Notch3 Overexpression Is Related to the Recurrence of Ovarian Cancer and Confers Resistance to Carboplatin

Park, Taezoon; Chen, Xu; Tropé, Claes G.; Davidson, Ben; Shih, Ie Ming; Wang, Tian Li

doi:10.2353/ajpath.2010.100316

Cited by 165 publications

(178 citation statements)

References 29 publications

(31 reference statements)

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“…Although elevated Notch signaling has been suggested in tumor development, 13,[30][31][32] neither an increase of NOTCH1 expression nor its nuclear translocation was observed in the cases we examined. The cDNA microarray of OSCC showed that neither NOTCH2 nor NOTCH3 was upregulated in OSCC, suggesting that quantitative compensation is unlikely.…”

Section: Discussionmentioning

confidence: 60%

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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Section: Discussionmentioning

confidence: 60%

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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“…Besides hematopoietic malignancy, PBX1 is also highly expressed in solid tumors including melanoma, prostate, ovarian, and breast cancers (23)(24)(25). In ovarian cancer, PBX1 has been identified as an effector in the NOTCH3 signaling pathway, which is known to maintain stemness and promote platinum drug resistance in ovarian cancer cells (10,26). The Notch pathway has also been demonstrated to regulate the PI3K/Akt pathway in stem cells (27) and to regulate ATP-binding cassette protein ABCG2 (28), which can confer multidrug resistance by regulating drug efflux (28,29).…”

Section: Discussionmentioning

confidence: 99%

Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

et al. 2016

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The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately defeats its clinical management. However, it may be possible improve patient outcomes significantly by defeating nodal resistance mechanisms which cancers rely upon during the evolution to an untreatable state.Here we report an essential role for upregulation of the stem cell reprogramming factor PBX1 in mediating chemoresistance in recurrent ovarian carcinomas. In clinical specimens, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients. In tumor cells with low endogenous expression of PBX1, its enforced expression promoted cancer stem cell-like phenotypes, including most notably an increase in resistance to platinum-based therapy used most commonly for management of this disease. Conversely, silencing PBX1 in platinum-resistant cells that overexpressed PBX1 sensitized them to platinum treatment and reduced their stem-likeproperties. An analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to promoters of genes involved in stem cell maintenance and the response to tissue injury. We confirmed direct regulation of one of these genes, STAT3, demonstrating that the PBX1 binding motif at its promoter acted to positively regulate STAT3 transcription. Pursing this connection, we determined that a STAT3/JAK2 inhibitor could potently sensitize platinum-resistant cells to carboplatin and suppress their growth in vivo. Our findings offer a mechanistic rationale to target the PBX1/STAT3 axis to defeat a key mechanism of chemoresistance in ovarian cancers and possibly other human cancers.3

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“…The initiation of signalling is the combination of Notch ligands with their receptors, which could in turn affect downstream effectors through releasing the intracellular domain of the receptor that is activated by a cascade of proteolytic cleavages mediated by γ‐secretase. For example, it has been reported that NOTCH3 participates in the pathogenesis of EOC recurrence through enhancing carboplatin resistance of cancer cells 15. A high NOTCH4 mRNA expression level was revealed to be significantly correlated with a favourable overall survival (OS) of EOC patients and thus was regarded as a prognostic factor 16.…”

Section: Introductionmentioning

confidence: 99%

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

Cheng

Dai

et al. 2018

J Cellular Molecular Medi

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To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r 2 = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.

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Notch3 Overexpression Is Related to the Recurrence of Ovarian Cancer and Confers Resistance to Carboplatin

Cited by 165 publications

References 29 publications

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

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

Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

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