PROTEIN KINASE D1: STRUCTURE, ACTIVATION, REGULATION, SUBSTRATES, AND FUNCTIONS. ROLE IN SKIN PATHOLOGY., 2021
Protein kinase D1 (PKD1) posses proproliferative and antidifferentiative functions in human and m... more Protein kinase D1 (PKD1) posses proproliferative and antidifferentiative functions in human and mouse keratinocytes, prodifferentive function in hTert (N/Tert-1 or N-hTERT) keratinocytes, participate also in
wound-healing process in mouse epidermis. Loss of PKD2 enhanced keratinocytes-proliferative potential, while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity, and diminished tissue regenerative ability. This proliferation defect was correlated with upregulation of CDK4/6 inhibitor p15INK4B and induction of a p53-independent G1 cell-cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating keratinocytes. There
are no data concerning regulation of the PKD1, 2 and/or 3 kinase expression in skin. The mechanisms regulating PKD1 expression are merely studied only in pancreatic and prostate cancer cells. In skin pathology, the kinase is with increased expression in psoriatic lesions and basocellular carcinoma (BCC) and downregulated in head and
neck spinocellular carcinoma (HNSCC). In the multistage mouse skin carcinogenesis model, the expression of PKD1 and CD34+ (cutaneous cancer stem-cell marker) are increased with increased expression of p53, p21, c-Myc, cyclin B, p-CDK1, and Cdc25A and inhibited activation of extracellular signal-regulated kinase 1/2 (ERK1/2), increased nuclear factor-kappaB (NF-kB), cyclic adenosine 3',5'-monophosphate-responsive element binding protein (CREB), and CCAATenhancer-binding protein (C/EBPs) activation by increased phosphorylation
of c-Jun-N-terminal kinase 1/2 (JNK1/2), p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by increased downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), ornithine decarboxylase (ODC), and vascular endothelial growth factor (VEGF). The hyperplastic and inflammatory responses in PKD1-deficient mice to topical phorbol ester were significantly suppressed suggesting involvement of PKD1 in tumor promotion (and inflammation). Consistently, when subjected to two-stage chemical skin carcinogenesis protocol, these mice were resistant to papilloma formation when compared to control littermates. There are no other data for PKD1 participation in inflammatory skin process and expression in other premalignant skin diseases. Recently, hotspot-activating mutation in PKD1, resulting in an p.Glu710Asp aminoacid
substitution, was detected in 73% of salivary Polymorphous low-grade adenocarcinoma (PLGA), associated with metastasis-free survival. Its increased expression is connected with late phases of malignant melanoma, associated with high metastatic potential. PKD1 participates in the pathology of inflammatory skin diseases and skin oncogenesis, but the mechanisms of regulation of its expression and action in skin in norm and in pathological processes are still unsufficient. PKD1 is upregulated merely in BCCs and in pancreatic cancer and downregulated
in HNSCC, prostate, breast gastric, and colon cancers.
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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 14-3-3σ 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 cyclindependent
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 tumorsuppressive 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]
wound-healing process in mouse epidermis. Loss of PKD2 enhanced keratinocytes-proliferative potential, while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity, and diminished tissue regenerative ability. This proliferation defect was correlated with upregulation of CDK4/6 inhibitor p15INK4B and induction of a p53-independent G1 cell-cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating keratinocytes. There
are no data concerning regulation of the PKD1, 2 and/or 3 kinase expression in skin. The mechanisms regulating PKD1 expression are merely studied only in pancreatic and prostate cancer cells. In skin pathology, the kinase is with increased expression in psoriatic lesions and basocellular carcinoma (BCC) and downregulated in head and
neck spinocellular carcinoma (HNSCC). In the multistage mouse skin carcinogenesis model, the expression of PKD1 and CD34+ (cutaneous cancer stem-cell marker) are increased with increased expression of p53, p21, c-Myc, cyclin B, p-CDK1, and Cdc25A and inhibited activation of extracellular signal-regulated kinase 1/2 (ERK1/2), increased nuclear factor-kappaB (NF-kB), cyclic adenosine 3',5'-monophosphate-responsive element binding protein (CREB), and CCAATenhancer-binding protein (C/EBPs) activation by increased phosphorylation
of c-Jun-N-terminal kinase 1/2 (JNK1/2), p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by increased downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), ornithine decarboxylase (ODC), and vascular endothelial growth factor (VEGF). The hyperplastic and inflammatory responses in PKD1-deficient mice to topical phorbol ester were significantly suppressed suggesting involvement of PKD1 in tumor promotion (and inflammation). Consistently, when subjected to two-stage chemical skin carcinogenesis protocol, these mice were resistant to papilloma formation when compared to control littermates. There are no other data for PKD1 participation in inflammatory skin process and expression in other premalignant skin diseases. Recently, hotspot-activating mutation in PKD1, resulting in an p.Glu710Asp aminoacid
substitution, was detected in 73% of salivary Polymorphous low-grade adenocarcinoma (PLGA), associated with metastasis-free survival. Its increased expression is connected with late phases of malignant melanoma, associated with high metastatic potential. PKD1 participates in the pathology of inflammatory skin diseases and skin oncogenesis, but the mechanisms of regulation of its expression and action in skin in norm and in pathological processes are still unsufficient. PKD1 is upregulated merely in BCCs and in pancreatic cancer and downregulated
in HNSCC, prostate, breast gastric, and colon cancers.
