A novel feedback loop between high MALAT-1 and low miR-200c-3p promotes cell migration and invasion in pancreatic ductal adenocarcinoma and is predictive of poor prognosis

作者：Zhuo, Meng; Yuan, Cuncun; Han, Ting; Cui, Jiujie; Jiao, Feng^*; Wang, Liwei^*

来源：BMC Cancer, 2018, 18(1): 1032.

DOI：10.1186/s12885-018-4954-9

• Pancreatic ductal adenocarcinoma
• Metastasis-associated lung adenocarcinoma transcript1
• miR-200c-3p
• ZEB1
• Feedback loop

BackgroundIt was demonstrated that long non-coding RNAs occupied an important position in tumor pathogenesis and progression. We have previously found that the metastasis-associated lung adenocarcinoma transcript1 (MALAT-1) promotes cell proliferation and metastases in pancreatic ductal adenocarcinoma (PDAC). The present study was aimed to discuss the underlying mechanisms.MethodsBioinformatics method was used to identify the miRNA target of MALAT-1. Expressions of relative genes were assessed by quantitative real-time PCR and western blotting, respectively. Sulforhodamine B assay and Transwell assay were employed to detect cell proliferation, migration and invasion, respectively. Moreover, RNA immunoprecipitation was performed to determine whether RNA-induced silencing complex contained MALAT-1 and its potential binding miRNA. Luciferase assays was used to confirm potential binding site.ResultsBioinformatics search predicted that miR-200c-3p was a direct target of MALAT-1. Further, we found a reciprocal suppression between MALAT-1 and miR-200c-3p expression. In terms of mechanisms, high MALAT-1 and low miR-200c-3p may form a novel feedback loop. On the one hand, MALAT-1 functioned as a competing endogenous RNA to suppress miR-200c-3p expression, leading to upregulation of ZEB1 expression. On the other hand, miR-200c-3p inhibited the level of MALAT-1 expression was in a way similar to miRNA-mediated downregulation of target genes. Clinical data further indicated that MALAT-1 and ZEB1 expression was negatively correlated with miR-200c-3p transcript level of PDAC tissues. There was a positive correlation between MALAT-1 and ZEB1 level. MALAT-1 (high)/miR-200c-3p (low) correlated with shorter overall survival of PDAC patients. Multivariate analysis revealed that both MALAT-1 and miR-200c-3p levels were independent prognostic factors.ConclusionOur findings firstly revealed a novel feedback loop between high MALAT-1 and low miR-200c-3p. Targeting the feedback loop between high MALAT-1 and low miR-200c-3p will be a therapeutic strategy for PDAC.

• 出版日期2018-10-23
• 单位复旦大学; 上海交通大学