p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs

Chang, Chun Ju; Chao, Chi-Hong; Xia, Weiya; Yang, Jer Yen; Xiong, Yan; Li, Chia Wei; Yu, Wangsheng; Rehman, Sumaiyah K.; Hsu, Jennifer L.; Lee, Heng-Huan; Liu, Mo; Chen, Chun‐Te; Yu, Dihua; Hung, Mien‐Chie

doi:10.1038/ncb2173

Cited by 661 publications

(479 citation statements)

References 19 publications

(32 reference statements)

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“…Furthermore, recent studies indicate that CSC phenotypes can reversibly turn on and off spontaneously or with the variation of their microenvironment niches [11][12][13][14] . Uncovering the molecular pathways involved in the control of TIC properties is critical for the understanding of TIC biology as well as for the development of novel therapies 3 .…”

mentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

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confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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“…30,31 Members of the miR-200 family are directly regulated by p53 at the transcriptional level and the loss of p53 is correlated with decreased miR-200c. Here, we demonstrated for the first time that a marked reduction of miR-200s was characteristic of undifferentiated endometrial carcinomas.…”

Section: Discussionmentioning

confidence: 99%

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma

et al. 2013

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Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (B33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelialto-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in 420% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.

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“…Using pancreatic epithelial cells derived from p53−/− mice that were also cultured under stress conditions, Pinho et al described similar EMT and stemness features mediated by the self-renewal factor Bmi1 [151]. Finally, Chang et al extended this observation in breast cancer by demonstrating that p53 is a transcriptional activator of the MIR200C gene [152].…”

Section: Inflammation-inducible Emt Drives Stemness and Contributes Tmentioning

confidence: 92%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs

Cited by 661 publications

References 19 publications

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

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