Molecular markers for progression of squamous cell carcinoma of the skin

Incidence of nonmelanoma skin cancer (NMSC) is increasing. Ultraviolet (UV) –light is a major risk factor for the development of cutaneous SCC. Cutaneous SCCs that develop to chronic ulcers are known to progress and metastasize more easily than UV-induced SCCs. Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes which are suggested to have a role in cancer growth and invasion. The molecular background for progression of cutaneous SCC was examined by immunohistochemistry (IHC) using tissue samples of recessive dystrophic epidermolysis bullosa (RDEB) –associated SCC, sporadic UV-induced SCC, and SCC precursors. IHC studies using tissue microarray (TMA) technique revealed overexpression of MMP-7 and MMP-13 in SCC tumor cells. MMP-7 expression was enhanced especially in the SCC tumor cells of the RDEB –associated SCCs. Studies with SCC cell lines showed that tumor cell derived MMP-7 activated heparin binding epidermal growth factor –like growth factor (HB-EGF) which enhanced the growth of SCC tumor cells. Further, it was shown that type VII collagen (COL7) is expressed in sporadic SCC tumor cells. Interestingly, it was shown that SCC –associated MMP-13 is capable of cleaving COL7 in vitro. COL7 cleavage may have a role in the progression of cutaneous SCC. Studies on serine proteinase inhibitor gene family using SCC tumor cell gene array, quantitative real-time PCR, SCC cell lines, normal human epidermal keratinocytes and IHC of TMA samples showed that serine proteinase inhibitor clade A, member 1 (serpinA1, alpha-1-antitrypsin) is expressed and produced by human SCC tumor cells but not by normal keratinocytes. Moreover, serpinA1 expression was shown to correlate with the progression of cutaneous SCC using transformed HaCaT-cell lines and mouse chemically induced skin SCC model. SerpinA1 may serve as a novel biomarker for the progression of cutaneous SCC. This study elucidated putative mechanisms of the progression of cutaneous SCC and revealed novel biomarker candidates for the progression of SCC of the skin.Ihon okasolusyövän etenemisen merkkitekijät Ei-melanoottisten ihosyöpien ilmaantuvuus on kasvussa. Auringon ultravioletti (UV) –säteily on tärkeimpiä ihon okasolusyövän kehittymisen riskitekijöitä. Ihon kroonisiin haavoihin kehittyvät okasolusyövät ovat luonteeltaan herkästi leviäviä ja ne lähettävät etäpesäkkeitä UV-valon aiheuttamia okasolusyöpiä useammin. Matriksin metalloproteinaasit (MMP) ovat ryhmä soluväliainetta pilkkovia entsyymejä, joiden on arveltu edesauttavan syövän kasvua ja leviämistä. Ihon okasolusyövän etenemiseen liittyviä tekijöitä tutkittiin kudosten immunovärjäysmenetelmällä käyttäen hyväksi resessiivistä dystrofista epidermolysis bullosa (RDEB) –tautia sairastavien potilaiden okasolusyöpäkudosnäytteitä sekä UVvalon aiheuttamia okasolusyöpiä ja niiden esiasteita. Merkkiaineiden tutkiminen kudossirutekniikalla osoitti, että MMP-7 ja MMP-13 ilmentyminen oli korostunutta ihon okasolusyöpäsoluissa. MMP-7 ilmentyminen oli erityisen voimakasta RDEB:aan liittyvissä okasolusyöpäsoluissa. Syöpäsolulinjoilla osoitettiin, että MMP-7 pystyy aktivoimaan erästä syöpäsolun pinnan kasvutekijää (hepariinia sitova epidermaalisen kasvutekijän kaltainen kasvutekijä, HB-EGF), jonka aktivoituminen lisäsi syöpäsolujen kasvua. Tässä työssä osoitettiin lisäksi, että tyypin VII kollageenia (COL7) tuotetaan UVvalon aiheuttamissa okasolusyöpäsoluissa. Uusi mielenkiintoinen havainto oli, että okasolusyöpiin liittyvä MMP-13 pystyy pilkkomaan COL7:a. COL7:n pilkkoutuminen voi edesauttaa okasolusyövän etenemistä. Seriiniproteaasin estäjien geeniperheen tutkiminen syöpäsolujen geenilastuanalyysillä, kvantitatiivisella käänteiskopioija-PCR menetelmällä, syöpäsolulinjoilla, normaaleilla ihon okasoluilla sekä kudossirutekniikalla osoitti, että seriiniproteaasin estäjä A1:tä (serpinA1, alfa-1-antitrypsiini) ilmennetään ja tuotetaan okasolusyöpäsoluissa, mutta ei normaaleissa ihon okasoluissa. Lisäksi transformoiduilla HaCaT-solulinjoilla ja hiiren ihoon kemiallisesti aiheutetulla okasolusyöpämallilla osoitettiin, että serpinA1:n ilmentyminen korreloi okasolusyövän etenemiseen. SerpinA1:tä voidaan mahdollisesti hyödyntää ihon okasolusyövän etenemisen merkkiaineena. Tässä tutkimuksessa saatiin uutta tietoa mahdollisista ihon okasolusyövän etenemisen mekanismeista sekä löydettiin uusia mahdollisia ihon okasolusyövän etenemisen merkkitekijöitä.Siirretty Doriast

Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal kerati-nocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell specific Labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the rotes of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.Peer reviewe

Long Noncoding RNA PICSAR Promotes Growth of Cutaneous Squamous Cell Carcinoma by Regulating ERK1/2 Activity

Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing globally. Long noncoding RNAs (lncRNA) are involved in various biological processes, and their role in cancer progression is emerging. Whole transcriptome analysis of cSCC cells (n = 8) and normal human epidermal keratinocytes (n = 4) revealed overexpression of long intergenic ncRNA (LINC00162) in cSCC cells. The expression of LINC00162 in cSCC cells was upregulated by inhibition of the p38α and p38δ mitogen-activated protein kinases. Analysis of tissue sections by RNA in situ hybridization showed that LINC00162 is specifically expressed by tumor cells in cSCCs but not by keratinocytes in normal skin in vivo. Knockdown of LINC00162 inhibited proliferation and migration of cSCC cells, and suppressed the growth of human cSCC xenografts in vivo. Furthermore, knockdown of LINC00162 inhibited extracellular signal-regulated kinase 1/2 activity and upregulated expression of dual specificity phosphatase 6 (DUSP6) in cSCC cells. Based on these observations, LINC00162 was named p38 inhibited cutaneous squamous cell carcinoma associated lincRNA (PICSAR). Our results provide mechanistic evidence for the role of PICSAR in promoting cSCC progression via activation of extracellular signal-regulated kinase 1/2 signaling pathway by downregulating DUSP6 expression. These results also identify PICSAR as a biomarker and putative therapeutic target in cSCC

EphB2 Promotes Progression of Cutaneous Squamous Cell Carcinoma

Keratinocyte-derived skin cancer, cutaneous squamous cell carcinoma (cSCC), is the most common metastatic skin cancer. We have examined the role of Eph/ephrin signaling in the progression of cSCC. Analysis of the expression of EPH and EFN families in cSCC cells and normal epidermal keratinocytes revealed overexpression of EPHB2 mRNA in cSCC cells and cSCC tumors in vivo. Tumor cell–specific overexpression of EphB2 was detected in human cSCCs and in chemically induced mouse cSCCs with immunohistochemistry, whereas the expression of EphB2 was low in premalignant lesions and normal skin. Knockdown of EphB2 expression in cSCC cells suppressed growth and vascularization of cSCC xenografts in vivo and inhibited proliferation, migration, and invasion of cSCC cells in culture. EphB2 knockdown downregulated expression of genes associated with biofunctions cell viability, migration of tumor cells, and invasion of tumor cells. Among the genes most downregulated by EphB2 knockdown were MMP1 and MMP13. Moreover, activation of EphB2 signaling by ephrin-B2-Fc enhanced production of invasion proteinases matrix metalloproteinase-13 (MMP13) and MMP1, and invasion of cSCC cells. These findings provide mechanistic evidence for the role of EphB2 in the early progression of cSCC to the invasive stage and identify EphB2 as a putative therapeutic target in this invasive skin cancer

Cutaneous lupus erythematosus after treatment with paclitaxel and bevacizumab for metastatic breast cancer: a case report

Abstract Introduction The monoclonal anti-vascular endothelial growth factor antibody bevacizumab is increasingly used in the treatment of several malignant tumors. The usual side effects of this drug are hypertension and proteinuria. Paclitaxel is widely used in the treatment of breast cancer and head and neck carcinomas. Neither of these two drugs typically causes skin disorders. Paclitaxel-related cutaneous lupus erythematosus has been described before, but in earlier cases patients had a history of autoimmune disease. Case presentation We report a case of a 65-year-old Caucasian woman who presented with cutaneous lupus erythematosus after receiving paclitaxel-bevacizumab combination treatment as first-line therapy for metastatic breast cancer. Her cutaneous symptoms and increased serum anti-SSA and anti-SSB antibodies disappeared shortly after the discontinuation of therapy. Conclusion We conclude that cutaneous lupus erythematosus can also be seen in patients without earlier anamnesis of autoimmune disorders and that, furthermore, bevacizumab might cause atypical cutaneous side effects.</p