Positive feedback regulation of lncRNA TPT1‐AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer

• Published in: Cancer science Vol. 113; no. 9; pp. 2986 - 3001
• Main Authors: Cheng, Chundong, Liu, Danxi, Liu, Zonglin, Li, Mengyang, Wang, Yongwei, Sun, Bei, Kong, Rui, Chen, Hua, Wang, Gang, Li, Le, Hu, Jisheng, Li, Yilong, Chen, Hongze, Zhao, Zhongjie, Zhang, Tao, Zhu, Siqiang, Pan, Shangha
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.09.2022; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Binding sites; Biomarkers; Carcinoma, Pancreatic Ductal - genetics; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cloning; Feedback; Gene Expression Regulation, Neoplastic; Humans; Integrin beta3 - genetics; Integrin beta3 - metabolism; ITGB3; Medical prognosis; Mesenchyme; Metastases; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐30a‐5p; Non-coding RNA; Original; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Patients; Plasmids; Prognosis; Proteins; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; STAT3; Stat3 protein; Statistical analysis; Survival analysis; Therapeutic targets; TPT1‐AS1; pancreatic cancer; miR-30a-5p; ITGB3; STAT3; TPT1-AS1
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15388

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1‐AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1‐AS1 for PDAC patients was explored, and the effects of TPT1‐AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1‐AS1 was highly expressed in PDAC, and high TPT1‐AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1‐AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial‐to‐mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1‐AS1 functioned as an endogenous sponge for miR‐30a‐5p, which increased integrin β3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1‐AS1 promoter and affected the expression of TPT1‐AS1, thus forming a positive feedback loop with TPT1‐AS1. Taken together, our results uncovered a reciprocal loop of TPT1‐AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1‐AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients. Functional analyses demonstrated that TPT1‐AS1 could promote pancreatic cancer cell proliferation, invasion, migration, and epithelial‐to‐mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1‐AS1 directly bound to miR‐30a‐5p and served as a ceRNA to upregulate ITGB3 expression. In turn, ITGB3 could increase the expression of TPT1‐AS1 via activating STAT3, thus forming a positive feedback loop. These findings demonstrate TPT1‐AS1 could serve as an oncogene in pancreatic cancer, which might provide potential diagnostic and therapeutic targets for pancreatic cancer patients.