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David A Greenhalgh - One of the best experts on this subject based on the ideXlab platform.
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14 3 3σ stratifin expression in hk1 ras fos δ5ptenflx transgenic mouse Skin Carcinogenesis reveals an early inhibitory role lost during mdm2 activated p53 inactivated malignant progression
2017Co-Authors: Carol Mcmenemy, Dajiang Guo, Ashley Cochrane, Karen Crookston, James Boyle, Jean A Quinn, David A GreenhalghAbstract:The mechanisms driving or inhibiting Skin Carcinogenesis depend upon the contexts created by temporal acquisition of each mutation when pitted against the sentinel systems that have evolved to resist progression at each stage. To model this process, transgenic mice have been established that express activated rasHa and fos oncogenes together with RU486-inducible [K14.creP/lox-P] PTEN [5PTENflx] mutation exclusively in the epidermis. HK1.ras/fos/Δ5PTEN mice exhibit papillomas that convert to well-differentiated SCC following p53 loss and progress to SCCs following subsequent p21 loss/p-AKT1 activation. In addition, recently a suprabasal-to-basal increase in MDM2 activation [p-MDM2166] was observed associated with this p53 loss. Thus, given that 14-3-3σ/stratifin is a chaperone protein which removes/relocates MDM2 for degradation, 14-3-3σ/stratifin expression status in papillomatogenesis and progression to carcinoma was investigated. Already 14-3-3σ/Stratifin is known to play pivotal roles in keratinocyte growth, differentiation, and Carcinogenesis but its exact protective [or potentially oncogenic] functions in differing tumour contexts remain unclear, as some studies show that 14-3-3σ/stratifin acts as a tumour suppressor and loss drives cancer; whilst others show increased expression associates with tumour invasion. Initially, compared to normal Skin, RU486-treated tri-genic ras/fos/PTENflx epidermis expressed elevated 14-3-3σ/stratifin in resultant hyperplasia, and 14-3-3σ/stratifin remained strongly expressed in both basal and suprabasal layers of p53+ve /p21+ve papillomas. However, 14-3-3σ/stratifin expression diminished following malignant conversion, concomitant with p53 loss but persistent p21 expression. New HK1.ras/fos/5PTEN data demonstrate that this 14-3-3σ reduction/loss in basal layer keratinocytes was also associated with the suprabasal-to-basal expression of activated p-MDM2166; consistent with a mechanism of reduced basal layer p53 expression driving the susceptibility of late-stage papillomas to malignant conversion. Further, in 3D living Skin assays, reduction/loss in 14-3-3σ expression was associated with an increased invasive potential. Collectively these data suggest that, in this context, 14-3-3σ plays important tumour suppressive roles in papillomas which inhibit MDM2 function and help maintain p53. However, diminished 14-3-3σ expression may facilitate MDM2-mediated loss of p53 which aids malignant conversion.
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abstract 930 induciblerock 2 rashacooperation requires wound promotion to achieve malignancy in transgenic mouse Skin Carcinogenesis whereas induciblerock 2 ptenloss fails to achieve benign papilloma
Cancer Research, 2014Co-Authors: Siti Fathiah Masre, Michael S Samuel, Michael F Olson, David A GreenhalghAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA To study tumour progression mechanism in vivo, ROCK 2 signalling deregulation and co-operation with activated rasHa or PTEN loss was investigated in transgenic mouse Skin Carcinogenesis. Transgenic mice that expressed a 4-hydroxytamoxifen (4HT)-activated human ROCK 2-estrogen receptor fusion transgene from a keratin 14 promoter [K14.ROCKer] were crossed to mice expressing activated rasHa exclusively in epidermal transit amplifying keratinocytes [HK1.ras-ROCKer] or mice where cutaneous PTEN loss was achieved in basal layers, hair follicles and stem cell keratinocytes via topical RU486 treatment of bi-genic K14.creP/Δ5PTENflx genotypes [K14.