c-Met Overexpression in Cervical Cancer: A Prognostic Factor and a Potential Molecular Therapeutic Target

Refaat, Tamer; Donnelly, Eric D.; Sachdev, Sean; Parimi, Vamsi; Achy, Samar El; Dalal, Prarthana; Farouk, Mohammed; Berg, K.; Helenowksi, I.; Gross, Jeffrey P.; Lurain, John R.; Strauss, Jonathan B.; Woloschak, Gayle E.; Wei, Jia; Small, William

doi:10.1016/j.ijrobp.2015.07.1182

Cited by 11 publications

(16 citation statements)

References 27 publications

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“…Upregulation of EGFR has been reported in cervical cancers; it contributes to cancer cell proliferation, migration, and invasion. Another highly expressed proto-oncogene in cervical cancer is c-MET (12), which is known to promote the occurrence and development of cervical cancer and has prognostic value (13). Given the fact that cervical carcinomas are caused by persistent HR HPVs infection, elevated proto-oncogene expression is also possibly a consequence of the HR HPVs infection (14).…”

Section: Introductionmentioning

confidence: 99%

E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

et al. 2018

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The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes and Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like and This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. .

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Section: Introductionmentioning

confidence: 99%

E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

et al. 2018

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“…The authors suggest that the negative relationship between c‐MET expression and cervical cancer prognosis may be due to the increased cell response to HGF that could in turn induce tumor cell metastasis (Baykal, Ayhan, Al, Yuce, & Ayhan, ). Refaat et al also suggest that the overexpression of c‐Met may be a potential therapeutic target, with a predictive value for subjects with local‐regional advanced cervical cancer treated definitively with concurrent chemoradiation (Refaat et al, ). A meta‐analysis by Peng et al found that c‐Met expression in cervical cancer was approximately 60.99% (222/364), and the c‐Met expression was higher in this malignancy rather than non‐neoplastic cervix tissue.…”

Section: Introductionmentioning

confidence: 99%

Clinical and prognostic value of the C‐Met/HGF signaling pathway in cervical cancer

Boromand

Hasanzadeh

Shahidsales

et al. 2017

Journal Cellular Physiology

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Aberrant activation of the HGF/c-Met signalling pathway is reported to be associated with cell proliferation, progression, and metastasis features of several tumor types, including cervical cancer, suggesting that it may be of potential value as a novel therapeutic target. Furthermore, HPV-positive patients had a higher serum level of HGF or c-Met protein, compared with HPV-negative patients. c-Met or HGF overexpression in lesions of cervical cancer is reported to be related to a poorer prognosis, and hence this may be of value as a prognostic and predictive biomarker. Several approaches have been developed for targeting HGF and/or c-Met. One of these is crizotinib (a dual c-Met/ALK inhibitor). This has been approved by FDA for the treatment of lung-cancer. Further investigations are required to evaluate and optimize the use of c-Met inhibitors in cervical cancer or parallel targeting signalling pathway associated/activated via MET/HGF pathway. The main aim of current review was to give an overview of the potential of the c-Met/HGF pathway as a prognostic, or predictive biomarker in cervical cancer.

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“…A large body of evidence has proven that c-Met is upregulated in several cancer types, including gastric ( 15 ), non-small-cell lung ( 16 ) and cervical cancer ( 17 ). In addition, previous studies demonstrated that overexpression of c-Met has as a significant prognostic value in early-stage invasive ( 18 ) and local-regional advanced cervical cancer patients ( 19 ). c-Met, acts as an oncogene, and has been widely documented to promote cell proliferation, migration and invasiveness ( 20 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-454-3p inhibits cervical cancer cell invasion and migration by targeting c-Met

2018

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Increasing evidence has demonstrated that microRNAs (miRNAs) have a crucial role in the initiation and progression of tumors. The present study aimed to investigate the expression and the role of miRNA-454-3p in human cervical cancer. Human cervical cancer cells were transfected with miRNA-454-3p mimics or negative control miRNA. MTT, Transwell and wound healing assays were performed to investigate the effects of miRNA-454-3p overexpression on cell proliferation, invasion and migration, respectively. The results indicated that miRNA-454-3p was down-regulated in human cervical cancer cell lines, while its ectopic overexpression significantly inhibited their proliferation, migration and invasion. Furthermore, a luciferase reporter assay confirmed that c-met was a novel target of miRNA-454-3p in HeLa cells. In conclusion, the results of the present study suggested that miRNA-454-3p exhibits significant tumor-suppressive effects in cervical cancer by targeting c-met, and may be a potential means of treating cervical cancer.

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c-Met Overexpression in Cervical Cancer: A Prognostic Factor and a Potential Molecular Therapeutic Target

Cited by 11 publications

References 27 publications

E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

Clinical and prognostic value of the C‐Met/HGF signaling pathway in cervical cancer

MicroRNA-454-3p inhibits cervical cancer cell invasion and migration by targeting c-Met

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