CircRTN4 promotes pancreatic cancer progression through a novel CircRNA-miRNA-lncRNA pathway and stabilizing epithelial-mesenchymal transition protein

• Published in: Molecular cancer 2022-01, Vol.21 (1), p.10-10, Article 10
• Main Authors: Wong, Chi Hin, Lou, Ut Kei, Fung, Frederic Khe-Cheong, Tong, Joanna H M, Zhang, Chang-Hua, To, Ka-Fai, Chan, Stephen Lam, Chen, Yangchao
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adult; Aged; Analysis; Animal models; Animals; Binding sites; Bioinformatics; Biomarkers, Tumor; Cadherins; Cancer; Cell Line, Tumor; circRTN4; Cloning; Development and progression; Disease Models, Animal; Epithelial-mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic; HOTTIP; Humans; Liver; Liver cancer; Male; Mass spectrometry; Mass spectroscopy; Medical prognosis; Mesenchyme; Metastases; Metastasis; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; MiRNAs; Molecular modelling; N-Cadherin; Neoplasm Grading; Neoplasm Staging; Nogo Proteins - genetics; Non-coding RNA; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - etiology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Plasmids; Proteins; RNA Interference; RNA, Circular; RNA, Long Noncoding - genetics; Snail protein; Statistical analysis; Stem cells; Tumor suppressor genes; Tumors; Ubiquitin; Ubiquitination
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01481-w

Circular RNAs (circRNAs) play important roles in many biological processes. However, the detailed mechanism underlying the critical roles of circRNAs in cancer remains largely unexplored. We aim to explore the molecular mechanisms of circRTN4 with critical roles in pancreatic ductal adenocarcinoma (PDAC). CircRTN4 expression level was examined in PDAC primary tumors. The oncogenic roles of circRTN4 in PDAC tumor growth and metastasis were studied in mouse tumor models. Bioinformatics analysis, luciferase assay and miRNA pulldown assay were performed to study the novel circRTN4-miRNA-lncRNA pathway. To identify circRTN4-interacting proteins, we performed circRNA-pulldown and mass spectrometry in PDAC cells. Protein stability assay and 3-Dimensional structure modeling were performed to reveal the role of circRTN4 in stabilizing RAB11FIP1. CircRTN4 was significantly upregulated in primary tumors from PDAC patients. In vitro and in vivo functional studies revealed that circRTN4 promoted PDAC tumor growth and liver metastasis. Mechanistically, circRTN4 interacted with tumor suppressor miR-497-5p in PDAC cells. CircRTN4 knockdown upregulated miR-497-5p to inhibit the oncogenic lncRNA HOTTIP expression. Furthermore, we identified critical circRTN4-intercting proteins by circRNA-pulldown in PDAC cells. CircRTN4 interacted with important epithelial-mesenchymal transition (EMT)- driver RAB11FIP1 to block its ubiquitination site. We found that circRTN4 knockdown promoted the degradation of RAB11FIP1 by increasing its ubiquitination. Also, circRTN4 knockdown inhibited the expression of RAB11FIP1-regulating EMT-markers Slug, Snai1, Twist, Zeb1 and N-cadherin in PDAC. The upregulated circRTN4 promotes tumor growth and liver metastasis in PDAC through the novel circRTN4-miR-497-5p-HOTTIP pathway. Also, circRTN4 stabilizes RAB11FIP1 to contribute EMT.