Li Fugui, Wang Miaomiao, Li Xun, Long Yihao, Chen Kaizhao, Wang Xinjie, Zhong Mingtian, Cheng Weimin, Tian Xuemei, Wang Ping, Ji Mingfang, Ma Xiaodong
Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, 528403 Zhongshan, China.
Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, 510631 Guangzhou, China.
Mol Ther Nucleic Acids. 2022 Jan 19;27:970-982. doi: 10.1016/j.omtn.2022.01.011. eCollection 2022 Mar 8.
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, , to facilitate development of inflammatory-induced PanIN and maintenance of PSC activation and desmoplasia in pancreatic cancer.
活化的胰腺星状细胞（PSC）是参与慢性胰腺炎和胰腺上皮内瘤变病变（PanIN）的主要细胞。微调PSC活化过程中的精确分子靶点可能有助于开发针对PSC的治疗策略，以应对胰腺癌相关纤维化的进展。miR-301a是一种促炎微RNA，已知可被肿瘤基质中的多种炎症因子激活。在此，我们表明miR-301a在小鼠活化的PSC中高度表达，在雨蛙素诱导的慢性胰腺炎中维持组织纤维化，并加速PanIN形成。在患有慢性胰腺炎和PanIN的小鼠模型中，miR-301a的基因敲除减少了胰腺纤维化。通过其两个靶点Tsc1和Gadd45g下调miR-301a可抑制PSC的细胞增殖和活化。此外，miR-301a和Gadd45g在PSC中的异常表达限制了PSC与胰腺癌细胞在肿瘤发生过程中的相互作用。我们的研究结果表明，miR-301a激活了两条主要的细胞增殖途径，即Tsc1/mTOR和Gadd45g/Stat3，以促进炎症诱导的PanIN的发展以及维持胰腺癌中PSC的活化和促结缔组织增生。