Δ5PTEN-ROCKer]. Initial 4HT-treatments of K14.ROCKer mice [3/wk; 26 wks] induced epidermal and follicular hyperplasia but no papillomas; whilst treatment of HK1.ras line 1205 gave ear tag papillomas [10-12 wks] typically smaller than vehicle controls, but no malignant conversion. In contrast, 4-HT treated HK1.ras-Rocker papillomas [10-12 wks] exhibited areas of carcinoma in situ and well-differentiated squamous cell carcinoma [wdSCC]. With time [16-20wks] wdSCC areas increased, concomitant with loss of p53, increased p-AKT and altered differentiation marker expression; however histotypes remained wdSCC despite continued 4HT-induced Rock 2 activity; as confirmed by downstream MYPT-1 phosphorylation. Furthermore, papillomas regressed whenever 4-HT treated HK1.ras-Rocker mice lost ear tags, suggesting that continued promotion from wounding during papillomatogenesis was critical to achieving the appropriate [late-stage] papilloma context that facilitated Rock 2-mediated conversion. To test this idea, K14.ROCKer mice were crossed to HK1.ras line 1276, which is insensitive to wound promotion, and such bi-genic mice did not exhibit papillomas; while in reverse, demonstrating the need for initiation, classic TPA-promoted K14.ROCKer mice were also devoid of papillomas. In addition, as previously rasHa/PTENnull mice exhibited papillomas prone to conversion on acquisition of an additional oncogene [e.g. fos], K14.ROCKer mice were bred into a K14.cre.Δ5PTEN strain and bi-genic mice treated with Ru486 [3wks] and 4HT [>26wks]. Again, in the absence of rasHa no papillomas were observed and mice exhibited increased hyperplasia and altered differentiation consistent with disruption of epidermal physiology. These data suggest that Rock 2 deregulation plays major roles in malignant conversion and progression, and in cooperation with rasHa activation or PTEN loss, the mechanism requires additional promotion/initiation events during papillomatogenesis to create the context of late-stage papilloma where Rock 2 activities become causal; an idea being tested in tri-genic HK1.ras/Δ5PTEN-Rocker genotypes. Citation Format: Siti F. Masre, Michael S. Samuel, Michael F. Olson, David A. Greenhalgh. Inducible ROCK 2/rasHa cooperation requires wound promotion to achieve malignancy in transgenic mouse Skin Carcinogenesis, whereas inducible ROCK 2/PTEN loss fails to achieve benign papilloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 930. doi:10.1158/1538-7445.AM2014-930
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pten ablation in ras ha fos Skin Carcinogenesis invokes p53 dependent p21 to delay conversion while p53 independent p21 limits progression via cyclin d1 e2 inhibition
Oncogene, 2014Co-Authors: Denggao Yao, Jean A Quinn, F H Macdonald, David A GreenhalghAbstract:To investigate tumour progression mechanism in transgenic mouse Skin Carcinogenesis, inducible PTEN ablation (Δ5PTENflx) was targeted to the epidermis of mice expressing activated rasHa/fos oncogenes (HK1.ras and HK1.fos). RU486-treated HK1.ras/fos-Δ5PTENflx epidermis exhibited significant keratinocyte proliferation resulting in hyperplasia and proliferating cysts. While HK1.ras/fos-Δ5PTENflx papillomatogenesis was accelerated, malignant conversion was delayed and tumours exhibited well-differentiated squamous cell carcinoma (wdSCC) histotypes, suggesting inhibition of early-stage malignant progression. Immediate elevated p53/p21 expression was observed in HK1.ras/fos-Δ5PTENflx hyperplasia, cysts and papillomas, and while malignant conversion required p53 loss, elevated p21 expression persisted in most wdSCCs to limit further progression, unless p21 was also lost and wdSCC progressed to more aggressive carcinomas. In contrast, TPA-promoted (that is, c-fos-activated) bi-genic HK1.ras-Δ5PTENflx cohorts lost p53/p21 expression during early papillomatogenesis and rapidly produced poorly differentiated carcinomas (pdSCCs) with high BrdU-labelling and elevated cyclin D1/E2 expression levels, indicative of a progression mechanism driven by failures in cell-cycle control. Intriguingly, HK1.ras/fos-Δ5PTENflx wdSCCs did not exhibit similar failures, as western and immunofluorescence analysis found downregulated cyclin E2 whenever p21 persisted; further, while westerns detected elevated cyclin D1, immunofluorescence identified reduced expression in proliferative basal layer nuclei and a redistributed expression profile throughout p21-positive wdSCC keratinocytes. These data demonstrate that rapid early epidermal responses to rasHa/fos/ΔPTEN co-operation involve induction of p53/p21 to alter differentiation and divert excessive proliferation into cyst formation. Further, despite three potent oncogenic insults p53 loss was required for malignant conversion, and following p53 loss persistent, p53-independent p21 expression possessed the potency to limit early-stage malignant progression via cyclin D1/E2 inhibition.