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-1a, a-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 NFKB-hTert-PKD1-NFKB-hTert, resulting in p16INK4a mutations and turn of PKD1 function, is connected with the progression of chronic inflammation in cancer development.
Remarkably, elevated VDR expression is associated with high tumor differentiation, absence of node involvement, and good prognosis in colon cancer, with lower tumor grade, late development of lymph node metastases, and longer disease-free survival in breast cancer, and
with improved overall survival in prostate and non-small cell lung cancer and melanoma. It was shown that the metabolites of vitamin D inhibit
proliferation and induce differentiation of melanoma cells expressing VDR. Reduced level or absence of VDR is associated with melanoma
progression (melanogenesis can suppress the expression of the receptor (bad prognostic marker), resulting in deteriorated survival of
melanoma patients. vitamin D suppresses a key tumour pathway in BCCs development - Hedgehog signalling pathway. 1α,25(OH)2D3 also
inhibits the growth of SCCs in vivo as well as in vitro, inhibiting Wnt/β-catenin and interferes in ERK1/2 signaling, connected with development of melanoma. Although the in vitro and animal studies suggested that vitamin D may prevent development of BCCs and SCCs, additional studies on humans are needed to assess the suitability of topical or oral vitamin D3 supplementation in chemoprevention of head and neck skin cancers. Administration of 1,25(OH)2D3 to cancer patients is restricted by its hypercalcemic effects at the therapeutic doses, enforcing the development of several analogs that maintain the antitumoral properties but have less calcemic actions, including pancreatic cancer patients, organ which is thought not to be target for vitamin D action.
least 229 genes through binding to at least 2,776 genomic DNA binding sites. The regulation of VDR expression is still incompletely understood,
implicating 1,25(OH)2D3, PKCa, PTH, glucocorticoids and 17p-estradiol (E2). It is well established that sunlight (mainly ultraviolet type B (UVB)) is required for the efficient production of vitamin D. Paradoxically, the same solar radiation is considered as one of the most harmful factors for the skin, thus contributes to the development of skin neoplasia.
1a,25(OH)2D3 up-regulated the expression of NAD+-dependent 15-hydroxy- prostaglandin dehydrogenase (15-PGDH) gene and down-regulated cyclooxygenase-2 (COX-2) expression. The cyclindependent
kinase inhibitor p21waf1/cip1 was first suggested as a VDR target gene, up-regulated with p27 kipi. The expression of VEGF (a major tumor
angiogenesis factor) related protein has been shown to be down-regulated by EB1089, a less calcemic analog of 1a,25(OH)2D3, function as a potent antiangiogenesis factor. Recently, effects of 1,25(OH)2D3
on the expression of several EMT-TFs have been described. Overexpression of VDR caused the downregulation of stem cell markers, including c-Met and CD44, in PDAC cells.
prohormones, which are converted in the body into a number of biologically active metabolites that function as true hormones, circulating in the blood and regulating the activities of various cell types - both calcemic and noncalcemic effects1. Cell responsiveness to 1,25(OH)2D3 mainly relays on VDR expression levels. The liganded VDR forms a heterodimer with retinoid X receptor (RXR) and binds to vitamin D response element (VDRE) to modulate the gene expression. The presence of
VDR in cells other than those of the intestine, bone, kidney, and parathyroid gland led to the recognition of noncalcemic actions of VDR ligands. VDR protein is expressed in almost all normal human cell types and tissues, and also in cancer cell lines and tumors of several origins. VDR downregulation has been observed in a proportion
of melanomas and colon, breast, lung, and ovarian tumors, which may jeopardize the response to therapy with vitamin D, 1,25(OH)2D3, or its analogs. 1,25(OH)2D3, and its synthetic analogs, is therapeutic efficacy in skin diseases involving Vitamin D is well known as being essential for bone health. It is a group of fat-soluble prohormones, which are converted in the body into a number of biologically active metabolites that
function as true hormones, circulating in the blood and regulating the activities of various cell types - both calcemic and noncalcemic effects1. Cell responsiveness to 1,25(OH)2D3 mainly relays on VDR expression levels. The liganded VDR forms a
heterodimer with retinoid X receptor (RXR) and binds to vitamin D response element (VDRE) to modulate the gene expression. The presence of VDR in cells other than those of the intestine, bone, kidney, and parathyroid gland led to the recognition of noncalcemic actions of VDR ligands. VDR protein is expressed in almost all normal
human cell types and tissues, and also in cancer cell lines and tumors of several origins. VDR downregulation has been observed in a proportion of melanomas and colon, breast, lung, and ovarian tumors, which may jeopardize the response to
therapy with vitamin D, 1,25(OH)2D3, or its analogs. 1,25(OH)2D3, and its synthetic analogs, is therapeutic efficacy in skin diseases involving defective keratinocyte differentiation, such as psoriasis, seborhheic dermatitis, and ichthyosis2. Promotion of epithelial differentiation by VDR ligands also provides a mechanistic basis for their
potential use in the treatment of actinic keratosis, head and neck squamous cell carcinoma (HNSCC), basal cell carcinoma3'4'56 (BCC) and melanomas.
