Fibroblast-derived exosomal microRNA regulates NKX3-1 expression in androgen-sensitive, androgen receptor-dependent prostate cancer cells.
Humans
Male
Androgen Antagonists
Androgens
Cell Line, Tumor
Fibroblasts
/ metabolism
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
/ genetics
MicroRNAs
/ genetics
Prostatic Neoplasms
/ genetics
Receptors, Androgen
/ metabolism
RNA, Messenger
/ genetics
Transcription Factors
/ genetics
Tumor Microenvironment
Exosomes
/ genetics
NKX3-1
cancer cell differentiation
exosomal microRNA
fibroblast
prostate cancer
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
25
05
2023
received:
02
03
2023
accepted:
05
06
2023
medline:
23
8
2023
pubmed:
19
6
2023
entrez:
19
6
2023
Statut:
ppublish
Résumé
Androgen deprivation therapy (ADT) targeting androgen production and androgen receptor (AR) signaling is the primary antihormonal therapy in the treatment of advanced prostate cancer (PCa). However, no clinically established molecular biomarkers have been identified to predict the effectiveness of ADT before starting ADT. The tumor microenvironment of PCa contains fibroblasts that regulate PCa progression by producing multiple soluble factors. We have previously reported that AR-activating factor-secreted fibroblasts increase the responsiveness of androgen-sensitive, AR-dependent PCa cells to ADT. Thus, we hypothesized that fibroblast-derived soluble factors may affect cancer cell differentiation by regulating cancer-related gene expression in PCa cells and that the biochemical characteristics of fibroblasts may be used to predict the effectiveness of ADT. Here, we investigated the effects of normal fibroblasts (PrSC cells) and three PCa patient-derived fibroblast lines (pcPrF-M5, -M28, and -M31 cells) on the expression of cancer-related genes in androgen-sensitive, AR-dependent human PCa cells (LNCaP cells) and three sublines showing different androgen sensitivities and AR dependencies. The mRNA expression of the tumor suppressor gene NKX3-1 in LNCaP cells and E9 cells (which show low androgen sensitivity and AR dependency) was significantly increased by treatment with conditioned media from PrSC and pcPrF-M5 cells but not from pcPrF-M28 and pcPrF-M31 cells. Notably, no upregulation of NKX3-1 was observed in F10 cells (AR-V7-expressing, AR-independent cells with low androgen sensitivity) and AIDL cells (androgen-insensitive, AR-independent cells). Among 81 common fibroblast-derived exosomal microRNAs that showed 0.5-fold lower expression in pcPrF-M28 and pcPrF-M31 cells than in PrSC and pcPrF-M5 cells, miR-449c-3p and miR-3121-3p were found to target NKX3-1. In only LNCaP cells, the NKX3-1 mRNA expression was significantly increased by transfection of an miR-3121-3p mimic but not that of the miR-449c-3p mimic. Thus, fibroblast-derived exosomal miR-3121-3p may be involved in preventing the oncogenic dedifferentiation of PCa cells by targeting NKX3-1 in androgen-sensitive, AR-dependent PCa cells.
Substances chimiques
Androgen Antagonists
0
Androgens
0
Homeodomain Proteins
0
MicroRNAs
0
NKX3-1 protein, human
0
Receptors, Androgen
0
RNA, Messenger
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1135-1144Informations de copyright
© 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
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