Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

• Authors: Yang Liu, Tianchi Tang, Xiaosheng Yang, Peng Qin, Pusen Wang, Huiping Zhang, Min Bai, Rong Wu, Fan Li
• Journal: Oncogene (Oncogene) Vol. 40 Issue 17 Pg. 3164-3179 (04 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33824474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Long Noncoding
• Glycogen Synthase Kinase 3

Topics

• Carcinoma, Pancreatic Ductal
• Cell Movement
• Epithelial-Mesenchymal Transition
• Exosomes
• Glycogen Synthase Kinase 3
• Humans
• Male
• RNA, Long Noncoding
• Wnt Signaling Pathway