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

Abstract

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.

The pathological significance of Notch1 in oral squamous cell carcinoma

“…34,35 However, a recent study demonstrated opposite results to this study. The study of Sakamoto et al 24 showed similar Notch1 expression to that observed in our study in normal tissues, whereas their results for dysplastic and cancerous tissues were different, and Notch1 was downregulated in the neoplastic lesions.Although the antibodies against Notch1 and staining method used in our study were different from those used by Sakamoto et al, 24 our immunohistochemical staining results showed clear and specific membranous staining. In our study, NICD was similarly detected by immunohistochemistry in Notch1-positive cells, which supports that our Notch1 immunohistochemical results were reliable.…”

“…21,22 However, some researchers have shown that Notch signaling has a tumor suppressive role. 23,24 To resolve the discrepancies between the reported roles of Notch signaling in OSCCs, the precise knowledge of the expression of Notch in normal and cancerous lesions of the oral cavity is crucial.…”

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

“…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.…”

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…It was reported that NOTCH1 was downregulated specifically in squamous neoplasms of oral mucosa and esophagus 57 and was variably reduced in primary oral SCC (OSCC) tissues 58. In another study, mRNA levels of HEY1 (a target gene of Notch/CSL/MAML‐mediated signaling pathway) were found to be underexpressed in a subset (26%) of ESCC sample, which was significantly correlated with tumor depth of invasion 59.…”