scholarly journals Identification of master regulator genes of UV response and their implications for skin carcinogenesis

2018 ◽  
Vol 40 (5) ◽  
pp. 687-694 ◽  
Author(s):  
Yao Shen ◽  
Gabriel Chan ◽  
Michael Xie ◽  
Wangyong Zeng ◽  
Liang Liu
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Genome Stability ◽  
Thyroid Hormone Receptor ◽  
Human Keratinocytes ◽  
Selective Inhibition ◽  
Skin Carcinogenesis ◽  
Specific Gene ◽  
Protein Activity ◽  
Skin Cell

AbstractSolar UV radiation is a major environmental risk factor for skin cancer. Despite decades of robust and meritorious investigation, our understanding of the mechanisms underlying UV-induced skin carcinogenesis remain incomplete. We previously performed comprehensive transcriptomic profiling in human keratinocytes following exposure to different UV radiation conditions to generate UV-specific gene expression signatures. In this study, we utilized Virtual Inference of Protein Activity by Enriched Regulon (VIPER), a robust systems biology tool, on UV-specific skin cell gene signatures to identify master regulators (MRs) of UV-induced transcriptomic changes. We identified multiple prominent candidate UV MRs, including forkhead box M1 (FOXM1), thyroid hormone receptor interactor 13 and DNA isomerase II alpha, which play important roles in cell cycle regulation and genome stability. MR protein activity was either activated or suppressed by UV in normal keratinocytes. Intriguingly, many of the UV-suppressed MRs were activated in human skin squamous cell carcinomas (SCCs), highlighting their importance in skin cancer development. We further demonstrated that selective inhibition of FOXM1, whose activity was elevated in SCC cells, was detrimental to SCC cell survival. Taken together, our study uncovered novel UV MRs that can be explored as new therapeutic targets for future skin cancer treatment.

Effect of Retinoic Acid on Apoptosis and DNA Repair in Human Keratinocytes after UVB Irradiation

2000 ◽  
Vol 4 (1) ◽  
pp. 2-7 ◽  
Author(s):  
Gang Li ◽  
Jason A. Bush ◽  
Vincent C. Ho
Keyword(s):  
Dna Repair ◽  
Retinoic Acid ◽  
Skin Cancer ◽  
Human Keratinocytes ◽  
Epidemiological Studies ◽  
Skin Carcinogenesis ◽  
Apoptosis Assay ◽  
Initiation Stage ◽  
Induced Apoptosis ◽  
Damaged Dna

Background: Skin cancer is extremely common. Epidemiological studies indicated that ultraviolet radiation (UV) is the primary cause for skin cancers, and that retinoic acid (RA) is able to inhibit this UV-induced skin carcinogenesis; however, the molecular mechanism of the anti-UV action of RA is unclear. Objective: The purpose of this study is to investigate if RA enhances the removal of UV-induced DNA damage. Methods: The effect of RA on UV-induced apoptosis and DNA repair was investigated by ELISA apoptosis assay and CAT assay. Results: Both all-trans-RA and 9-cis-RA did not promote UV-induced apoptosis nor the repair of UV-damaged DNA in human keratinocytes. Furthermore, RA did not induce the expression of p53. Conclusion: The inhibition of RA on skin carcinogenesis is not due to enhanced removal of UV-damaged DNA. Therefore, RA does not inhibit skin cancer development at the initiation stage, but possibly at the promotion and progression stages.

scholarly journals UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
Laura Pacini ◽  
Maria Grazia Ceraolo ◽  
Assunta Venuti ◽  
Giusi Melita ◽  
Uzma A. Hasan ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Uv Radiation ◽  
Uv Irradiation ◽  
Human Keratinocytes ◽  
Skin Carcinogenesis ◽  
Primary Human Keratinocytes ◽  
Tlr9 Expression ◽  
Hpv Types ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

ABSTRACT Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist ΔNp73α, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis. IMPORTANCE Beta HPV types have been suggested to act as cofactors in UV-induced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation.

scholarly journals Exploiting DNA Endonucleases to Advance Mechanisms of DNA Repair

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 530
Author(s):  
Marlo K. Thompson ◽  
Robert W. Sobol ◽  
Aishwarya Prakash
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Gene Editing ◽  
Adaptive Immune System ◽  
Zinc Finger Nucleases ◽  
Specific Gene ◽  
Target Sequence ◽  
Transcription Activator ◽  
Low Cytotoxicity