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activated p akt but not mdm2 drives malignant progression in ras fos pten null Skin Carcinogenesis via p53 p21 loss and elevated cyclin d1 e2 expression
2013Co-Authors: F H Macdonald, Denggao Yao, Jean A Quinn, David A GreenhalghAbstract:Tumour progression depends on a complex combination of the genetic mutation milieu pitted against the sentinel systems that have evolved to resist Carcinogenesis at each specific stage. To investigate tumour progression mechanism in transgenic mouse Skin Carcinogenesis, inducible PTEN ablation [Δ5PTEN] was introduced into the epidermis of mice expressing activated rasHa/fos oncogenes. RU486-treated HK1.ras/fos-Δ5PTEN mice exhibited accelerated papillomatogenesis but malignant conversion was delayed due to compensatory p53/p21 expression. Following p53 loss malignant progression was limited to well-differentiated squamous cell carcinoma via persistent p21 expression and down regulation of cyclin E2. Analysis of AKT activity during papillomatogenesis showed reduced p-AKT expression, associated with fos/PTEN feedback, which returned following p53 loss to circumvent/antagonise p21 expression; co-operate with MAPK signalling [i.e. elevated ERK1/2 expression]; and accelerate tumour progression via increased cyclin D1 and E2 expression. In contrast elevated, suprabasal MDM2 expression in p53-positive papillomas was lost in parallel to p53 loss; hence sustained MDM2-mediated p53 ubiquination does not appear to influence this progression mechanism. These data suggest p53/p21 counter deregulated MAPK signalling during papillomatogenesis and help minimise consequences of PTEN loss via p-AKT inhibition. Stepwise p53/p21 loss subsequently facilitates ras/MAPK/fos co-operation with PTEN/AKT activities to accelerate malignant progression via major failures in cell cycle control. The interplay between these common mutations thus create unique contexts that have important implications for therapies geared to reactivating p53/p21 functions or that target ras/MAPK/fos and PTEN/AKT signalling pathways.
John Digiovanni - One of the best experts on this subject based on the ideXlab platform.
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abstract 4071 targeted disruption of t cell protein tyrosine phosphatase in mouse epidermis reveals its critical role in chemically induced Skin Carcinogenesis
Cancer Research, 2016Co-Authors: Hyunseung Lee, John Digiovanni, Mihwa Kim, Liza D Morales, Thomas J Slaga, Dae Joon KimAbstract:Environmental factors such as chemical toxicants contribute to the development of Skin cancer by creating mutations in housekeeping genes and proto-oncogenes which disrupt intracellular signaling mechanisms. One vital signaling mechanism is tyrosine phosphorylation signaling. Phosphotyrosine signaling is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Recently we reported TC-PTP (PTPN2) is critical regulator of STAT3 signaling in mouse keratinocytes. To assess the role of TC-PTP in Skin Carcinogenesis, we generated epidermal-specific TC-PTP-deficient (K14Cre.PTPN2 fl/fl ) transgenic mice. Loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency in epidermis resulted in a significant increase in epidermal thickness and hyperproliferation (assessed by bromodeoxyuridine (BrdU) labeling index) compared to control mice following treatment with the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Consistently, primary keratinocytes derived from TC-PTP-deficient mice showed a faster growth rate. To further investigate the role of TC-PTP in Skin Carcinogenesis, TC-PTP-deficient mice were subjected to two-stage Skin Carcinogenesis analysis. TC-PTP-deficient mice showed a shortened latency of tumor development and significantly increased numbers of tumors compared to control mice, demonstrating TC-PTP deficiency predisposes mice to Skin Carcinogenesis. The data reveals TC-PTP may be a novel potential target for the prevention of Skin cancer due to its role in the regulation of proliferation and apoptosis in epidermis. Citation Format: Hyunseung Lee, Mihwa Kim, Liza D. Morales, Thomas J. Slaga, John DiGiovanni, Dae J. Kim. Targeted disruption of T-cell protein tyrosine phosphatase in mouse epidermis reveals its critical role in chemically-induced Skin Carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4071.
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Increased susceptibility to Skin Carcinogenesis associated with a spontaneous mouse mutation in the palmitoyl transferase Zdhhc13 gene
Journal of Investigative Dermatology, 2015Co-Authors: Carlos J Perez, L. Martínez-santamaría, Gyu Song, Eleonora Napoli, Brian M Iritani, Jean Jaubert, Alexsandra Espejo, Lars Mecklenburg, John DigiovanniAbstract:Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated Skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical Skin Carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in Skin Carcinogenesis.
