Dataset Information

MiR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis.

ABSTRACT: MicroRNAs are a novel class of gene regulators that function as oncogenes or tumor suppressors. In our current study, we investigated the role of miR-15a-3p and miR-16-1-3p in the regulation of Twist1 expression and EMT process. Our bioinformatics analysis suggested that on the 3' UTR of Twist1, there are two conserved miRNA recognition sites for miR-15a-3p and miR-16-1-3p respectively. Interestingly, overexpression of miR-15a-3p and miR-16-1-3p significantly suppressed the activity of luciferase reporter containing Twist1-3' UTR, reduced mRNA and protein level of EMT related genes such as TWIST1, N-cadherin, ?-SMA and Fibronectin, and repressed MMP9 and MMP2 activity, as well as cell migration and invasion. Conversely, inhibition of miR-15a-3p and miR-16-1-3p significantly increased TWIST1, N-cadherin, ?-SMA and Fibronectin protein expression. In addition, Twist1 co-transfection significantly ameliorated the loss of cell migration and invasion. Moreover, overexpression of miR-15a-3p and miR-16-1-3p dramatically suppressed the ability of BGC823 cells to form colonies in vitro and develop tumors in vivo in nude mice. Finally, qPCR and Western blot analysis showed that miR-15a-3p and miR-16-1-3p were significantly reduced in clinical gastric cancer tissue, whereas Twist1 mRNA and protein were significantly up-regulated, suggesting that this aberrant down-regulation of miR-15a-3p and miR-16-1-3p might be associated with the abnormal regulation of Twist1 and the EMT process in gastric cancer development. Our results help to elucidate a novel and important mechanism for the regulation of Twist1 in the development of cancer.

SUBMITTER: Wang T

PROVIDER: S-EPMC5264267 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis.

Wang Tao T Hou Jingjing J Li Zengpeng Z Zheng Zihan Z Wei Jie J Song Dan D Hu Tao T Wu Qiao Q Yang James Y JY Cai Jian-Chun JC

International journal of biological sciences 20170115 1

MicroRNAs are a novel class of gene regulators that function as oncogenes or tumor suppressors. In our current study, we investigated the role of miR-15a-3p and miR-16-1-3p in the regulation of <i>Twist1</i> expression and EMT process. Our bioinformatics analysis suggested that on the 3' UTR of <i>Twist1</i>, there are two conserved miRNA recognition sites for miR-15a-3p and miR-16-1-3p respectively. Interestingly, overexpression of miR-15a-3p and miR-16-1-3p significantly suppressed the activit ...[more]

PMID: 28123352

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Project description:MicroRNAs are small non-coding RNAs that have emerged as post-transcriptional regulators involved in development and function of different types of immune cells, and aberrant miRNA expression has often been linked to cancer. One prominent miRNA family in the latter setting is the miR-15 family, consisting of the three clusters miR-15a/16-1, miR-15b/16-2 and miR-497/195, which is best known for its prominent tumor suppressive role in chronic lymphocytic leukemia (CLL). However, little is known about the physiological role of the miR-15 family. In this study, we provide a comprehensive in vivo analysis of the physiological functions of miR-15a/16-1 and miR-15b/16-2, both of which are highly expressed in immune cells, in early B cell development. In particular, we report a previously unrecognized physiological function of the miR-15 family in restraining progenitor B cell expansion, as loss of both clusters induces an increase of the pro-B as well as pre-B cell compartments. Mechanistically, we find that the miR-15 family mediates its function through repression of at least two different types of target genes: First, we confirm that the miR-15 family suppresses several prominent cell cycle regulators such as Ccne1, Ccnd3 and Cdc25a also in vivo, thereby limiting the proliferation of progenitor B cells. Second, this is complemented by direct repression of the Il7r gene, which encodes the alpha chain of the IL-7 receptor (IL7R), one of the most critical growth factor receptors for early B cell development. In consequence, deletion of the miR-15a/16-1 and miR-15b/16-2 clusters stabilizes Il7r transcripts, resulting in enhanced IL7R surface expression. Consistently, our data show an increased activation of PI3K/AKT, a key signaling pathway downstream of the IL7R, which likely drives the progenitor B cell expansion we describe here. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu that manifests in an enlarged progenitor B cell pool.

Dataset Information

MiR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis.

Publications

miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis.

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