The role of Notch signaling in human cervical cancer: implications for solid tumors

Maliekal, Tessy Thomas; Bajaj, Jeevisha; Giri, Venkat G.; Subramanyam, Deepa; Krishna, Sudhir

doi:10.1038/onc.2008.224

Cited by 78 publications

(53 citation statements)

References 27 publications

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“…All these data strongly suggest that aberrant Notch signaling is involved in the carcinogenesis of a subset of HPV À squamous cell carcinomas from both vulvar and head and neck origin. Aberrant notch function has been found in many other tumor types (14,(28)(29)(30)(31) and intriguingly is associated with both tumor suppressor as well as an oncogenic function (29,32). Previous studies found a clear association in HNCs between inactivating mutations in NOTCH1 and carcinogenesis.…”

Section: Discussionmentioning

confidence: 97%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

121

167

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Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPVnegative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P ¼ 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV þ , HPV À /p53wt, HPV À /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV þ , 16.3% for HPV À /p53wt and 22.6% for HPV À /p53abn tumors (P ¼ 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P ¼ 0.020).Conclusions: HPV À and HPV þ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV À /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV þ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.

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Section: Discussionmentioning

confidence: 97%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

121

167

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“…On the basis of these observations, activation of Notch signaling is thought to be associated with the development of cervical cancer. 18 However, promotion of carcinogenesis by Notch signal activation seems contradictory to the phenotypes observed in the Notch1 knockout mouse, which exhibits an increase in the incidence of papilloma and chemical-induced skin cancer, 8 and the transgenic mouse of the pan-Notch inhibitor, dominant-negative Mastermind-like 1, which shows dysplasia and SCC of skin. 19 In fact, expression of NOTCH1 is decreased in skin cancer, 20,21 suggesting that NOTCH1 acts as a tumor suppressor.…”

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confidence: 99%

Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms

Sakamoto

Fujii

Kawachi

et al. 2012

Laboratory Investigation

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Notch is a transmembrane receptor functioning in the determination of cell fate. Abnormal Notch signaling promotes tumor development, showing either oncogenic or tumor suppressive activity. The uncertainty about the exact role of Notch signaling, partially, stems from inconsistencies in descriptions of Notch expression in human cancers. Here, we clarified basal-cell dominant expression of NOTCH1 in squamous epithelium. NOTCH1 was downregulated in squamous neoplasms of oral mucosa, esophagus and uterine cervix, compared with the normal basal cells, although the expression tended to be retained in cervical lesions. NOTCH1 downregulation was observed even in precancers, and there was little difference between cancers and high-grade precancerous lesions, suggesting its minor contribution to cancer-specific events such as invasion. In culture experiments, reduction of NOTCH1 expression resulted in downregulation of keratin 13 and keratin 15, and upregulation of keratin 17, and NOTCH1 knockdown cells formed a dysplastic stratified epithelium mimicking a precancerous lesion. The NOTCH1 downregulation and the concomitant alterations of those keratin expressions were confirmed in the squamous neoplasms both by immunohistochemical and cDNA microarray analyses. Our data indicate that reduction of NOTCH1 expression directs the basal cells to cease terminal differentiation and to form an immature epithelium, thereby playing a major role in the histopathogenesis of epithelial dysplasia. Furthermore, downregulation of NOTCH1 expression seems to be an inherent mechanism for switching the epithelium from a normal and mature state to an activated and immature state, suggesting its essential role in maintaining the epithelial integrity.

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“…Nowadays, it has been studied as an important factor in multiple contexts such as organ development (Hansson et al, 2004), tissue regeneration (Lovschall et al, 2005) and carcinogenesis (Liao et al, 2007;Maliekal et al, 2008;Talora et al, 2008). Briefly, it serves a fundamental role in many cell fate decisions, maintaining the balance between cell differentiation and proliferation (Katoh and Katoh, 2007).…”

Section: Introductionmentioning

confidence: 99%

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

et al. 2009

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The role of Notch signaling in human cervical cancer: implications for solid tumors

Cited by 78 publications

References 27 publications

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms

DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells

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