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protective role of cathepsin l in mouse Skin Carcinogenesis
Molecular Carcinogenesis, 2012Co-Authors: Fernando Jose Benavides, Susan M. Fischer, Jorge Blando, Donna Frances Kusewitt, Carlos A Perez, Oscar Contreras, Jianjun Shen, Lisa M Coussens, John DigiovanniAbstract:Lysosomal cysteine protease cathepsin L (CTSL) is believed to play a role in tumor progression and is considered a marker for clinically invasive tumors. Studies from our laboratory using the classical mouse Skin Carcinogenesis model, with 7,12-dimethyl-benz[a]anthracene (DMBA) for initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) for promotion, showed that expression of CTSL is increased in papillomas and squamous cell carcinomas (SCC). We also carried out Carcinogenesis studies using Ctsl-deficient nackt (nkt) mutant mice on three different inbred backgrounds. Unexpectedly, the multiplicity of papillomas was significantly higher in Ctsl-deficient than in wild-type mice on two unrelated backgrounds. Topical applications of TPA or DMBA alone to the Skin of nkt/nkt mice did not induce papillomas, and there was no increase in spontaneous tumors in nkt/nkt mice on any of the three inbred backgrounds. Reduced epidermal cell proliferation in Ctsl-deficient nkt/nkt mice after TPA treatment suggested that they are not more sensitive than wild-type mice to TPA promotion. We also showed that deficiency of CTSL delays terminal differentiation of keratinocytes, and we propose that decreased elimination of initiated cells is at least partially responsible for the increased papilloma formation in the nackt model. Mol. Carcinog. © 2011 Wiley Periodicals, Inc.
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skhin sprd a new genetically defined inbred hairless mouse strain for uv induced Skin Carcinogenesis studies
Experimental Dermatology, 2012Co-Authors: Carlos A Perez, John Digiovanni, Donna F. Kusewitt, Claudio J. Conti, Susan M. Fischer, Jan Parkerthornburg, Carol Mikulec, Fernando BenavidesAbstract:Abstract: Strains of mice vary in their susceptibility to ultra-violet (UV) radiation-induced Skin tumors. Some strains of hairless mice (homozygous for the spontaneous Hrhr mutation) are particularly susceptible to these tumors. The Skin tumors that develop in hairless mice resemble, both at the morphologic and molecular levels, UV-induced squamous cell carcinomas (SCC) and their precursors in human. The most commonly employed hairless mice belong to the SKH1 stock. However, these mice are outbred and their genetic background is not characterized, which makes them a poor model for genetic studies. We have developed a new inbred strain from outbred SKH1 mice that we named SKHIN/Sprd (now at generation F31). In order to characterize the genetic background of this new strain, we genotyped a cohort of mice at F30 with 92 microsatellites and 140 single nucleotide polymorphisms (SNP) evenly distributed throughout the mouse genome. We also exposed SKHIN/Sprd mice to chronic UV irradiation and showed that they are as susceptible to UV-induced Skin Carcinogenesis as outbred SKH1 mice. In addition, we proved that, albeit with low efficiency, inbred SKHIN/Sprd mice are suitable for transgenic production by classical pronuclear microinjection. This new inbred strain will be useful for the development of transgenic and congenic strains on a hairless inbred background as well as the establishment of syngeneic tumor cell lines. These new tools can potentially help elucidate a number of features of the cutaneous response to UV irradiation in humans, including the effect of genetic background and modifier genes.
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lack of effect of 94 ghz radio frequency radiation exposure in an animal model of Skin Carcinogenesis
Carcinogenesis, 2001Co-Authors: Patrick A Mason, John Digiovanni, Thomas J Walters, Charles W Beason, James R Jauchem, Edward J Dick, Kavita MahajanAbstract:Although there is no evidence that electromagnetic energy in the radio frequency radiation (RFR) band is mutagenic, there have been suggestions that RFR energy might serve as either a promoter or co-promoter in some animal models of Carcinogenesis. Recent developments in electromagnetic technology have resulted in the manufacture of RFR sources capable of generating frequencies in the millimeter wavelength (MMW) range (30-300 GHz). Because absorption of MMW energy occurs in the Skin, it is to be expected that long-term detrimental health effects, if any, would most likely be manifest in the Skin. In this study we investigated whether a single (1.0 W/cm(2) for 10 s) or repeated (2 exposures/week for 12 weeks, 333 mW/cm(2) for 10 s) exposure to 94 GHz RFR serves as a promoter or co-promoter in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced SENCAR mouse model of Skin Carcinogenesis. Neither paradigm of MMW exposure significantly affected papilloma development, as evidenced by a lack of effect on tumor incidence and multiplicity. There was also no evidence that MMW exposure served as a co-promoter in DMBA-induced animals repeatedly treated with 12-O-tetradecanoylphorbol 13-acetate. Therefore, we conclude that exposure to 94 GHz RFR under these conditions does not promote or co-promote papilloma development in this animal model of Skin Carcinogenesis.
