 may serve as potential therapeutic target for the treatment of PC.

Cancer-associated fibroblasts and its derived exosomes: a new perspective for reshaping the tumor microenvironment

“…In the TME, CDEs containing various miRNAs are internalized by recipient cells. This causes a reduction in mRNA expression as well as various phenotypic changes such as tumor progression, therapy resistance, metastasis, and metabolic reprogramming (Zhang et al 2020a , b , c ; Peng et al 2021a , b ; Qin et al 2019 ; Fang et al 2022 ; Wang et al 2022a , b ). Similarly, hnRNPA1 regulates the packaging of miR-196a into CDEs.…”

“…Exosomes are endosome-derived EVs that contain numerous signaling molecules, especially various non-coding RNAs. These RNAs play an important role in CAF-induced tumor cell stemness (Zhan et al 2021 ; Qu et al 2022 ; Hu et al 2015 ; Lin et al 2019 ; Liu et al 2020 ; (Wang et al 2022a , b ). circHIF1A (Zhan et al 2021 ) and cricN4BP2L2 (Qu et al 2022 ) contained in CDEs also regulate pro-tumor downstream signaling pathways by acting on tumor cells, thereby facilitating therapy resistance and tumor cell stemness.…”

“…Furthermore, the reduction in tumor-suppressive signaling molecules in CDEs indirectly enhances the development of cancer. The expression of miR-34c-5p with its tumor-inhibitory function decreases in CDEs, which indirectly promotes proliferation, invasion, drug resistance, and the maintenance of stem-like phenotype in laryngeal cancer cells (Wang et al 2022a , b ).…”

Perspective Chapter: Clinical Application of Exosome Components

“…As discussed earlier, several circulating RNAs are excellent as potential diagnostic markers of GC. Circulating exosomal miR-1290 has been reported to be upregulated in various malignant cancers, including GC [74], LUAD [75], epithelial ovarian cancer [76], and PCa [77]. Kumata et al observed that the miR-23b in exosomes from the plasma of GC patients was significantly lower than that of the healthy donors [78].…”

Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

“… [ 190 ] miR-1290 Prostate cancer Promote EMT and metastasis via targeting GSK3β expression in cancer cell. [ 197 ] miR-146a-5p Prostate cancer Promote cancer metastasis. Treatment of Dihydrotestosterone (DHT) decrases miR-146a-5p in CAF-derived EVs and attenuate cancer promoting function.…”