Skin Cancer: New Markers for Better Prevention

Greinert, Rüdiger

doi:10.1159/000201675

Cited by 77 publications

(65 citation statements)

References 311 publications

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“…Epidemiological data (5,6,8,9,(11)(12)(13)(14)(15)(16) show clearly that ultraviolet (UV) radiation, particularly UVB, is an essential etiological factor in the carcinogenesis of skin tumors. UV exposure is a chronic oxidative stress (17) that causes DNA damage with specific mutations of suppressor genes such as p53 (14,16,(18)(19)(20)(21)(22): it is activated along with telomerase (23)(24)(25)(26)(27). Molecular changes in the skin are associated with local cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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Abstract.In previous studies we demonstrated telomerase activity in frozen tissues from BCC and their tumor-free margins by the PCR ELISA. In this study we examined in the same frozen sections immunohistochemical presence of hTERT in the nucleus. After fixation in acetone and methanol followed by steaming we used for visualization the antigenantibody reactions by APAAP. This was the best method of preparation of the frozen sections in our preliminary hTERT-study with squamous cell carcinomas. This study was supplemented with antibodies against Ki-67, nucleolin, common leucocyte antigen CD45 and mutated p53. The immunoreactive scores were determined and included the comparison with telomerase activity. The investigation of hTERT expression was performed in the tissues of 41 patients with BCC and control tissues of 14 patients without tumor. Eleven commercial antibodies were used for a nuclear staining of hTERT expression. With the anti-hTERT antibodies we looked for both satisfactory distribution and intensity of immunohistochemical labeling in the carcinomas and in the squamous epithelia of the tumor centers, of the tumor-free margins and of the control tissues. The hTERT expression in the BCC was distributed heterogeneously. The score values established by the anti-hTERT antibodies used were variably or significantly increased. In the stroma they tended to be negative, so we disregarded stroma hTERT. Proof of hTERT did not differ uniformly from telomerase activity. We compared the high with the lower median hTERT values in the Kaplan-Meier curve. Patients with lower hTERT scores in the center or tumor margin as shown by some of the antibodies suffered relapse earlier. Finally, we compared the hTERT expression in BCC tissues with the hTERT scores in HNSCC tissues from our previous study. Only one anti-hTERT antibody (our Ab 7) yielded significantly higher scores in BCC than in HNSCC.

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Section: Introductionmentioning

confidence: 99%

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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“…One such skindamaging effect is sunlight, a major cause of human skin cancer and aging changes within the skin (4). Although a unique cellular system of pigment cells has evolved within the skin for protection against sunlight, the skin's carcinogenic vulnerability is evident, because no organ forms more malignant neoplasms in humans (5).…”

mentioning

confidence: 99%

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

Geyfman¹,

Kumar

Liu³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

225

322

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The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day-dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.Arntl gene | circadian rhythm | UVB damage | cell cycle T he highly conserved circadian clock regulates organismal adaptation to the light:dark (LD) cycles caused by the rotation of the Earth (1). Located in the suprachiasmatic nucleus of the vertebrate hypothalamus, the central clock is an intrinsic pacemaker with a spontaneous firing rate and a nearly 24-h rhythmic gene expression. This central pacemaker is thought to synchronize peripheral clocks found in the vast majority of tissues and cells. The core circadian clock machinery is composed of the heterodimeric bHLH-PAS transcription factors CLOCK and BMAL1 that bind E-box elements to activate clock-controlled genes, as well as Period (Per1, 2, and 3) and Cryptochrome (Cry1 and 2). PERs and CRYs inhibit CLOCK/BMAL1 activity upon their translocation into the nucleus, thus constituting a negative arm in the circadian feedback loop. CLOCK/ BMAL1 also activate expression of nuclear receptors ROR and REV-ERBα, which in turn respectively activate and inhibit the transcription of Bmal1 and other target genes containing retinoic acid-related orphan receptor response elements.Although the circadian clock is active in most mammalian tissues, the battery of genes under circadian regulation is largely tissue specific (2), suggesting that the circadian clock modulates physiological processes unique to each organ. Here we have focused on the role of the clock within skin, an organ dominated on the one hand by the cycling hair follicles and on the other by the continuously r...