Sukta Das - One of the best experts on this subject based on the ideXlab platform.
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eugenol restricts dmba croton oil induced Skin Carcinogenesis in mice downregulation of c myc and h ras and activation of p53 dependent apoptotic pathway
Journal of Dermatological Science, 2010Co-Authors: Debolina Pal, Sarmistha Banerjee, Sudeshna Mukherjee, Anup Roy, Chinmay Kumar Panda, Sukta DasAbstract:Abstract Background Eugenol is the active component of essential oil isolated from clove ( Syzigium aromaticum ). Eugenol has antimutagenic, antigenotoxic, anti-inflammatory properties. The anticarcinogenic effect of eugenol was evident in different types of cell lines. However, its anticarcinogenic effect in in vivo has not yet been fully explored. Objective The aim of this study is to evaluate the chemopreventive potential of eugenol in an experimental Skin Carcinogenesis mice model system. Method Skin tumor was induced by topical application of DMBA croton oil in Swiss mice. To assess the chemopreventive potential of eugenol, it was orally administered 15 days prior carcinogen treatment. The development of Skin Carcinogenesis was confirmed by histopathological analysis. Cellular proliferation and apoptosis in the Skin tumor were analyzed by in situ cellular proliferation and in situ cell death assay. Expression of some proliferation and apoptosis associated genes was analyzed by RT-PCR and protein expression was analyzed by Western blot. Results Reduction in incidence and sizes of Skin tumors along with overall increase in survival of mice were seen due to eugenol treatment. Restriction of Skin Carcinogenesis at the dysplastic stage along with reduced rate of cellular proliferation and increase in apoptosis were evident in eugenol treated Skin tumors. Eugenol treatment led to the downregulation of c-Myc , H-ras and Bcl2 expression along with upregulation of P53 , Bax and active Caspase-3 expression in the Skin lesions. Conclusion Restriction of Skin Carcinogenesis at dysplastic stage by eugenol was due to attenuation of c-Myc, H-ras and modification of some p53 associated gene expression.
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amarogentin can reduce hyperproliferation by downregulation of cox ii and upregulation of apoptosis in mouse Skin Carcinogenesis model
Cancer Letters, 2006Co-Authors: Prosenjit Saha, Suvra Mandal, Ashes Das, Sukta DasAbstract:Swertia chirata, is a bitter plant, used in the Indian system of medicine (Ayurveda) for various human ailments. Our laboratory was the first to report the chemopreventive effect of this plant. The antiproliferative and pro-apoptotic action of amarogentin rich fraction of S. chirata is now demonstrated on a mouse Skin Carcinogenesis model. Immunohistochemical localization revealed a reduction in proliferating and increase in apoptotic cells in Skin lesion following treatment, also reflected in the expression of molecular markers--Cox-II and caspase-3 proteins. It may be possible to calculate relative risk, relative protection and attributable risk from the action of test agents on proliferation and apoptosis.
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Anticarcinogenic effects of an aqueous infusion of cloves on Skin Carcinogenesis.
Asian Pacific Journal of Cancer Prevention, 2005Co-Authors: Sarmistha Banerjee, Sukta DasAbstract:Abstract Spices and flavouring agents are now receiving incresaing attention as many of them have been shown to haveanticarcinogenic properties. Cloves, sundried unopened flower buds from the plant Syzygium aromaticum L, arecommonly used as a spice and food flavour. The present study was designed to investigate the chemopreventiveaction of aqueous infusion of cloves on 9,10-dimethyl benz(a)anthracene (DMBA) and croton oil induced SkinCarcinogenesis in Swiss mice. The results indicate protection against Skin papilloma formation in a dose dependentmanner. It has been shown that oral administration of aqueous infusions of clove at a dose of 100 µ l/ mouse/day notonly delays the formation of papilloma but also reduces the incidence of papilloma as well as the cumulative numberof papillomas per papilloma bearing mouse. Our observations suggest a promising role for cloves in restriction ofthe Carcinogenesis process.Key Words : Clove - Skin Carcinogenesis - Cancer chemoprevention - Anticarcinogen.
