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(searched for: doi:10.1002/jsscb.380170306)
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Weston Kenneth Ryan, Josiah Fernandez, Mikayla Katherine Peterson, David William Sheneman, Brendan Keefe Podell, Subhajyoti De, Enrique Carlo Torchia
Published: 26 July 2018
Cell Death & Differentiation, Volume 26, pp 548-564; https://doi.org/10.1038/s41418-018-0167-7

Abstract:
The role of mitosis in the progression of precancerous skin remains poorly understood. To address this question, we deleted the mitotic Kinase Aurora-A (Aur-A) in hyperplastic mutant p53 mouse skin as an experimental tool to study the G2/M transition in precancerous keratinocytes and AUR-A’s role in this process. Epidermal Aur-A deletion (Aur-AepiΔ) led to marked keratinocyte enlargement, pleomorphism, multinucleation, and attenuated induction of cell death. This phenotype was characteristic of slippage after a stalled mitosis. We also observed altered or impaired epidermal differentiation, indicative of a partial skin barrier defect. The upregulation of mTOR/PI3K signaling was implicated as a mechanism by which keratinocytes may evade cell death after AUR-A deficiency. This was evidenced by the ectopic expression of the pathway readout, p-S6, in the basal layer of Aur-AepiΔ skin and its mitotic upregulation in isolated keratinocytes. We further tested whether our findings were extended to skin carcinoma cells. The chemical inhibition of AUR-A led to a similar mitotic delay, polyploidy/multinucleation, and attenuated cell death in skin cancer cell lines. Moreover, inhibition of mTOR/PI3K signaling ameliorated the effects caused by the deficiency of AUR-A activity but was also associated with the persistence of mitotic p-S6 detection in surviving cancer cells. These results show the induction of multinucleation/polyploidy may be a compensatory state in keratinocytes that allows for cellular survival and maintenance of partial barrier function in face of aberrant cell division or differentiation. Moreover, mTOR/PI3K signaling is active in the mitosis of hyperplastic keratinocytes expressing mutant p53 and is further enhanced by stalled mitosis, indicating a potential resistance mechanism to the use of anti-mitotic drugs in the treatment of skin cancers.
Jessica S. Kelsey, Christophe Cataisson, Jinqiu Chen, Michelle A. Herrmann, Mark E. Petersen, David O. Baumann, Kevin M. McGowan, Stuart H. Yuspa, Gary E. Keck, Peter M. Blumberg
Published: 9 February 2016
Molecular Carcinogenesis, Volume 55, pp 2183-2195; https://doi.org/10.1002/mc.22460

The publisher has not yet granted permission to display this abstract.
Jan Hönnemann, Adrián Sanz-Moreno, , , Hans-Peter Elsasser
Published: 11 April 2012
Abstract:
The transcription factor Miz1 forms repressive DNA-binding complexes with the Myc, Gfi-1 and Bcl-6 oncoproteins. Known target genes of these complexes encode the cyclin-dependent kinase inhibitors (CKIs) cdkn2b (p15Ink4), cdkn1a (p21Cip1), and cdkn1c (p57Kip2). Whether Miz1-mediated repression is important for control of cell proliferation in vivo and for tumor formation is unknown. Here we show that deletion of the Miz1 POZ domain, which is critical for Miz1 function, restrains the development of skin tumors in a model of chemically-induced, Ras-dependent tumorigenesis. While the stem cell compartment appears unaffected, interfollicular keratinocytes lacking functional Miz1 exhibit a reduced proliferation and an accelerated differentiation of the epidermis in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tumorigenesis, proliferation and normal differentiation are restored in animals lacking cdkn1a, but not in those lacking cdkn2b. Our data demonstrate that Miz1-mediated attenuation of cell cycle arrest pathways via repression of cdkn1a has a critical role during tumorigenesis in the skin.
Joydeb Kumar Kundu, Dal-Mi Hwang, Jung-Chul Lee, Eun-Jin Chang, , Hajime Fujii, Buxiang Sun, Young-Joon Surh
Published: 8 January 2009
Cancer Letters, Volume 273, pp 86-97; https://doi.org/10.1016/j.canlet.2008.07.039