So-called, non-genomic mechanism of rapid vitamin D response has been described recently. This mechanism does not directly affect VDR, its expression, gene expression of target proteins or require additional protein synthesis75.
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 14-3-3σ 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 cyclindependent
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 tumorsuppressive 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]
wound-healing process in mouse epidermis. Loss of PKD2 enhanced keratinocytes-proliferative potential, while loss of PKD3 resulted in a progressive proliferation defect, loss of clonogenicity, and diminished tissue regenerative ability. This proliferation defect was correlated with upregulation of CDK4/6 inhibitor p15INK4B and induction of a p53-independent G1 cell-cycle arrest. Simultaneous silencing of PKD isoforms resulted in a more pronounced proliferation defect consistent with a predominant role for PKD3 in proliferating keratinocytes. There
are no data concerning regulation of the PKD1, 2 and/or 3 kinase expression in skin. The mechanisms regulating PKD1 expression are merely studied only in pancreatic and prostate cancer cells. In skin pathology, the kinase is with increased expression in psoriatic lesions and basocellular carcinoma (BCC) and downregulated in head and
neck spinocellular carcinoma (HNSCC). In the multistage mouse skin carcinogenesis model, the expression of PKD1 and CD34+ (cutaneous cancer stem-cell marker) are increased with increased expression of p53, p21, c-Myc, cyclin B, p-CDK1, and Cdc25A and inhibited activation of extracellular signal-regulated kinase 1/2 (ERK1/2), increased nuclear factor-kappaB (NF-kB), cyclic adenosine 3',5'-monophosphate-responsive element binding protein (CREB), and CCAATenhancer-binding protein (C/EBPs) activation by increased phosphorylation
of c-Jun-N-terminal kinase 1/2 (JNK1/2), p38 and phosphatidylinositol 3-kinase (PI3K)/Akt and by increased downstream target gene expression, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), ornithine decarboxylase (ODC), and vascular endothelial growth factor (VEGF). The hyperplastic and inflammatory responses in PKD1-deficient mice to topical phorbol ester were significantly suppressed suggesting involvement of PKD1 in tumor promotion (and inflammation). Consistently, when subjected to two-stage chemical skin carcinogenesis protocol, these mice were resistant to papilloma formation when compared to control littermates. There are no other data for PKD1 participation in inflammatory skin process and expression in other premalignant skin diseases. Recently, hotspot-activating mutation in PKD1, resulting in an p.Glu710Asp aminoacid
substitution, was detected in 73% of salivary Polymorphous low-grade adenocarcinoma (PLGA), associated with metastasis-free survival. Its increased expression is connected with late phases of malignant melanoma, associated with high metastatic potential. PKD1 participates in the pathology of inflammatory skin diseases and skin oncogenesis, but the mechanisms of regulation of its expression and action in skin in norm and in pathological processes are still unsufficient. PKD1 is upregulated merely in BCCs and in pancreatic cancer and downregulated
in HNSCC, prostate, breast gastric, and colon cancers.
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-1a, a-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 NFKB-hTert-PKD1-NFKB-hTert, resulting in p16INK4a mutations and turn of PKD1 function, is connected with the progression of chronic inflammation in cancer development.