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inhibition of dmba croton oil induced two stage mouse Skin Carcinogenesis by diphenylmethyl selenocyanate
European Journal of Cancer Prevention, 2004Co-Authors: Rajat Kumar Das, Sukta Das, Samit Ghosh, Archana Sengupta, Sudin BhattacharyaAbstract:Selenium, an essential micronutrient, is associated with antioxidant functions, physiological defence mechanisms against different diseases including several types of cancers. Search for new selenium compounds with more chemopreventive activities and lesser toxicities are in progress. In the present study, the antioxidative roles of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated against 7,12-dimethylbenz(a)anthracene (DMBA)/croton oil-induced two-stage mouse Skin Carcinogenesis model. The compound was administered orally in carcinogen-induced mice in two different non-toxic doses: 2 mg/kg body weight and 3 mg/kg body weight. Significant inhibition in the incidence of papilloma formation (58-80%) as well as in the cumulative number of papilloma per papilloma-bearing mouse were observed in the treated groups as compared with the carcinogen control group. The compound was also found to significantly upregulate different phase II detoxifying enzymes in liver cytosol such as glutathione-S-transferase (P<0.01), catalase (P<0.01) and superoxide dismutase (SOD) (P<0.01) when measured after 15 days and also after 12 weeks of first DMBA treatment. Lipid peroxidation measured as the thiobarbituric acid reactive substances in liver microsomes was significantly inhibited (P<0.05) in a dose-dependent manner by diphenylmethyl selenocyanate. Thus the compound exerts its chemopreventive activity by reducing papilloma formation during chemically induced Carcinogenesis, which in turn, may be through modulating the level of lipid peroxidation and phase II detoxifying enzyme system at the doses evaluated.
Zigang Dong - One of the best experts on this subject based on the ideXlab platform.
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bestatin cream impairs solar simulated light driven Skin inflammation and Skin Carcinogenesis in mice
Journal of Investigative Dermatology, 2021Co-Authors: Simin Zhao, Ke Yao, Kangdong Liu, Limeng Huang, Yanan Jiang, Ziming Dong, Zigang DongAbstract:Leukotriene A4 hydrolase (LTA4H) is an enzyme that catalyzes the production of the inflammatory mediator leukotriene B4, which is involved in inflammatory responses mediated through the leukotriene B4/leukotriene B4 receptor type 1 (BLT1) signaling pathway. In this study, we investigated whether bestatin, an LTA4H inhibitor, could suppress Skin acute inflammation and Carcinogenesis. In the clinical sample, BLT1 was significantly induced in human Skin tissues after acute solar simulated light (SSL) exposure. BLT1 and NF-κB p65 expressions were also increased in acute SSL‒induced mouse Skin tissue. Furthermore, LTA4H and BLT1 were highly expressed in Skin chronic inflammation and squamous cell carcinomas. More importantly, topical administration of bestatin cream dramatically inhibited BLT1 expression in acute SSL‒induced human Skin tissues. BLT1 and NF-κB p65 expressions were also suppressed in acute SSL‒induced Lta4h-knockout and bestatin-treated mice Skin tissues. Moreover, we conducted long-term prevention and therapeutic studies, which showed that bestatin significantly attenuated SSL-induced Skin Carcinogenesis. Mechanistic studies showed that bestatin inhibited Skin Carcinogenesis by suppressing cell proliferation and inducing cell apoptosis through LTA4H‒BLT1‒protein kinase B‒NF-κB p65 pathway. Overall, our results suggest that topical application of novel cream containing bestatin might open a helpful avenue for SSL-induced Skin Carcinogenesis.
