Abstract
ObjectiveTo explore the possible misexpression of the microRNA miR-196b in colorectal cancer (CRC) and its role in controlling the expression of GATA6, a putative target gene crucial to intestinal cell homeostasis and tumorigenesis.DesignThe expression of miR-196b was analysed by qRT-PCR in surgical resection samples from a cohort of sporadic colon cancer patients. Manipulations of miR-196b expression were performed to demonstrate its inhibition of GATA6 protein levels.ResultsWe found that miR-196b is significantly upregulated in pre-treatment surgical resection samples from a cohort of sporadic colon cancer patients. The upregulation of miR-196b correlates with less severe clinicopathological characteristics, such as early tumor stage and absence of lymph node metastases. We show that in CRC cells, miR-196b targets the mRNA of GATA6, a transcription factor involved in the homeostasis and differentiation of intestinal epithelial cells, and a positive regulator of the Wnt/β-catenin pathway. We moreover found that the increase of miR-196b correlates with a reduced GATA6 protein expression in colon cancer patients.ConclusionOur results establish miR-196b as a post-transcriptional inhibitor of GATA6 in CRC cells, implicating miR-196b function in gene regulatory pathways crucial to intestinal cell homeostasis and tumorigenesis. Our results furthermore suggest a role of miR-196b expression in CRC, as an antagonist of GATA6 function in tumor cells, thus providing the basis for a potential targeting strategy for the treatment of CRC.
Highlights
MicroRNAs are involved in the regulation of a wide array of biological processes, ranging from cell cycle regulation to differentiation and development
We found that miR-196b is significantly upregulated in pre-treatment surgical resection samples from a cohort of sporadic colon cancer patients
We show that in colorectal cancer (CRC) cells, miR-196b targets the mRNA of GATA6, a transcription factor involved in the homeostasis and differentiation of intestinal epithelial cells, and a positive regulator of the Wnt/β-catenin pathway
Summary
MicroRNAs (miRNAs) are involved in the regulation of a wide array of biological processes, ranging from cell cycle regulation to differentiation and development. MiRNAs are small non-coding RNAs of ~20-24 nucleotides (nt) in length, which negatively control gene expression at the posttranscriptional level They derive from larger primary miRNAs (pri-miRNAs), in many cases non-coding, which are processed by endonucleases to nuclear precursors (premiRNAs), and eventually to their mature cytoplasmic form. Www.impactjournals.com/oncotarget miR-196 family members have been reported to participate in relevant biological processes, such as embryonic development (reviewed in 4) and tumorigenesis, where they have been found to be aberrantly expressed in various malignancies, including glioblastoma, colorectal cancer, melanoma, and leukemia (reviewed in 5). We reported that the evolutionarily conserved genomic region upstream to the pri-miR-196b transcriptional start site (TSS) contains several binding sites for Cdx and 5'Hox transcription factors, that these sites are bound in vivo by Cdx, and that Cdx is necessary for the expression of miR-196 in human embryonal carcinoma (EC) cells, establishing Cdx as a major regulator of miR-196b expression [7]. Evidence has been increasing in the past years that CRC is a heterogeneous disease, whose molecular features decide the response to treatment and the prognosis [16]
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