Matrix Metalloproteinases (MMPs) in skin and oral pathology - Premalignant Diseases, Spinocellular Carcinoma and Basocellular Carcinoma (markers).
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Keywords
Abstract
Matrix metalloproteinases (MMPs) are a family of more than 28 enzymes that were initially identified on the basis of their ability to cleave most elements of the extracellular matrix (ECM), but have subsequently been found to be upregulated in EMT and nearly every tumor type.[1,21] The expression of metalloproteinases is a poor prognostic marker in both BCCs and SCCs, but some PMDs express also MMPs. Some Actinic Keratoses (AK) express MMP-1, its up-regulation has been associated with the early events in SCC development,[4,19] but it is expressed also in chronic wounds[11, 301] and Oral Lichen Planus (OLP).[12.293] Overexpression of MMP-2[18,15] MMP-9, -11, and MT1-MMP (MMP-14)[18] was also increased in AK,[18,19,15] MMP-3, -7[16],-10 and -13 has not been observed in this PMD.[4] According Hernández-Pérez M et al. MMP-9 and MMP-14 (MT1-MMP) could not be used as a marker of early SCC diagnosis.[15] MMP-2 and MMP-9 are increased in all PMDs, MT1-MMP, which is an activator of MMP-2, was expressed in all groups – chronic wound[301] OLP,[294] Bowen's disease (BD),[320] and similarly in AK, SCC, and BCC,[18,15,19] not detected in leucoplakia and Keratoacanthomas (KA).
The differentiatial dignose between Oral Lichen Planus (OLP) and SCC could be made on the basess of lack of expression of MMP-8, -10, -11 and MM-15 in OLP. A controversial study by Subdo et al. of 150 patients with dysplastic leukoplakias found that 70% were low-risk diploid lesions (3% progressed to OSCC), 13% were intermediate-risk tetraploid lesions (60% progressed to OSCC) and 17% were high-risk aneuploid lesions (84% progressed to OSCC).[312] Aneuploid oral leukoplakia lesions show higher rates of malignant progression to OSCC.[311] MMPs expressed in this lesion are few – MMPs-2,-3,-9, and -13 compared wth much more expressed in SCC (Table 4). Early mutations of the p53 gene was linked to the high malignant potential of Oral Erythroplakia[207], expressed only MMP-9.[230]
Herein, differentiatial dignose between Actinic keratose and SCC could be made by the lack of MMP-3,-7,-10,-13 and -15 in AK compared with SCC and between AK and BCC by the lack of the same MMPs, with exception of MMP-15. GLI1 showed the nuclear staining pattern in 100% 3.5% (1/28) Actinic Keratosis, 15.1% (5/33) Bowen's disease, (4/4) cases of Trichoblastoma, 12.5% (4/32) Squamous cell carcinoma (SCC) and 98.2% cases of BCC, regardless of the histological subtype.[167] p27 positivity (for DD. of SCC)[198] and lack of mutations in 14-3-3? by CpG-methylation, as well as PTCH/SMO mutations, which was also showed as an early event in BCC – D.D. AK / BCC.[194,195,36] p27 is not down-regulated in BCCs. [356,153]
Bowen's disease is negative for MMP—3,11,-12, -13 compared with SCC (Table 4). According Boyd S et al. MMP-10 expression was observed already in Bowen's disease (SCC in situ), while MMP-21 was absent.[120] There is no data for the expression of MMP-21 in other PMDs, its expression is increaser in the stroma of SCC120 and could be used in the differebtiatial diagnose of both cancers. Significantly down-regulated c-Myc, increased in cSCC samples,[162,163] p27 positivity[198] and early detected p53 mutations,[231] were also detected in BD. p27 kip1 was positive in 23.4%, 26.2%, 25.9% and 4.5% of specimens in the normal skin, AK (Actinic Keratosis), BD (Bowen’s Disease) and SCC groups, respectively.[198] Due to the lack of SOX9 in seborrheic keratosis, Bowen's diseases, and Merkel cell carcinomas, Shi HZ and Hao C speculate that SOX9 may become a hallmark of BCC diagnosis and differentiation.[168] Inhibition of Wnt signal pathway by GLI could be the main reason for decreased Myc protein expression in Bowen’s disease and in BCC (leucoplakia is under question) and down-regulation of GLI could be the main reason for progression of Bowen’s disease into invasive SCC.
MMP-3 expression (serum and saliva) was increased gradually when they analyzed cases of reticular OLP, erosive OLP, early-stage OSCC, and advanced OSCC.[13,17] Salivary MMP-9 could be a useful, non-invasive adjunct technique in the diagnosis, treatment, and follow-up of oral OPMD (leucoplakia, erythroplakia and oral submucous fibrosis (OSMF)) and OSCC.[230] We could not succeed in finding data for MMP expression in oral erythroplakia, with exception for MMP-9.[230] Estimation of salivary MMP-12 serves as a valuable non-invasive early diagnostic tool in diagnosing oral submucous fibrosis and oral squamous cell carcinoma.[299]
Bmi-1 is positively regulated by c-MYC and increases cellular proliferation by suppressing the INK4a locus.[310] p21Cip1 is induced in tumors by the activated Ras-ERK1/2 pathway, but repressed by c-Myc. This identifies c-Myc-mediated repression of p21Cip1 as a key step for Ras-driven epidermal tumorigenesis.[152] p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage permitting DNA repair.[97] p27 is closely involved in malignant transformation of oral mucosa cells (tumour suppressor by inhibiting TERT expression,[184] downregulated in SCC), and may be a reliable biomarker for this purpose.[197] Our search in the literature showed that p53 mutations could be observed also early in the pathogenesis of HNC[171] - 33% Oral Lichen Planus (OLP),[151,36] 13.3% Leucoplakia,[151,209] 46% Erythroplakia,[207] Actinic keratose (AK),[171,196,224] 47% of samples of Bowen's disease,[211] associated with higher malignant potential of this lesions. p53 is a target for new treatment strategies in cancer.[273,274] Restoration of p53 resulted in potent inhibition in production of proMMP-13 (by 71 to 92%) and collagenase-1 (MMP-1) (by 27 to 93%) by all cell lines in 24 h, whereas production of gelatinase-A (MMP-2) and gelatinase-B (MMP-9) was not altered in four head and neck SCC cell lines with mutated p53.[100] P53 suppress EMT[247] and metastasis. In fact, growth-inhibitory and tumor-suppressive functions of p53 may depend on its ability to directly repress CD44 expression,.[247] and p53 –dependent E3- ubiquitin ligase degradation of GLI1.[212]
Specifically, cutaneous SCCs harbor a high mutation rate caused by UV damage; recurrent mutations in TP53, CDKN2A, and NOTCH1/2; focal or arm-level gains affecting chromosomes 3q26, 5p, 7q21, and 11q22; and CDKN2A loss (on chromosome 9p21),[171] EGFR[216] and HTERT.[36,90]