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abstract 5746 traf1 is required for solar uv induced Skin Carcinogenesis
Cancer Research, 2017Co-Authors: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Ruihua Bai, Tatyana A Zykova, Kenji Moriyama, Ann M Bode, Margarita Malakhova, Zigang DongAbstract:Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a member of the TRAF protein family, which regulates the canonical and non-canonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors is reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for Skin Carcinogenesis induced by chronic solar UV radiation. In vivo studies with solar UV exposure indicate that the deletion of TRAF1 results in the inhibition of AP-1 activity by down-regulating the induction of c-Fos and c-Jun by regulating ERK5 activity. Furthermore, we show that TRAF1 is required for solar UV-induced ERK5 activation. Mechanistic studies revealed that TRAF1 expression enhances the ubiquitination of ERK5 on K184, which is necessary for AP-1 activation. Altogether, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating Skin cancer. Citation Format: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Naomi Oi, Ruihua Bai, Tatyana A. Zykova, Dong Hoon Yu, Margarita Malakhova, Kenji Moriyama, Ann M. Bode, Zigang Dong. TRAF1 is required for solar UV-induced Skin Carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5746. doi:10.1158/1538-7445.AM2017-5746
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traf1 is critical for dmba solar uvr induced Skin Carcinogenesis
Journal of Investigative Dermatology, 2017Co-Authors: Hiroyuki Yamamoto, Joohyun Ryu, Eli Min, Ruihua Bai, Tatyana A Zykova, Kenji Moriyama, Ann M Bode, Zigang DongAbstract:TRAF1 is a member of the TRAF protein family, which regulates the canonical and noncanonical NF-κB signaling cascades. Although aberrant TRAF1 expression in tumors has been reported, the role of TRAF1 remains elusive. Here, we report that TRAF1 is required for solar UV-induced Skin Carcinogenesis. Immunohistochemical analysis showed that TRAF1 expression is up-regulated in human actinic keratosis and squamous cell carcinoma. In vivo studies indicated that TRAF1 expression levels in mouse Skin are induced by short-term solar UV irradiation, and a long-term Skin Carcinogenesis study showed that deletion of TRAF1 in mice results in a significant inhibition of Skin tumor formation. Moreover, we show that TRAF1 is required for solar UV-induced extracellular signal-regulated kinase–5 (ERK5) phosphorylation and the expression of AP-1 family members (c-Fos/c-Jun). Mechanistic studies showed that TRAF1 expression enhances the ubiquitination of ERK5 on lysine 184, which is necessary for its kinase activity and AP-1 activation. Overall, our results suggest that TRAF1 mediates ERK5 activity by regulating the upstream effectors of ERK5 and also by modulating its ubiquitination status. Targeting TRAF1 function might lead to strategies for preventing and treating Skin cancer.
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p38 map kinase plays a functional role in uvb induced mouse Skin Carcinogenesis
Molecular Carcinogenesis, 2011Co-Authors: Sally E Dickinson, Erik R Olson, Jack Zhang, Simon J Cooper, Tania Melton, Jane P Criswell, Ana Casanova, Zigang Dong, Kathylynn Saboda, Elizabeth T JacobsAbstract:UVB irradiation of epidermal keratinocytes results in the activation of the p38 mitogen-activated protein kinase (MAPK) pathway and subsequently activator protein-1 (AP-1) transcription factor activation and cyclooxygenase-2 (COX-2) expression. AP-1 and COX-2 have been shown to play functional roles in UVB-induced mouse Skin Carcinogenesis. In this study, the experimental approach was to express a dominant negative p38α MAPK (p38DN) in the epidermis of SKH-1 hairless mice and assess UVB-induced AP-1 activation, COX-2 expression, and the Skin Carcinogenesis response in these mice compared to wild-type littermates. We observed a significant inhibition of UVB-induced AP-1 activation and COX-2 expression in p38DN transgenic mice, leading to a significant reduction of UVB-induced tumor number and growth compared to wild-type littermates in a chronic UVB Skin Carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki-67 staining in p38DN mice compared to wild-type. Although we detected no difference in chronic apoptotic rates between transgenic and nontransgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB-induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the Skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV-induced Skin cancer in patients with sun damaged Skin, and suggest that inhibition of p38 signaling reduces Skin Carcinogenesis by inhibiting COX-2 expression and proliferation of UVB-irradiated cells.
Sudin Bhattacharya - One of the best experts on this subject based on the ideXlab platform.