Abstract:
Plant polyphenols possess anti-oxidant and anti-inflammatory activities and are hence potential candidates for preventing cancer. The present study was aimed at evaluating the anti-inflammatory and anti-tumor promoting activity of oligonol, a formulation of catechin-type oligomers, in mouse skin stimulated with a proto-type tumor promoter 12- O -tetradecanoylphorbol-13-acetate (TPA). Pretreatment of mouse skin with oligonol significantly inhibited TPA-induced expression of cyclooxygenase-2 (COX-2). Oligonol diminished nuclear translocation and DNA binding of nuclear factor-kappaB (NF-κB) via blockade of phosphorylation and subsequent degradation of IκBα in TPA-treated mouse skin. Moreover, oligonol suppressed TPA-induced DNA binding of CCAAT/enhancer-binding protein (C/EBP) in mouse skin. Oligonol pretreatment also attenuated the phosphorylation and/or catalytic activities of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinase. Moreover, p38 MAP kinase inhibitor SB203580, but not the MEK inhibitor U0126, negated TPA-induced DNA binding of C/EBP. In addition, oligonol reduced the incidence and the multiplicity of papillomas and squamous cell carcinomas in 7,12-dimethylbenz[ a ]anthracene (DMBA)-initiated and TPA-promoted mouse skin, and prolonged the survival of tumor-bearing mice. Pretreatment with oligonol diminished the levels of proliferating cell nuclear antigen and expression of COX-2 in papillomas and carcinomas, respectively, as compared to DMBA plus TPA treatment alone. Taken together, the above findings suggest that oligonol inhibits TPA-induced COX-2 expression by blocking the activation of NF-κB and C/EBP via modulation of MAP kinases and suppresses chemically induced mouse skin tumorigenesis.
Ulrike Lichti, Stuart H. Yuspa
Published: 30 May 2008
Abstract:
Retinoids are physiological regulators of growth and differentiation for a number of epithelial tissues. In several of these, retinoids also act as pharmacological anticarcinogens. Retinoids are most effective as anticarcinogens in the post-initiation portion of carcinogenesis. In mouse skin, retinoids are inhibitors of phorbol ester-mediated tumour promotion and can cause regression of pre-existing benign tumours. Studies in vivo and in vitro have indicated that phorbol ester-mediated skin tumour promotion results from selective clonal expansion of initiated cells. We have proposed that the biological basis for selection resides in the induction of terminal differentiation in subpopulations of keratinocytes while other keratinocytes, including initiated cells, are stimulated to proliferate. Terminal differentiation is accelerated by phorbol esters through the induction of epidermal transglutaminase and consequent cornification. Retinoids inhibit terminal differentiation of keratinocytes. Retinoids also induce transglutaminase in epidermis, but they inhibit cornification. Recent results suggest a biochemical basis for this paradox. The phorbol ester-induced transglutaminase is primarily particulate but the retinoid-induced enzyme is cytosolic. The induced enzymes differ in kinetic parameters, thermal stability and in elution from ion-exchange columns. Induction of the retinoid enzyme is associated with suppression of the induction of transglutaminase by phorbol esters. The retinoid-induced epidermal transglutaminase could interfere with normal or promoter-induced differentiation by inappropriately cross-linking precursor proteins before their assembly at the cell periphery. This could explain one aspect of the inhibitory action of retinoids on tumour promotion.
Yafan Li, Deric L. Wheeler, Honnavara N. Ananthaswamy, Ajit K. Verma,
Published: 1 December 2007
Toxicologic Pathology, Volume 35, pp 942-951; https://doi.org/10.1080/01926230701748164