Remarkably, elevated VDR expression is associated with high tumor differentiation, absence of node involvement, and good prognosis in colon cancer, with lower tumor grade, late development of lymph node metastases, and longer disease-free survival in breast cancer, and
with improved overall survival in prostate and non-small cell lung cancer and melanoma. It was shown that the metabolites of vitamin D inhibit
proliferation and induce differentiation of melanoma cells expressing VDR. Reduced level or absence of VDR is associated with melanoma
progression (melanogenesis can suppress the expression of the receptor (bad prognostic marker), resulting in deteriorated survival of
melanoma patients. vitamin D suppresses a key tumour pathway in BCCs development - Hedgehog signalling pathway. 1α,25(OH)2D3 also
inhibits the growth of SCCs in vivo as well as in vitro, inhibiting Wnt/β-catenin and interferes in ERK1/2 signaling, connected with development of melanoma. Although the in vitro and animal studies suggested that vitamin D may prevent development of BCCs and SCCs, additional studies on humans are needed to assess the suitability of topical or oral vitamin D3 supplementation in chemoprevention of head and neck skin cancers. Administration of 1,25(OH)2D3 to cancer patients is restricted by its hypercalcemic effects at the therapeutic doses, enforcing the development of several analogs that maintain the antitumoral properties but have less calcemic actions, including pancreatic cancer patients, organ which is thought not to be target for vitamin D action.
least 229 genes through binding to at least 2,776 genomic DNA binding sites. The regulation of VDR expression is still incompletely understood,
implicating 1,25(OH)2D3, PKCa, PTH, glucocorticoids and 17p-estradiol (E2). It is well established that sunlight (mainly ultraviolet type B (UVB)) is required for the efficient production of vitamin D. Paradoxically, the same solar radiation is considered as one of the most harmful factors for the skin, thus contributes to the development of skin neoplasia.
1a,25(OH)2D3 up-regulated the expression of NAD+-dependent 15-hydroxy- prostaglandin dehydrogenase (15-PGDH) gene and down-regulated cyclooxygenase-2 (COX-2) expression. The cyclindependent
kinase inhibitor p21waf1/cip1 was first suggested as a VDR target gene, up-regulated with p27 kipi. The expression of VEGF (a major tumor
angiogenesis factor) related protein has been shown to be down-regulated by EB1089, a less calcemic analog of 1a,25(OH)2D3, function as a potent antiangiogenesis factor. Recently, effects of 1,25(OH)2D3
on the expression of several EMT-TFs have been described. Overexpression of VDR caused the downregulation of stem cell markers, including c-Met and CD44, in PDAC cells.
prohormones, which are converted in the body into a number of biologically active metabolites that function as true hormones, circulating in the blood and regulating the activities of various cell types - both calcemic and noncalcemic effects1. Cell responsiveness to 1,25(OH)2D3 mainly relays on VDR expression levels. The liganded VDR forms a heterodimer with retinoid X receptor (RXR) and binds to vitamin D response element (VDRE) to modulate the gene expression. The presence of
VDR in cells other than those of the intestine, bone, kidney, and parathyroid gland led to the recognition of noncalcemic actions of VDR ligands. VDR protein is expressed in almost all normal human cell types and tissues, and also in cancer cell lines and tumors of several origins. VDR downregulation has been observed in a proportion
of melanomas and colon, breast, lung, and ovarian tumors, which may jeopardize the response to therapy with vitamin D, 1,25(OH)2D3, or its analogs. 1,25(OH)2D3, and its synthetic analogs, is therapeutic efficacy in skin diseases involving Vitamin D is well known as being essential for bone health. It is a group of fat-soluble prohormones, which are converted in the body into a number of biologically active metabolites that
function as true hormones, circulating in the blood and regulating the activities of various cell types - both calcemic and noncalcemic effects1. Cell responsiveness to 1,25(OH)2D3 mainly relays on VDR expression levels. The liganded VDR forms a
heterodimer with retinoid X receptor (RXR) and binds to vitamin D response element (VDRE) to modulate the gene expression. The presence of VDR in cells other than those of the intestine, bone, kidney, and parathyroid gland led to the recognition of noncalcemic actions of VDR ligands. VDR protein is expressed in almost all normal
human cell types and tissues, and also in cancer cell lines and tumors of several origins. VDR downregulation has been observed in a proportion of melanomas and colon, breast, lung, and ovarian tumors, which may jeopardize the response to
therapy with vitamin D, 1,25(OH)2D3, or its analogs. 1,25(OH)2D3, and its synthetic analogs, is therapeutic efficacy in skin diseases involving defective keratinocyte differentiation, such as psoriasis, seborhheic dermatitis, and ichthyosis2. Promotion of epithelial differentiation by VDR ligands also provides a mechanistic basis for their
potential use in the treatment of actinic keratosis, head and neck squamous cell carcinoma (HNSCC), basal cell carcinoma3'4'56 (BCC) and melanomas.
So-called, non-genomic mechanism of rapid vitamin D response has been described recently. This mechanism does not directly affect VDR, its expression, gene expression of target proteins or require additional protein synthesis75.