Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4

Li, Liang; Tang, Jing; Zhang, Baohua; Yang, Wen; Liu-Gao, Miyang; Wang, Ruoyu; Tan, Ye-Xiong; Fan, Jianling; Chang, Yan–Xin; Fu, Jing; Jiang, Feng; Chen, Cai–Yang; Yang, Yuting; Gu, Jin; Wu, Dingming; Guo, Linna; Cao, Dan; Li, Hengyu; Cao, Guangwen; Wu, Mengchao; Zhang, Michael Q.; Chen, Lei; Wang, Hongyang

doi:10.1136/gutjnl-2013-305715

Cited by 123 publications

(101 citation statements)

References 41 publications

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“…Accumulating evidence supports the involvement of some miRNAs in the regulation of CSC function (30,31); in particular, reduced let-7 expression was associated with tumorinitiating cells after the initiation of chemotherapy in breast cancer, and is thought to result in the maintenance of their undifferentiated status and proliferative potential (32). Similarly, miR-429 contributes to hepatocyte self-renewal, malignant proliferation, tumorigenicity, and chemoresistance, making it an attractive potential target to inactivate tumor-initiating cells in the liver (33). We show that miR-644a functions as an upstream activator of the Wnt/b-catenin pathway in ESCC, a pathway well characterized in the development of stem cell-like properties in a wide variety of cancer types, including ESCC (25,26).…”

Section: Discussionmentioning

confidence: 97%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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Purpose: We previously reported the oncogenic role of pairedlike homeodomain 2 (PITX2) in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify the miRNA regulators of PITX2 and the mechanism underlying the pathogenesis of ESCC.Experimental Design: Using miRNA profiling and bioinformatics analyses, we identified miR-644a as a negative mediator of PITX2 in ESCC. A series of in vivo and in vitro assays were performed to confirm the effect of miR-644a on PITX2-mediated ESCC malignancy.Results: ESCC cells and tissues expressed less miR-644a than normal epithelial controls. In patient samples, lower expression of miR-644a in ESCC tissues was significantly correlated with tumor recurrence and/or metastasis, such that miR-644a, PITX2, and the combination of the two were independent prognostic indicators for ESCC patient's survival (P < 0.05). Gain-and lossof-function studies demonstrated that miR-644a inhibited ESCC cell growth, migration, and invasion in vitro and suppressed tumor growth and metastasis in vivo. In addition, miR-644a dramatically suppressed self-renewal and stem cell-like traits in ESCC cells. Furthermore, the effect of upregulation of miR-644a was similar to that of PITX2 knockdown in ESCC cells. Mechanistic studies revealed that miR-644a attenuates ESCC cells' malignancy and stem cell-associated phenotype, at least partially, by inactivation of the Akt/GSK-3b/b-catenin signaling pathway through PITX2. Furthermore, promoter hypermethylation caused downregulation of miR-644a in ESCC.Conclusions: Downregulation of miR-644a plays an important role in promoting both aggressiveness and stem-like traits of ESCC cells, suggesting that miR-644a may be useful as a novel prognostic biomarker or therapeutic target for the disease. Clin Cancer Res; 23(1); 298-310. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 97%

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Zhang

Chen

et al. 2017

Clinical Cancer Research

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“…Intriguingly, miR-429 secreted by high-expressing liver T-ICs has the potential of turning into a proactive signaling molecule to mediate intercellular communication through microvesicle (MV)-mediated intercellular exchange, and providing a permissive niche for malignant transformation of surrounding normal hepatocytes. Moreover, secreted miR-429 can be absorbed into circulation and developed as a noninvasive diagnostic biomarker for HCC [67].…”

Section: Microenvironment Discrepanciesmentioning

confidence: 99%

Heterogeneity of liver cancer and personalized therapy

2016

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“…Azumi et al [61] found that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. MiR-429 [62] promotes liver tumour-initiating cell properties by targeting Rb binding protein 4, and the ectopic expression of miR-484 [63] initiates tumourigenesis and cell malignant transformation through the synergistic activation of the transforming growth factor-β/Gli and nuclear factor-κB/type I IFN pathways to enhance chemotherapeutic resistance and increase tumorigenicity.…”

Section: Epigenetic Regulation Involved In Drug Resistancementioning

confidence: 99%

New knowledge of the mechanisms of sorafenib resistance in liver cancer

et al. 2017

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Sorafenib is an oral multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis and promotes tumor cell apoptosis. It was approved by the FDA for the treatment of advanced renal cell carcinoma in 2006, and as a unique target drug for advanced hepatocellular carcinoma (HCC) in 2007. Sorafenib can significantly extend the median survival time of patients but only by 3-5 months. Moreover, it is associated with serious adverse side effects, and drug resistance often develops. Therefore, it is of great importance to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with these problems. Recent studies have revealed that in addition to the primary resistance, several mechanisms are underlying the acquired resistance to sorafenib, such as crosstalk involving PI3K/Akt and JAK-STAT pathways, the activation of hypoxia-inducible pathways, and epithelial-mesenchymal transition. Here, we briefly describe the function of sorafenib, its clinical application, and the molecular mechanisms for drug resistance, especially for HCC patients.

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Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4

Abstract: Epigenetic modification of miR-429 can manipulate liver T-ICs by targeting the RBBP4/E2F1/OCT4 axis. This miRNA might be targeted to inactivate T-ICs, thus providing a novel strategy for HCC prevention and treatment.

Cited by 123 publications

References 41 publications

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Downregulation of MicroRNA-644a Promotes Esophageal Squamous Cell Carcinoma Aggressiveness and Stem Cell–like Phenotype via Dysregulation of PITX2

Heterogeneity of liver cancer and personalized therapy

New knowledge of the mechanisms of sorafenib resistance in liver cancer

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