Abstract:
Our previous studies showed that protein kinase Cepsilon (PKCɛ) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma formation as is typically observed in wild type mice. The present study demonstrates that double-DMBA initiation modulates tumor incidence, multiplicity, and latency period in both wild type and PKCɛoverexpression transgenic (PKCɛ-Tg) mice. After 17 weeks (wks) of tumor promotion, a reduction in papilloma multiplicity was observed in double- versus single-DMBA initiated wild type mice. Papilloma multiplicity was inversely correlated with cell death indices of interfollicular keratinocytes, indicating decreased papilloma formation was caused by increased cell death and suggesting the origin of papillomas is in interfollicular epidermis. Double-initiated PKCɛ-Tg mice had accelerated carcinoma formation and cancer incidence in comparison to single-initiated PKCɛ-Tg mice. Morphologic analysis of mouse skin following double initiation and tumor promotion showed a similar if not identical series of events to those previously observed following single initiation and tumor promotion: putative preneoplastic cells were observed arising from hyperplastic hair follicles (HFs) with subsequent cancer cell infiltration into the dermis. Single-initiated PKCɛ-Tg mice exhibited increased mitosis in epidermal cells of HFs during tumor promotion.
Reshmi A. Rambaratsingh, James C. Stone, Peter M. Blumberg, Patricia S. Lorenzo
Published: 1 December 2003
Journal of Biological Chemistry, Volume 278, pp 52792-52801; https://doi.org/10.1074/jbc.m308240200

Abstract:
The mouse skin model of carcinogenesis has been instrumental in our appreciation of the multistage nature of carcinogenesis. In this system, tumor promotion is a critical step in the generation of tumors and is usually achieved by treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Although it is generally assumed that protein kinase C (PKC) is the sole receptor for TPA in this system, we sought to evaluate whether non-PKC pathways could also contribute to the effects of phorbol esters in skin. We documented expression of the high affinity non-PKC phorbol ester receptor and Ras activator RasGRP1 in mouse primary keratinocytes. Overexpression of RasGRP1 in keratinocytes increased the level of active GTP-loaded Ras. TPA treatment further elevated this Ras activation in a PKC-independent manner and induced the translocation and down-regulation of RasGRP1. Overexpression of RasGRP1 in keratinocytes also caused apoptosis. Finally, induction of keratinocyte differentiation by elevation of extracellular calcium suppressed expression of endogenous RasGRP1, whereas overexpression of RasGRP1 inhibited expression of the differentiation markers keratins 1 and 10 induced by high calcium in the medium. Taken together, our results demonstrate that RasGRP1 is an additional diacylglycerol/phorbol ester receptor in epidermal keratinocytes and suggest that activation of this novel receptor may contribute to some of the phorbol ester- and Ras-mediated effects in mouse epidermis.
Raymond L. Konger, Thomas C. K. Chan
Published: 1 September 1993
Journal of Cellular Physiology, Volume 156, pp 515-521; https://doi.org/10.1002/jcp.1041560310

The publisher has not yet granted permission to display this abstract.
, N. Scott McNutt, D. Martin Carter, Alice B. Gottlieb, Amy Hsu, James Krueger
Archives of Dermatology, Volume 126, pp 78-83; https://doi.org/10.1001/archderm.1990.01670250084014

