Regulation of the transcription factor NF-κB1 by microRNA-9 in human gastric adenocarcinoma

Abstract

BackgroundMicroRNAs (miRNAs) are a new class of naturally occurring, small, non-coding RNAs that regulate protein-coding mRNAs by causing mRNA degradation or repressing translation. The roles of miRNAs in lineage determination and proliferation, as well as the localization of several miRNA genes at sites of translocation breakpoints or deletions, have led to speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state.ResultsWe showed that miR-9 was downregulated in human gastric adenocarcinoma. Overexpression of miR-9 suppressed the growth of human gastric adenocarcinoma cell line MGC803 cell as well as xenograft tumors derived from them in SCID mice. Bioinformatics analysis indicated a putative miR-9 binding site in the 3'-untranslated region (3'UTR) of the tumor-related gene NF-κB1 mRNA. In an EGFP reporter system, overexpression of miR-9 downregulated EGFP intensity, and mutation of the miR-9 binding site abolished the effect of miR-9 on EGFP intensity. Furthermore, both the NF-κB1 mRNA and protein levels were affected by miR-9. Finally, knockdown of NF-κB1 inhibited MGC803 cell growth in a time-dependent manner, while ectopic expression of NF-κB1 could rescue MGC803 cell from growth inhibition caused by miR-9.ConclusionThese findings indicate that miR-9 targets NF-κB1 and regulates gastric cancer cell growth, suggesting that miR-9 shows tumor suppressive activity in human gastric cancer pathogenesis.

Aberrant hypermethylation ofmiR-9genes in gastric cancer

“…Similar findings indicate that miR-9 plays a tumor-suppressive role via repressing tumor-associated genes (NFκB1 and RAB34) in gastric cancer. 29,33 Significantly, in human cancers, miR-9 expression levels or methylation status are associated with several clinicopathological features, such as tumor grade, metastatic status and survival rate. 23,27,31 Contrary to the above results, it has been showed that miR-9 is significantly deregulated in breast cancer or colorectal cancer, with increasing cancer migration, through repression of α-cadherin or E-cadherin expression.…”

“…Dysregulation of miR-9 expression has profound effects on physiology and pathology, including cancer, neuronal differentiation and myocardial hypertrophy. [23][24][25][26][27][28][29][30] Several lines of evidence have indicated that miR-9 can function as a tumor suppressor in various cancers. 23,24,27,29,[31][32][33] In gastric cancer, miR-9 is under-expressed and ectopic expression of miR-9 can influence cell growth and the cell cycle.…”

“…[23][24][25][26][27][28][29][30] Several lines of evidence have indicated that miR-9 can function as a tumor suppressor in various cancers. 23,24,27,29,[31][32][33] In gastric cancer, miR-9 is under-expressed and ectopic expression of miR-9 can influence cell growth and the cell cycle. 24,29,32,33 However, there is no study examining the mechanisms involved in the differential regulation of all three miR-9 gene loci.…”

“…23,24,27,29,[31][32][33] In gastric cancer, miR-9 is under-expressed and ectopic expression of miR-9 can influence cell growth and the cell cycle. 24,29,32,33 However, there is no study examining the mechanisms involved in the differential regulation of all three miR-9 gene loci. In this study, we explore the promoter methylation status of the miR-9-1, miR-9-2 and miR-9-3 gene loci in gastric cancer tissues.…”

MicroRNA‐181b targets cAMP responsive element binding protein 1 in gastric adenocarcinomas

“…For example, miR-375 and miR-142-5p have been identified as classifiers used to recognize recurrence and non-recurrence in gastric cancer; a high frequency recurrence and poor survival were observed in gastric cancer cases with high levels of miR-375 and low levels of miR-142-5p (6). miR-9, which is downregulated in human gastric cancer cells, plays a role in regulating gastric cancer cell growth by targeting NF-jB1 (7).…”