A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

• Published in: Theranostics Vol. 10; no. 22; pp. 10120 - 10140
• Main Authors: Hu, Yuhang, Wang, Fan, Xu, Fengyu, Fang, Kaifeng, Fang, Zhi, Shuai, Xiaoming, Cai, Kailin, Chen, Jinhuang, Hu, Ping, Chen, Ding, Xu, Peng, Hu, Chaojie, Zeng, Zhu, Zhong, Jianxin, Li, Wei, Tang, Jiang, Huang, Mengqi, Zhao, Yong, Wang, Chunyou, Zhao, Gang
• Format: Journal Article
• Language: English
• Published: Wyoming Ivyspring International Publisher Pty Ltd 01.01.2020; Ivyspring International Publisher
• Subjects: Acidification; Acidosis; Acids; Antibodies; Cell cycle; Colorectal cancer; Investigations; Kinases; Metabolism; Metastasis; Pancreatic cancer; Proteins; Research Paper; Transcription factors; United States > US; China
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.49147

Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.