miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

Orso, Francesca; Quirico, Lorena; Virga, Federico; Penna, Elisa; Dettori, Daniela; Cimino, Daniela; Coppo, Roberto; Grassi, Elena; Elia, Angela Rita; Brusa, Davide; Deaglio, Silvia; Brizzi, Maria Felice; Stadler, Michael; Provero, Paolo; Caselle, Michele; Taverna, Daniela

doi:10.1158/0008-5472.can-15-1322

Cited by 64 publications

(75 citation statements)

References 48 publications

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“…Interestingly, HIF-1α, but not HIF-2α, was also required for the hypoxia-induced expression of ITGB1 (the obligate partner of ITGA1). The findings suggest that integrin inhibitors, which are being tested in clinical trials (28,60), may hold promise for patients with hypoxic tumors and patients with increased levels of ITGA5 due to oncogene activation by ERBB2 (61), c-Myc (62), or by miRNA regulation (63). ATN-161 (Ac-PHSCN-NH2), a peptide that binds to α5β1 and αvβ3, was shown to block breast cancer growth and bone colonization after intracardiac injection of MDA-MB-231 cells (64).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis

Godet

et al. 2017

Molecular Cancer Research

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Metastasis is the leading cause of breast cancer (BCa) mortality. Previous studies have implicated hypoxia-induced changes in the composition and stiffness of the extracellular matrix (ECM) in the metastatic process. Therefore, the contribution of potential ECM binding receptors in this process was explored. Using a bioinformatics approach the expression of all integrin receptor subunits, in two independent BCa patient data sets, were analyzed to determine if integrin status correlates with a validated hypoxiainducible gene signature. Subsequently, a large panel of breast cancer cell lines were used to validate that hypoxia induces the expression of integrin's that bind to collagen (ITGA1, ITGA11, ITGB1) and fibronectin (ITGA5, ITGB1). Hypoxia-inducible factors (HIF-1 and HIF-2) are directly required for ITGA5 induction under hypoxic conditions, which leads to enhanced migration and invasion of single cells within a multicellular 3D tumor spheroid but did not affect migration in a 2D microenvironment. ITGB1 expression requires HIF-1α, but not HIF-2α, for hypoxic induction in breast cancer cells. ITGA5 (α5 subunit) is required for metastasis to lymph nodes and lungs in breast cancer models and high ITGA5 expression in clinical biopsies is associated with an increased risk of mortality. Implications These results reveal that targeting ITGA5 using inhibitors that are currently under consideration in clinical trials may be beneficial for patients with hypoxic tumors.

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Section: Discussionmentioning

confidence: 99%

Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis

Godet

et al. 2017

Molecular Cancer Research

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“…It has been previously reported that miR-148b serves a role in regulating several types of tumors (27)(28)(29). Furthermore, it has been demonstrated that miR-148b expression is reduced in the plasma samples of patients with NSCLC (23).…”

Section: Discussionmentioning

confidence: 98%

MicroRNA‑148b inhibits proliferation and the epithelial‑mesenchymal transition and increases radiosensitivity in non‑small cell lung carcinomas by regulating ROCK1

Luo

Liang

2018

Exp Ther Med

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Abstract. Non-small cell lung cancer (NSCLC) accounts for ~80% of all types of lung cancer, which has the highest morbidity and mortality of all types of cancer worldwide. It is important to identify novel biomarkers and the molecular mechanism of NSCLC to improve current treatments of NSCLC. The present study aimed to investigate the effect of miR-148b expression on the proliferation, epithelial-mesenchymal transition (EMT) and radiosensitivity of NSCLC cells. It was demonstrated that miR-148b expression was significantly decreased in NSCLC tissues and cell lines. A549 cells were then transfected with a miR-148b mimic and a miR-148b inhibitor. Transfection with the miR-148b mimic decreased proliferation whereas transfection with the miR-148b inhibitor increased the proliferation of A549 cells. Additionally, the miR-148b mimic increased E-cadherin expression and decreased N-cadherin and vimentin expression. By contrast, transfection with the miR-148b inhibitor decreased E-cadherin expression and increased N-cadherin and vimentin expression. Irradiation-induced cell death was significantly promoted by the miR-148b mimic but inhibited by the miR-148b inhibitor. The miR-148b mimic significantly decreased the expression of Rho-associated protein kinase 1 (ROCK1) and it was demonstrated that overexpression of ROCK1 significantly inhibited the effects of miR-148b on cell proliferation, the EMT and irradiation-induced cell death. Therefore, the current study revealed that miR-148b inhibited NSCLC cell proliferation and the EMT, and increased the radiosensitivity of NSCLC cells by inhibiting ROCK1 expression. Therefore, miR-148b/ROCK1 signaling may be a novel therapeutic target to inhibit the growth of NSCLC cells and enhance the effects of radiotherapy to treat patients with NSCLC.

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“…Similarly, miR‐214 was reported to act as a tumor suppressor in cervical cancer by suppressing RelA, β‐catenin and STAT3 . However, in breast cancer and melanoma, miR‐214 was shown to inhibit tumor cell dissemination . In gastric cancer tissue (GCT) and GCT‐derived mesenchymal stem cells, from 10 patients, miR‐214 expression was higher compared with noncancerous gastric tissue .…”

Section: Discussionmentioning

confidence: 99%

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Prabhakar

Rodríguez

Jayanthy

et al. 2019

Molecular Carcinogenesis

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Wnt/β‐catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β‐catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β‐catenin signaling is frequently activated in melanoma through oncogenic mutations of β‐catenin and elevated β‐catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β‐catenin expression in melanoma are not fully understood. MicroRNA‐214 is known to function as a tumor suppressor by targeting β‐catenin in several types of cancer cells. Here, we investigated the regulation of β‐catenin by miR‐214 and its role in melanoma. We show that β‐catenin mRNA levels are negatively correlated with miR‐214 in melanoma. However, overexpression of miR‐214 paradoxically increased β‐catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen‐activated protein kinase inhibitors (MAPKi). RNA‐seq analysis revealed that melanoma cells predominantly express a β‐catenin mRNA isoform lacking miR‐214 target site. Using matched miRNA and mRNA‐seq and bioinformatics analysis, we identified novel miR‐214 targets, ankyrin repeat domain 6 (ANKRD6) and C‐terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR‐214 or knockdown of the novel miR‐214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β‐catenin is not regulated by miR‐214 and the functions of miR‐214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β‐catenin signaling.

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miR-214 and miR-148b Targeting Inhibits Dissemination of Melanoma and Breast Cancer

Cited by 64 publications

References 48 publications

Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis

Hypoxia Selectively Enhances Integrin α5β1 Receptor Expression in Breast Cancer to Promote Metastasis

MicroRNA‑148b inhibits proliferation and the epithelial‑mesenchymal transition and increases radiosensitivity in non‑small cell lung carcinomas by regulating ROCK1

Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

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