Abstract:
• Epidermolysis bullosa represents a grouping of inherited skin diseases characterized by epidermal fragility and frequently wounded skin. The recessive dystrophic subtype of epidermolysis bullosa (RDEB) is characterized by extensive dermal scarring after healing of repeated epidermal injuries and by an unusually high incidence of squamous cell carcinoma occurring in chronically wounded skin. In contrast, the simplex form of epidermolysis bullosa usually heals without scarring and does not predispose to malignant neoplasms of the skin. The differences in scarring and the neoplastic potential of these two forms of epidermolysis bullosa prompted us to investigate growth activation and differentiation characteristics in epidermal keratinocytes in individuals with these disorders. The expression of filaggrin, involucrin, cytokeratins, and the growth activation marker psi-3 was examined by immunohistochemistry in skin biopsy specimens from four individuals with epidermolysis bullosa simplex and six individuals with RDEB. Previous experiments using this technique have demonstrated that these antibodies are good markers for identifying growth-activated keratinocytes in wounded and hyperplastic epidermis. All biopsy specimens of healed wounds in skin from patients with RDEB showed epidermis that reacted with antibodies to filaggrin, involucrin, specific cytokeratins, and psi-3 in a growth-activated pattern. This growth-activated phenotype was maintained in keratinocytes from previously wounded skin that had been healed for more than 2 years. The RDEB growth-activated phenotype detected by immunohistochemistry was not associated with microscopically detectable epidermal hyperplasia. In contrast, all cases of epidermolysis bullosa simplex examined showed an epidermal phenotype similar to that of keratinocytes in normal skin. Thus, healing with dermal scar formation in RDEB is associated with a persistent growth-activated immunophenotype of epidermal keratinocytes. This chronic growth activation state or failure of cells to differentiate in a normal fashion may be directly linked to the high incidence of squamous cell cancers in individuals with RDEB. (Arch Dermatol. 1990;126:78-83)
M. A. Knowles
Published: 1 January 1990
The publisher has not yet granted permission to display this abstract.
, Margaret A. George, George R. Pettit, Cherry L. Herald, James I. Rearick
Journal of Investigative Dermatology, Volume 93, pp 108-115; https://doi.org/10.1111/1523-1747.ep12277374

Abstract:
This study examines the action of phorbol 12-myristate 13-acetate (PMA) on the synthesis of cholesterol sulfate in cultured normal and transformed human epidermal keratinocytes and assesses the antagonistic effects by retinoids and bryostatins on PMA action in relation to the multistep program of squamous differentiation. Treatment of normal human epidermal keratinocytes (NHEK) with PMA induces terminal cell division (irreversible growth-arrest) and causes a time- and dose-dependent increase in the incorporation of Na235SO4 into cholesterol sulfate, a marker for squamous cell differentiation. This stimulation in sulfate incorporation appears specific for cholesterol sulfate and is due to increased levels of cholesterol sulfotransferase activity. The increase in cholesterol sulfate accumulation parallels the increase in transglutaminase type I, another marker for squamous differentiation. Several transformed NHEK cell lines do not exhibit increased levels of cholesterol sulfate and transglutaminase type I activity after PMA treatment, indicating that they acquired defects in the regulation of squamous differentiation. Bryostatins 1 and 2, and several diacylglycerol analogues neither inhibit cell proliferation nor increase cholesterol sulfate synthesis or transglutaminase activity, indicating that these agents do not induce terminal differentiation. In contrast, the bryostatins block the increase in cholesterol sulfate and transglutaminase activity as well as the commitment to terminal cell division by PMA. Bryostatin 1 inhibits the commitment to terminal cell division and the accumulation of cholesterol sulfate significantly even when added 8 h after PMA administration. Retinoids inhibit cholesterol sulfate accumulation and the increase in transglutaminase activity by PMA but do not affect the commitment to terminal cell division. In summary, phorbol esters induce in NHEK cells a program of squamous differentiation. This process of differentiation consists of the commitment to terminal cell division and expression of the squamous phenotype. Expression of this phenotype is accompanied by an accumulation of cholesterol sulfate and increased cholesterol sulfotransferase activity. Bryostatins 1 and 2 and retinoic acid affect this differentiation process at different stages.
N. M. Boyd, P. C. Reade
Journal of Oral Pathology & Medicine, Volume 17, pp 257-265; https://doi.org/10.1111/j.1600-0714.1988.tb01534.x

Abstract:
A number of changes occur in preneoplastic and neoplastic cells as they progress towards a greater degree of malignancy. These alterations include genetic changes, epigenetic changes, surface alterations and alterations in intercellular interactions. In some instances, these changes are contributing factors to the degree of pathology noted, whilst other are resultant. In many situations, the relationship between these changes and the progression towards neoplasia is not understood. Nevertheless, it seems probable that these changes are ultimately involved in driving cells further along the path to neoplastic transformation. It is the purpose of this review to consider the changes which occur as cells progress from normality to being neoplastic, with particular reference to the cells of the oral mucosa, and the use to which detectable changes can be used as prognostic indicators.
, Anne E. Kilkenny, John Stanley,
Published: 1 April 1985
Nature, Volume 314, pp 459-462; https://doi.org/10.1038/314459a0

