Inflammatory-miR-301a circuitry drives mTOR and Stat3-dependent PSC activation in chronic pancreatitis and PanIN

• Published in: Molecular therapy. Nucleic acids Vol. 27; pp. 970 - 982
• Main Authors: Li, Fugui, Wang, Miaomiao, Li, Xun, Long, Yihao, Chen, Kaizhao, Wang, Xinjie, Zhong, Mingtian, Cheng, Weimin, Tian, Xuemei, Wang, Ping, Ji, Mingfang, Ma, Xiaodong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: chronic pancreatitis; Gadd45g; miR-301a; Original; pancreatic intraepithelial neoplasia; Tsc1; miR-301a; Tsc1; Gadd45g; chronic pancreatitis; pancreatic intraepithelial neoplasia
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.01.011

Activated pancreatic stellate cells (PSCs) are the main cells involved in chronic pancreatitis and pancreatic intraepithelial neoplasia lesion (PanIN). Fine-tuning the precise molecular targets in PSC activation might help the development of PSC-specific therapeutic strategies to tackle progression of pancreatic cancer-related fibrosis. miR-301a is a pro-inflammatory microRNA known to be activated by multiple inflammatory factors in the tumor stroma. Here, we show that miR-301a is highly expressed in activated PSCs in mice, sustained tissue fibrosis in caerulein-induced chronic pancreatitis, and accelerated PanIN formation. Genetic ablation of miR-301a reduced pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. Cell proliferation and activation of PSCs was inhibited by downregulation of miR-301a via two of its targets, Tsc1 and Gadd45g. Moreover, aberrant PSC expression of miR-301a and Gadd45g restricted the interplay between PSCs and pancreatic cancer cells in tumorigenesis. Our findings suggest that miR-301a activates two major cell proliferation pathways, Tsc1/mTOR and Gadd45g/Stat3, in vivo, to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer. [Display omitted] Activation of pancreatic stellate cells is the key event of pancreatic tissue fibrosis. Here, Fugui Li et al. report that miR-301a deficiency reduces pancreatic fibrosis in mouse models with chronic pancreatitis and PanIN. These findings might lead to the development of feasible therapeutic strategies in pancreatic cancer.