Tumor-Associated Fibroblast-Derived Exosomal circDennd1b Promotes Pituitary Adenoma Progression by Modulating the miR-145-5p/ONECUT2 Axis and Activating the MAPK Pathway
Author:
Jiang Qian12, Lei Zhuowei3, Wang Zihan12ORCID, Wang Quanji12, Zhang Zhuo12, Liu Xiaojin12ORCID, Xing Biao12, Li Sihan12, Guo Xiang12, Liu Yanchao12, Li Xingbo12, Qi Yiwei12, Shu Kai1, Zhang Huaqiu12ORCID, Huang Yimin12, Lei Ting12ORCID
Affiliation:
1. Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue. 1095, Wuhan 430030, China 2. Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan 430030, China 3. Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Jiefang Avenue. 1095, Wuhan 430030, China
Abstract
TAF participated in the progression of various cancers, including PA via the release of soluble factors. Exosomes belonged to extracellular vesicles, which were revealed as a crucial participator in intercellular communication. However, the expression pattern and effect of TAF-derived exosomes remained largely unknown in PA. In the present study, we performed in silico analysis based on public RNA-seq datasets to generate the circRNA/miRNA regulatory network. The qRT-PCR, Western blotting, RNA pull-down, and luciferase assay were performed to investigate the effect of TAF-derived exosomes. TAF-derived exosomal circDennd1b was significantly upregulated in PA and promoted the proliferation, migration, and invasion of PA cells via sponging miR-145-5p in PA cells. In addition, miR-145-5p directly regulated One Cut homeobox 2 (ONECUT2/OC2) expression and inhibited the promoting effect of ONECUT2 on PA. We further demonstrated that ONECUT2 transcriptionally increased fibroblast growth factor receptor 3 (FGFR3) expression, which further activates the mitogen-activated protein kinases (MAPK) pathway, thus promoting PA progression. Moreover, the suppression of TAFs by ABT-263 and ONECUT2 by CSRM617 inhibited the growth of PA. In conclusion, our study illustrated that TAF-derived exosomal circDennd1b affected PA progression via regulating ONECUT2 expression, which provides a potential therapeutic strategy against aggressive PA.
Funder
Natural Science Foundation of China
Subject
Cancer Research,Oncology
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