Abstract:
It has been suggested that the initiation step in mouse skin carcinogenesis involves an alteration in epidermal-differentiation, as mouse basal keratinocytes exposed to initiators resist the arrest of cell growth that is normally associated with the induction of terminal differentiation by calcium ions. The growth of epidermal basal cells infected by Kirsten (Ki) or Harvey (Ha) sarcoma viruses is, however, arrested in response to calcium ions, although the cells do not progress through their entire maturation programme when a functioning ras gene of those viruses is expressed. If continuous proliferation in the differentiating cell layers is a requirement for tumour formation in skin, the response of sarcoma virus-infected cells seems inconsistent with the suggestion that an activated ras gene is sufficient to initiate skin carcinogenesis. We now show that sarcoma virus-infected keratinocytes, when induced to differentiate, are blocked at an early, reversible stage of maturation. Furthermore, the cells respond to phorbol ester tumour promoters by undergoing a phenotypic reversion to a less mature stage. These results suggest that activation of a ras gene can produce conditionally initiated cells, in which the full expression of tumorigenicity depends on exposure to tumour promoters.
Shigeaki Yokoyama, Benito Lombardi
Published: 31 March 1985
Cancer Letters, Volume 26, pp 171-176; https://doi.org/10.1016/0304-3835(85)90023-0

Abstract:
An experiment was performed to investigate whether the incidence of chemical carcinogen-induced liver tumors in rats is increased by administration, during promotion, of a second dose of carcinogen. Seven groups of male Fischer-344 rats were administered a dose of diethylnitrosamine (DEN), and were placed, 1 month thereafter, on a liver-tumor promotion-regimen, consisting of a choline-devoid diet containing 0.06% phenobarbital. A second dose of the carcinogen was administered, at monthly intervals of promotion, to some of the groups of animals. The experiment was terminated after 7 months of promotion, and the incidence of hepatic tumors was determined histopathologically. In rats administered the second dose of carcinogen after 2 months of promotion, the incidence of hepatocellular carcinomas was 2-3 times greater than that in the other groups of rats. The results are consistent with the proposal, advanced by others, that development of hepatocellular carcinomas may be a multi-hit process, and indicate that, after the first induced at initiation, further genomic alteration(s) may have to occur at very discrete stage(s) in the evolution of initiated cells to tumors.
Stuart H. Yuspa, Molly Kulesz-Martin, Theresa Ben, Henry Hennings
Journal of Investigative Dermatology, Volume 81; https://doi.org/10.1111/1523-1747.ep12540999

Abstract:
Studies performed on mouse skin have indicated that chemical carcinogenesis can be subdivided into two distinct stages, initiation and promotion. Initiation results from exposure to a classical mutagenic carcinogen and is irreversible even after a single exposure. The permanently altered initiated cell and its progeny may never form a tumor or in any way be recognizable in the target tissue. Exposure to tumor promoters permits the expression of the neoplastic change in initiated cells, and tumors develop. In contrast to initiators, promoters must be given repeatedly to be effective; individual exposures are reversible. A similar biology is suggested by epidemiologic studies of certain human cancers, particularly lung, breast, colon, and uterine malignancies. Studies in mouse skin cell culture have provided new insights into the changes associated with initiation and promotion. Initiated cells appear to be resistant to signals for terminal differentiation and can proliferate under conditions where normal epidermal cells are obligated to cease proliferation and begin their maturation program. This change is essential for an epithelial tumor cell since it provides the ability to grow away from a basement- membrane attachment site. In cultured epidermal cells, tumor promoters are capable of selectively stimulating the growth of certain cells, including initiated cells, while simultaneously inducing terminal differentiation in other epidermal cells. The net effect of these responses to promoters is the clonal expansion of cells stimulated to proliferate. In this way, promoters are capable of increasing the clone size of initiated cells. These cell culture data provided a biological framework for understanding initiation and promotion in terminally differentiating epithelial tissues
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