Exosomal miR‐199a‐3p Secreted From Cancer‐Associated Adipocytes Promotes Pancreatic Cancer Progression

• Published in: Cancer medicine (Malden, MA) MA), 2024-10, Vol.13 (20), p.e70265-n/a
• Main Authors: Noda, Kazuyoshi, Sato, Yasushi, Okada, Yasuyuki, Nishida, Kensei, Kawano, Yutaka, Tanahashi, Toshihito, Bando, Masahiro, Okamoto, Koichi, Takehara, Masanori, Sogabe, Masahiro, Miyamoto, Hiroshi, Daizumoto, Kei, Kanayama, Hiroomi, Takayama, Tetsuji
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adipocytes; Adipocytes - metabolism; Adipocytes - pathology; biomarker; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biopsy; Body fat; Cancer therapies; cancer‐associated adipocytes; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation; Chemotherapy; Disease Progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Exosomes; Exosomes - genetics; Exosomes - metabolism; Extracellular vesicles; Female; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic; Genotype & phenotype; Humans; Lipids; Male; Medical prognosis; Metabolism; MicroRNAs; MicroRNAs - genetics; miRNA; miR‐199a‐3p; Molecular modelling; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phosphorylation; Prognosis; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Therapeutic targets; Transfection; Western blotting
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.70265

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer‐associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression. Methods CAAs were generated by co‐culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA‐conditioned medium (CAA‐CM). Small RNA‐seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real‐time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC. Results miR‐199a‐3p expression was significantly increased in CAA‐CM‐derived exosomes. CAA‐derived exosomes transferred miR‐199a‐3p to pancreatic cancer cells. Transfection with miR‐199a‐3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR‐199a‐3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR‐199a‐3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR‐199a is an independent prognostic factor for PDAC. Conclusion miR‐199a‐3p in CAA‐derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC. miR‐199a‐3p in CAA‐derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.