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MicroRNA-1229 overexpression promotes cell proliferation and tumorigenicity and activates Wnt/?-catenin signaling in breast cancer.

ABSTRACT: Constitutive activation of the Wnt/?-catenin pathway promotes malignant proliferation and it is inversely correlated with the prognosis of patients with breast cancer. However, mutations in key regulators, such as APC, Axin and ?-catenin, contribute to aberrant activation of the Wnt/?-catenin signaling pathway in various cancers, but rarely found in breast cancer, suggesting that other mechanisms might be involved in the activation of Wnt/?-catenin signaling in breast cancer. In the present study, we found that miR-1229 expression was markedly upregulated in breast cancer and associated with poor survival. Overexpressing miR-1229 promoted while inhibiting miR-1229 reduced, proliferation of breast cancer cell proliferation in vitro and tumor growth in vivo. Furthermore, we found that overexpression of miR-1229 activated the Wnt/?-catenin signaling pathway in breast cancer by directly targeting the multiple important negative regulators of Wnt/?-catenin signaling, including adenomatous polyposis coli (APC), glycogen synthase kinase-3? (GSK-3?), and inhibitor of ?-catenin and T cell factor (ICAT). Taken together, our results suggest that miR-1229 plays an important role in promotion breast cancer progression and may represent a novel therapeutic target in breast cancer.

SUBMITTER: Tan Z

PROVIDER: S-EPMC5029685 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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MicroRNA-1229 overexpression promotes cell proliferation and tumorigenicity and activates Wnt/β-catenin signaling in breast cancer.

Tan Zhanyao Z Zheng Haiqing H Liu Xiangxia X Zhang Wenhui W Zhu Jinrong J Wu Geyan G Cao Lixue L Song Junwei J Wu Shu S Song Libing L Li Jun J

Oncotarget 20160401 17

Constitutive activation of the Wnt/β-catenin pathway promotes malignant proliferation and it is inversely correlated with the prognosis of patients with breast cancer. However, mutations in key regulators, such as APC, Axin and β-catenin, contribute to aberrant activation of the Wnt/β-catenin signaling pathway in various cancers, but rarely found in breast cancer, suggesting that other mechanisms might be involved in the activation of Wnt/β-catenin signaling in breast cancer. In the present stud ...[more]

PMID: 26992223

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Project description:BackgroundThe Wnt/β-catenin signaling pathway plays an important role in the development of second heart field (SHF Isl1+) that gives rise to the anterior heart field (AHF) cardiac progenitor cells (CPCs) for the formation of the right ventricle, outflow tract (OFT), and a portion of the inflow tract (IFT). During early cardiogenesis, these AHF CPCs reside within the pharyngeal mesoderm (PM) that provides a microenvironment for them to receive signals that direct their cell fates. Here, N-cadherin, which is weakly expressed by CPCs, plays a significant role by promoting the adhesion of CPCs within the AHF, regulating β-catenin levels in the cytoplasm to maintain high Wnt signaling and cardioproliferation while also preventing the premature differentiation of CPCs. On the contrary, strong expression of N-cadherin observed throughout matured myocardium is associated with downregulation of Wnt signaling due to β-catenin sequestration at the cell membrane, inhibiting cardioproliferation. As such, upregulation of Wnt signaling pathway to enhance cardiac tissue proliferation in mature cardiomyocytes can be explored as an interesting avenue for regenerative treatment to patients who have suffered from myocardial infarction.MethodsTo investigate if Wnt signaling is able to enhance cellular proliferation of matured cardiomyocytes, we treated cardiomyocytes isolated from adult mouse heart and both murine and human ES cell-derived matured cardiomyocytes with N-cadherin antibody or CHIR99021 GSK inhibitor in an attempt to increase levels of cytoplasmic β-catenin. Immunostaining, western blot, and quantitative PCR for cell proliferation markers, cell cycling markers, and Wnt signaling pathway markers were used to quantitate re-activation of cardioproliferation and Wnt signaling.ResultsN-cadherin antibody treatment releases sequestered β-catenin at N-cadherin-based adherens junction, resulting in an increased pool of cytoplasmic β-catenin, similar in effect to CHIR99021 GSK inhibitor treatment. Both treatments therefore upregulate Wnt signaling successfully and result in significant increases in matured cardiomyocyte proliferation.ConclusionAlthough both N-cadherin antibody and CHIR99021 treatment resulted in increased Wnt signaling and cardioproliferation, CHIR99021 was found to be the more effective treatment method for human ES cell-derived cardiomyocytes. Therefore, we propose that CHIR99021 could be a potential therapeutic option for myocardial infarction patients in need of regeneration of cardiac tissue.

Project description:BackgroundNeuro-oncological ventral antigen 1 (NOVA1) is a neuron-specific RNA-binding protein which regulates alternative splicing in the developing nervous system. Recent research has found that NOVA1 plays a significant role in carcinogenesis. In this paper, we examine the role of NOVA1 in non-small cell lung cancer (NSCLC) and its underlying molecular mechanisms.MethodsThe expression of NOVA1 in NSCLC was detected by immunohistochemistry and correlations between NOVA1 expression and clinicopathological factors were analyzed by chi-square tests. Kaplan-Meier survival analysis and the Cox regression model were used to evaluate the predictive effect of prognostic factors. Western blotting, Cell Counting Kit-8, colony formation, apoptosis, migration and invasion assays were used to detect the effects of silencing (si)NOVA1 RNA on Wnt/β-catenin signaling and biological behavior in NSCLC cell lines.ResultsOur study showed that expression of NOVA1 was up-regulated and significantly correlated with poor differentiation (p = 0.020), advanced TNM stage (P = 0.001), T stage (P = 0.001) and lymph node metastasis (P = 0.000) as well as the expression of β-catenin (P = 0.012) in NSCLC. The down-regulation of NSCLC by siRNA significantly inhibited proliferation, migration and invasion and promoted apoptosis in NSCLC cells. Expression of Wnt signaling molecules, including β-catenin, activated β-catenin, cyclin D1, matrix metalloproteinase (MMP)-2 and MMP-7, was also significantly reduced by siNOVA1. The inhibition of Wnt/β-catenin signaling in A549 and H1299 cells by siNOVA1 was reversed after treatment with a β-catenin expression plasmid.ConclusionThe present study suggests that NOVA1 may serve as a potential prognosis biomarker in NSCLC. High NOVA1 expression was associated with poor survival rate. Finally, in vitro experiments verified that NOVA1 promotes NSCLC cell proliferation and invasion by regulating Wnt/β-catenin signaling.

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MicroRNA-1229 overexpression promotes cell proliferation and tumorigenicity and activates Wnt/?-catenin signaling in breast cancer.

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MicroRNA-1229 overexpression promotes cell proliferation and tumorigenicity and activates Wnt/β-catenin signaling in breast cancer.

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