OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway

Lu, Ya‐Ching; Chang, Joseph T.; Liao, Chun‐Ta; Kang, Chung‐Jan; Huang, Shiang‐Fu; Chen, I-How; Huang, Chi‐Che; Huang, Yu‐Chen; Chen, Wen-Ho; Tsai, Chi-Ying; Wang, Hung‐Ming; Yen, Tzu‐Chen; You, Guo-Rung; Cw, Chiang; Cheng, Ann‐Joy

doi:10.1186/1476-4598-13-218

Cited by 83 publications

(85 citation statements)

References 46 publications

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“…Accumulating studies demonstrates that miR-196 plays critical roles in normal development and in the pathogenesis of human diseases such as cancer (He et al, 2011; Lu et al, 2014). Our studies demonstrate that miR-196b-3p is one of the key components of the constitutively activated signaling circuit, where the expression of miR-196b-3p is driven by constitutively activated NF-κB (p65) in CRPC cells.…”

Section: Discussionmentioning

confidence: 99%

A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

et al. 2017

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SUMMARY Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, however, almost all cancer eventually become castration-resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feed-forward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKβ/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration-resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.

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Section: Discussionmentioning

confidence: 99%

A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

et al. 2017

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“…The mechanisms through which miR-196b impacts cancer development are likely influenced by cell function and the local microenvironment. With respect to cancers of the digestive track that includes oral, esophagus, and gastric, miR-196b expression is increased and postulated to promote an invasive phenotype through the NME4-JNK-TIMP1-MMP signaling pathway (34–36). MiR-196b over expression has also been implicated in the development of Mixed Lineage Leukemia through inhibiting cell differentiation and apoptosis, while promoting cell proliferation and survival (37, 38).…”

Section: Discussionmentioning

confidence: 99%

miR-196b Is Epigenetically Silenced during the Premalignant Stage of Lung Carcinogenesis

et al. 2016

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MicroRNA silencing by promoter hypermethylation may represent a mechanism by which lung cancer develops and progresses, but the microRNAs involved during malignant transformation are unknown. We previously established a model of pre-malignant lung cancer wherein we treated human bronchial epithelial cells (HBEC) with low doses of tobacco carcinogens. Here, we demonstrate that next-generation sequencing of carcinogen-transformed HBECs treated with the demethylating agent 5-aza-2′deoxycytidine revealed miR-196b and miR-34c-5p to be epigenetic targets. Bisulfite sequencing confirmed dense promoter hypermethylation indicative of silencing in multiple malignant cell lines and primary tumors. Chromatin immunoprecipitation studies further demonstrated an enrichment in repressive histone marks on the miR-196b promoter during HBEC transformation. Restoration of miR-196b expression by transfecting transformed HBECs with specific mimics led to cell cycle arrest mediated in part through transcriptional regulation of the FOS oncogene, and miR-196b re-expression also significantly reduced the growth of tumor xenografts. Luciferase assays demonstrated that forced expression of miR-196b inhibited the FOS promoter and AP-1 reporter activity. Finally, a case-control study revealed that methylation of miR-196b in sputum was strongly associated with lung cancer (OR = 4.7, p<0.001). Collectively, these studies highlight miR-196b as a tumor suppressor whose silencing early in lung carcinogenesis may provide a selective growth advantage to pre-malignant cells. Targeted delivery of miR-196b could therefore serve as a preventive or therapeutic strategy for the management of lung cancer.

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“…miR-196b was demonstrated to have oncogenic functions in many cancers except ovarian cancer. miR-196b promotes invasiveness in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway (11), and miR196b overexpression in gastric cancer was correlated with poor prognosis (23).…”

Section: Discussionmentioning

confidence: 99%

“…Among the overexpressed miRNAs, miR-19b has a role in oncogenic progression via targeting TP53 (11,21,22). miR551b and miR-3198 were poorly discovered with tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of microRNA-196b Accelerates Invasiveness of Cancer Cells in Recurrent Epithelial Ovarian Cancer Through Regulation of Homeobox A9

Chong

Jeon²,

Han

et al. 2017

CGP

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OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway

Abstract: Background: , which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed.

Cited by 83 publications

References 46 publications

A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

miR-196b Is Epigenetically Silenced during the Premalignant Stage of Lung Carcinogenesis

Overexpression of microRNA-196b Accelerates Invasiveness of Cancer Cells in Recurrent Epithelial Ovarian Cancer Through Regulation of Homeobox A9

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