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“…Badania epidemiologiczne wskazują, że w procesie inicjacji SCC dużą rolę odgrywa przewlekła ekspozycja na promieniowanie UV, a rozwój tego raka jest ściśle skorelowany z regularnym, długotrwałym narażeniem na UV, czego oznaką jest fotostarzenie skóry i objawy elastozy [3,37].…”

Section: Rak Płaskonabłonkowyunclassified

“…W rozwoju raka podstawnokomórkowego, podobnie jak w przypadku raka kolczystokomórkowego, główną rolę odgrywa długotrwała ekspozycja na promieniowanie UV. Należy podkreślić, że wyższe ryzyko rozwoju BCC niesie przede wszystkim ostra ekspozycja skóry na UV, powodująca wielokrotnie powtarzające się w ciągu życia oparzenia słonecz-ne [3,37].…”

Section: Rak Podstawnokomórkowyunclassified

The effect of solar ultraviolet radiation (UVR) on induction of skin cancers

Pacholczyk¹,

Czernicki²,

Ferenc³

2016

Med Pr

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StreszczeniePromieniowanie ultrafioletowe (UV) jest fizycznym czynnikiem mutagennym i karcynogennym. Do powierzchni Ziemi dociera ok. 95% promieniowania ultrafioletowego A (UVA) (320-400 nm) i ok. 5% UVB (280-320 nm). Naturalnym czynnikiem ochronnym skóry przed UV jest melanina. Do raków skóry, których rozwój jest związany z długotrwałym narażeniem na promieniowanie UV, zalicza się niebarwnikowe raki skóry (non-melanoma skin cancers -NMSC) -raka podstawnokomórkowego (basal cell carcinoma -BCC) i raka kolczystokomórkowego (squamous cell carcinoma -SCC) oraz czerniaka złośliwego skóry (cutaneous malignant melanoma -CMM). Wysokie ryzyko rozwoju BCC związane jest z ostrą i wielokrotną ekspozycją na UV, powodującą oparzenia słoneczne. Badania molekularne BCC wykazały zaburzenia na szlaku regulacji sygnalizacji komórkowej sonic hedgehog (SHH), które były związane z mutacjami genu supresorowego PTCH1 (protein patched homolog 1). Ryzyko rozwoju BCC jest również związane z polimorfizmem genu receptora melanokortyny-1 (MC1R). Obserwowane w komórkach BCC mutacje genu P53 klasyfikowano jako wtórne zmiany genetyczne. W komórkach SCC mutacje indukowane UV najczęściej dotyczyły genu P53. W rozwoju SCC istotne znaczenie ma zwiększona ekspresja genu enzymu cyklooksygenazy-2 (COX-2). Innym czynnikiem patogenetycznym SCC jest nasilenie syntezy cytokin prozapalnych (czynnika martwicy nowotworu α (tumor necrosis factor α -TNF-α), interleukiny-1 α (IL-1α), IL-1β i IL-6). Obecnie w patogenezie CMM powszechnie uznawana jest rola UVB. W komórkach CMM notowano mutacje w genach: p16 INK4A (cyclin-dependent kinase inhibitor 2A INK4A), genie kodującym cyklinozależną kinazę 4 (cyclin-dependent kinase 4 -CDK4), Ras, PTEN (phosphatase and tensin homolog deleted on chromosome 10) i BRAF (proto-oncogene B-Raf). Mutacje genu BRAF stwierdzano w ok. 50% przypadków CMM. Mutacje genu P53 nie są charakterystyczne dla komórek CMM. Med. Pr. 2016;67(2):255-266 Słowa kluczowe: rak podstawnokomórkowy, promieniowanie UV, czerniak, rak płaskonabłonkowy, uszkodzenia DNA, melanina AbstractUltraviolet radiation is a physical mutagenic and cancerogenic factor. About 95% of ultraviolet A (UVA) (320-400 nm) and 5% of UVB (280-320 nm) reach the Earth's surface. Melanin is a natural skin protective factor against UV radiation. Skin cancers associated with long-term exposure to UV radiation are: basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). The high risk of BCC development is related to acute and repeated exposure to UV causing sunburn. Molecular studies of BBC demonstrated disorders in sonic hedgehog (SHH) cell signaling regulation pathway, associated with the suppressor protein patched homolog 1 gene (PTCH1) mutations. The risk of the BCC development is related to the polymorphism of melanokortin-1 receptor gene (MC1R). Tumor P53 gene mutations observed in BCC cells has been classified as secondary genetic changes. In SCC cells UV-induced mutations were mostly related to P53 gene. Increased expression of cyclooxig...

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Skin Cancer: New Markers for Better Prevention

Cited by 77 publications

References 311 publications

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis

The effect of solar ultraviolet radiation (UVR) on induction of skin cancers

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