Abstract
BackgroundKeratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development.MethodsWe evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL), oral squamous cell carcinoma (OSCC) and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO) mice.ResultsWe observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue.ConclusionThe present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted.
Highlights
Keratins are filament forming proteins of epithelial cells and are essential for normal tissue structure and function [1]
Majority of oral precancerous lesion (OPL) had mild to severe hyperplasia and few showed presence of focal mild to moderate dysplasia
Validation of Microarray Results by Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) Microarray analysis of 27 gingivobuccal cancer (GBC) cases showed a significant downregulation of KRT76, as reported previously [26]
Summary
Keratins are filament forming proteins of epithelial cells and are essential for normal tissue structure and function [1]. In contrast to actin filaments and microtubules, keratins are encoded by a large family of genes clustered at two divergent chromosomal sites: 17q21.2 (type I keratins, except K18) and 12q13.13 (type II keratins, including K18). These are expressed in tissue and differentiation state-specific manner and play an important role in protecting epithelial cells from mechanical and non-mechanical stress and injury [2,3,4,5]. Keratins are structural marker proteins with tissue specific expression; recent reports indicate their involvement in cancer progression. We evaluate the role of KRT76 downregulation in oral precancer and cancer development
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