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Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer.

ABSTRACT: Although there are reports of miR-125b being dysregulated in colorectal cancer (CRC) and associated with CRC progression, little is known about its intrinsic regulatory mechanisms. Here we detected the expression of miR-125b in CRC tissues, subsequently investigated the effect of miR-125b on the proliferation, apoptosis, cell cycle and metastasis on CRC cells. Our results showed that the expression of miR-125b was significantly decreased in CRC tissues comparing to adjacent tissues. However, with the stimulation of Granulocyte colony-stimulating factor (G-CSF), which was highly expressed in CRC tissues, the expression of miR-125b could be improved. Analysis of patient samples revealed that miR-125b presented a clear association with poor differentiation, positive lymph node metastasis, and advanced TNM stage. Overexpression of miR-125b inhibited cell proliferation, triggered G2/M cell cycle arrest, induced subsequent apoptosis, and promoted cell migration and invasion. Moreover, luciferase reporter assays and western blot clarified that the myeloid cell leukemia 1 (MCL1) was a direct target of miR-125b. Thus overexpression of MCL1 attenuated the pro-metastasis function of miR-125b in CRC cell lines. In addition, the protein expression level of MCL1 was decreased in CRC tissues from patients with positive lymph node metastasis, which had high miR-125b expression. Collectively, our study suggested that miR-125b induced by G-CSF plays a promoting role in the metastasis of CRC by targeting MCL1, which may serve as a novel therapeutic target for CRC metastasis.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5584181 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer.

Zhang Xinghua X Ma Xiao X An Huaying H Xu Changqing C Cao Wenjo W Yuan Wei W Ma Jie J

Oncotarget 20170406 31

Although there are reports of miR-125b being dysregulated in colorectal cancer (CRC) and associated with CRC progression, little is known about its intrinsic regulatory mechanisms. Here we detected the expression of miR-125b in CRC tissues, subsequently investigated the effect of miR-125b on the proliferation, apoptosis, cell cycle and metastasis on CRC cells. Our results showed that the expression of miR-125b was significantly decreased in CRC tissues comparing to adjacent tissues. However, wit ...[more]

PMID: 28881590

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Project description:IntroductionIncreasing evidence indicates that microRNAs (miRNAs) are important players in oncogenesis. Considering the widespread use of aromatase inhibitors (AIs) in endocrine therapy as a first-line treatment for postmenopausal estrogen receptor α-positive breast cancer patients, identifying deregulated expression levels of miRNAs in association with AI resistance is of utmost importance.MethodsTo gain further insight into the molecular mechanisms underlying the AI resistance, we performed miRNA microarray experiments using a new model of acquired resistance to letrozole (Res-Let cells), obtained by long-term exposure of aromatase-overexpressing MCF-7 cells (MCF-7aro cells) to letrozole, and a model of acquired anastrozole resistance (Res-Ana cells). Three miRNAs (miR-125b, miR-205 and miR-424) similarly deregulated in both AI-resistant cell lines were then investigated in terms of their functional role in AI resistance development and breast cancer cell aggressiveness and their clinical relevance using a cohort of 65 primary breast tumor samples.ResultsWe identified the deregulated expression of 33 miRNAs in Res-Let cells and of 18 miRNAs in Res-Ana cells compared with the sensitive MCF-7aro cell line. The top-ranked Kyoto Encyclopedia of Genes and Genomes pathways delineated by both miRNA signatures converged on the AKT/mTOR pathway, which was found to be constitutively activated in both AI-resistant cell lines. We report for the first time, to our knowledge, that ectopic overexpression of either miR-125b or miR-205, or the silencing of miR-424 expression, in the sensitive MCF-7aro cell line was sufficient to confer resistance to letrozole and anastrozole, to target and activate the AKT/mTOR pathway and to increase the formation capacity of stem-like and tumor-initiating cells possessing self-renewing properties. Increasing miR-125b expression levels was also sufficient to confer estrogen-independent growth properties to the sensitive MCF-7aro cell line. We also found that elevated miR-125b expression levels were a novel marker for poor prognosis in breast cancer and that targeting miR-125b in Res-Let cells overcame letrozole resistance.ConclusionThis study highlights that acquisition of specific deregulated miRNAs is a newly discovered alternative mechanism developed by AI-resistant breast cancer cells to achieve constitutive activation of the AKT/mTOR pathway and to develop AI resistance. It also highlights that miR-125b is a new biomarker of poor prognosis and a candidate therapeutic target in AI-resistant breast cancers.

Dataset Information

Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer.

Publications

Upregulation of microRNA-125b by G-CSF promotes metastasis in colorectal cancer.

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