EPIDERMAL GROWTH FACTOR RECEPTOR, HUMAN TELOMERASE SUBUNIT - HTERT, PROTEIN KINASE D1 AND P16INK4A IN NORMAL KERATINOCYTES AND PREMALIGNANT LESIONS OF SKIN AND ORAL CAVITY.
Keywords:
PKD1, Protein Kinase D1, hTert, EGFR, p16INK4a, mutations, MMPs, Metalloproteinases, PMDs, Potentially Malignant Disorders, Leukoplakia, Erythroplakia, Actinic keratose (AK), Keratoacanthoma (KA), SCC, Spinocellular carcinoma, BCC, Basocellular carcinoma;Abstract
Abstract. Identification of mutations as markers for early malignant transformation could be more appropriate not only for early diagnosis of cancer but could potentially influence treatment strategies in HNC, since mutations in EGFR and Ras genes are closely associated with resistance to cancer treatment. Mutations in Ras, p53 (early), the gene of EGFR (in BCCs not detected), and HTERT promoter could be used as markers of cancer transformation. Mutations in p53 are detected early in PMDs, associated with high risk for early transformation into Oral SCC. Mutations in Ras are not detected in Potentially Malignant Disorders (PMDs), with exception of Actinic keratoses (AK), Keratoacanthomas (KA) and papillomas. Since increased expression of hTERT is an early event in the pathogenesis of hyperproliferative skin deseases, overexpressed hTERT is considered as a proproliferative (proinflammatory) marker, rather than cancer marker, in contrary to its mutations. Mutations in HTERT are detected in both Spinocellular carcinoma (SCC) and Basocellular carcinoma (BCC), UVsignature.
Increased expression mainly of MMP-9 and MT1-MMP (MMP-2), are now considered as markers for aggressive cancer phenotype in both cancers. Using EMT markers (vimentin, fibronectin, N-cadherin, vs, Ecadherin; and transcriptional factors - Snail, Slug, Twist; HIF-1α, α-SMA), we could not differentiate late PMDs of early cancer lesions. These markers are useful for detection of aggressive alteration in tumour pathogenesis, which is of importance when a surgical procedure is planned. COX-2 stain was highest in SCCs and aggressive BCCs. Increased expression of PKD1 was detected in BCCs in contrary to SCC. There is no currently data for the expression of PKD1 in PMDs, leading to SCC, nor for detected mutations in PKD1 gene in SCC and BCCs. PKD1 is upregulated and down-regulated in BCC and SCC, respectively. We speculate here that the molecular mechanism - increased NFκB-hTert-PKD1-NFκB-hTert, resulting in p16INK4a mutations and turn of PKD1 function, is connected with the progression of chronic inflammation in cancer development.
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