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diphenylmethyl selenocyanate inhibits dmba croton oil induced two stage mouse Skin Carcinogenesis by inducing apoptosis and inhibiting cutaneous cell proliferation
Cancer Letters, 2005Co-Authors: Rajat Kumar Das, S Ugir K Hossain, Sudin BhattacharyaAbstract:Numerous epidemiological and experimental studies have showed the inverse relationship between dietary selenium intake and different types of cancer. Continuous efforts are going on to develop suitable organoselenium compounds, which can be used as cancer chemopreventive agents for human. In the present study, a synthetic organoselenium compound diphenylmethyl selenocyanate was evaluated for its ability to arrest cell proliferation and to induce apoptosis against 7,12-dimethylbenz[a]anthracene-croton oil induced two-stage mouse Skin Carcinogenesis model. Reduction in the incidence and number of papilloma, the preneoplastic lesion, was considered to be the mean of assessment. Significant decrease in the level of cell proliferation (p<0.01) and significant enhancement in the level of apoptosis (p<0.01) were found. Caspase-3, which contribute a part in the process of cellular apoptosis to prevent further cellular differentiation was also elevated significantly (P<0.01) during the treatment with the Se compound. These observations seem to be correlated with the significant reduction in the corresponding number of Skin papilloma formation after 12 weeks of experiment. Thus the compound, diphenylmethyl selenocyanate may be considered for further research to establish it as an effective cancer chemopreventive agent.
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inhibition of dmba croton oil induced two stage mouse Skin Carcinogenesis by diphenylmethyl selenocyanate
European Journal of Cancer Prevention, 2004Co-Authors: Rajat Kumar Das, Sukta Das, Samit Ghosh, Archana Sengupta, Sudin BhattacharyaAbstract:Selenium, an essential micronutrient, is associated with antioxidant functions, physiological defence mechanisms against different diseases including several types of cancers. Search for new selenium compounds with more chemopreventive activities and lesser toxicities are in progress. In the present study, the antioxidative roles of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated against 7,12-dimethylbenz(a)anthracene (DMBA)/croton oil-induced two-stage mouse Skin Carcinogenesis model. The compound was administered orally in carcinogen-induced mice in two different non-toxic doses: 2 mg/kg body weight and 3 mg/kg body weight. Significant inhibition in the incidence of papilloma formation (58-80%) as well as in the cumulative number of papilloma per papilloma-bearing mouse were observed in the treated groups as compared with the carcinogen control group. The compound was also found to significantly upregulate different phase II detoxifying enzymes in liver cytosol such as glutathione-S-transferase (P<0.01), catalase (P<0.01) and superoxide dismutase (SOD) (P<0.01) when measured after 15 days and also after 12 weeks of first DMBA treatment. Lipid peroxidation measured as the thiobarbituric acid reactive substances in liver microsomes was significantly inhibited (P<0.05) in a dose-dependent manner by diphenylmethyl selenocyanate. Thus the compound exerts its chemopreventive activity by reducing papilloma formation during chemically induced Carcinogenesis, which in turn, may be through modulating the level of lipid peroxidation and phase II detoxifying enzyme system at the doses evaluated.
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inhibition of dmba croton oil two stage mouse Skin Carcinogenesis by diphenylmethyl selenocyanate through modulation of cutaneous oxidative stress and inhibition of nitric oxide production
Asian Pacific Journal of Cancer Prevention, 2004Co-Authors: Rajat Kumar Das, Sudin BhattacharyaAbstract:Selenium, an essential micronutrient, plays important roles against different diseases, including several types of cancer. In the present study, antioxidative and chemopreventive properties of a synthetic organoselenium compound, diphenylmethyl selenocyanate, were evaluated with a 7,12-dimethylbenz (a) anthracene - croton oil induced twostage mouse Skin Carcinogenesis model. The compound was administered orally to carcinogen-treated mice at two different non-toxic doses, 2mg/kg. b.w. and 3mg/kg. b.w. Significant inhibition in the incidence of papilloma formation (53-80%) as well as in the cumulative numbers of papillomas per papilloma bearing mouse were observed in the treated groups as compared to the carcinogen control group. The compound was also found to upregulate significantly different phase II detoxifying enzymes such as glutathione-S-transferase (p<0.01) and superoxide dismutase (p<0.01) in Skin cytosol when measured after 15 days and also after 12 weeks of the first 7,12-dimethylbenz (a) anthracene treatment. Lipid peroxidation measured with reference to thiobarbituric acid reactive substances in Skin microsomes was significantly inhibited (p<0.05) in a dose dependent manner by diphenylmethyl selenocyanate. Considerable inhibition of the level of nitric oxide production in peritoneal macrophages was observed after 12 weeks (p<0.05). Thus the compound appears to exert chemopreventive activity in terms of papilloma formation, which may be through modulation of cutaneous lipid peroxidation, the phase II detoxifying enzyme system and nitric oxide production.