The earliest methods of genome editing, such as zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENs), utilize customizable DNA-binding motifs to target the genome at specific loci. While these approaches provided sequence-specific gene-editing capacity, the laborious process of designing and synthesizing recombinant nucleases to recognize a specific target sequence, combined with limited target choices and poor editing efficiency, ultimately minimized the broad utility of these systems. The discovery of clustered regularly interspaced short palindromic repeat sequences (CRISPR) in Escherichia coli dates to 1987, yet it was another 20 years before CRISPR and the CRISPR-associated (Cas) proteins were identified as part of the microbial adaptive immune system, by targeting phage DNA, to fight bacteriophage reinfection. By 2013, CRISPR/Cas9 systems had been engineered to allow gene editing in mammalian cells. The ease of design, low cytotoxicity, and increased efficiency have made CRISPR/Cas9 and its related systems the designer nucleases of choice for many. In this review, we discuss the various CRISPR systems and their broad utility in genome manipulation. We will explore how CRISPR-controlled modifications have advanced our understanding of the mechanisms of genome stability, using the modulation of DNA repair genes as examples.

scholarly journals Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Ling-I Hsu ◽  
Meei-Maan Wu ◽  
Yuan-Hung Wang ◽  
Cheng-Yeh Lee ◽  
Tse-Yen Yang ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Cancer Risk ◽  
Arsenic Exposure ◽  
Skin Carcinogenesis ◽  
Glutathione S Transferase ◽  
Xenobiotic Detoxification ◽  
Skin Cancer Risk ◽  
Metabolic Genes ◽  
Skin Cancers ◽  
And Gender

Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated.

Multiple Keratoacanthomas Arising Post-UVB Therapy

2004 ◽  
Vol 8 (4) ◽  
pp. 239-243 ◽  
Author(s):  
Kenneth J. Craddock ◽  
Jaggi Rao ◽  
Gilles J. Lauzon ◽  
Victor A. Tron
Keyword(s):  
Adverse Effect ◽  
Squamous Cell Carcinoma ◽  
Skin Cancer ◽  
Cell Carcinoma ◽  
Uv Radiation ◽  
Squamous Cell ◽  
Etiologic Agent ◽  
Etiologic Factor ◽  
Uv Treatment ◽  
Uvb Phototherapy

Background: Ultraviolet (UV) radiation is known to be an important etiologic agent in the development of skin cancer. Keratoacanthoma is an unusual, well-described cutaneous neoplasm that resembes squamous cell carcinoma but spontaneously resolves. Rarely, multiple keratoacanthomas may develop. Objective We present a case of multiple keratoacanthomas in a patient with psoriasis who had received UVB phototherapy. These lesions were hyperkeratotic papules, many of which spontaneously resolved and demonstrated the histologic characteristics of keratoacanthoma. Conclusion: We believe that UV radiation is the most likely etiologic factor in this patient's development of multiple keratoacanthomas. We wish to bring to the attention of clinicians this unusual adverse effect of UV treatment.

scholarly journals Anti-Skin Cancer Activities of Apostichopus japonicus Extracts from Low-Temperature Ultrasonification Process

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Nam Young Kim ◽  
Woon Yong Choi ◽  
Soo Jin Heo ◽  
Do Hyung Kang ◽  
Hyeon Yong Lee
Keyword(s):  
Skin Cancer ◽  
Low Temperature ◽  
Apostichopus Japonicus ◽  
Human Keratinocytes ◽  
Malignant Cell ◽  
Extraction Process ◽  
Hot Water ◽  
Skin Tumor ◽  
Bioactive Substances ◽  
Marine Biomass

Objectives. This work aimed to enhance anti-skin cancer activities of Apostichopus japonicus, spiky sea cucumber, through ultrasonification extraction process at low temperature. Methods. Dried Apostichopus japonicus was extracted with an ultrasonification process at 50°C and 95 kHz for two hours (UE), and anti-skin cancer activities of the extract from the UE were also compared with those from conventional extraction processes using hot water (WE) or 70% ethanol at 80°C (EE) for 12 hours. Results. The amount of canthaxanthin in the UE was higher than that in the WE or EE, and its cytotoxicity against human keratinocytes was less than the others. The extract from the UE showed 93.5% inhibition against human malignant cell growth, which was also higher than those from both WE and EE. The extract from the UE demonstrated the ability of inhibiting both cancer cell proliferation and metastasis by downregulating the skin tumor-promoting genes such as Bcl-2, STAT3, and MMP-9. Conclusions. The ultrasonification process was proved to be effective especially in extracting heat-sensitive marine biomass, A. japonicus having higher amounts of canthaxanthin and better anti-skin cancer activities, possibly due to less destruction and high elution of bioactive substances under low temperature extraction condition.

scholarly journals Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression

2002 ◽  
Vol 195 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Jeffrey P. Walterscheid ◽  
Stephen E. Ullrich ◽  
Dat X. Nghiem
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Immune Suppression ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Cellular Damage ◽  
Uv Exposure ◽  
Delayed Type Hypersensitivity ◽  
Lipid Mediator ◽  
Paf Receptor

Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E2, interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.

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