Beta3-Tubulin is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375).

Microtubules (MTs), microfilaments, and intermediate filaments, the main constituents of the cytoskeleton, undergo continuous structural changes (metamorphosis), which are central to cellular growth, division, and release of microvesicles (MVs). Altered MTs dynamics, uncontrolled proliferation, and increased production of MVs are hallmarks of carcinogenesis. Class III beta-tubulin (ß3-tubulin), one of seven ß-tubulin isotypes, is a primary component of MT, which correlates with enhanced neoplastic cell survival, metastasis and resistance to chemotherapy. We studied the effects of ß3-tubulin gene silencing on MTs dynamics, cell cycle, and MVs release in human malignant melanoma cells (A375). The knockdown of ß3-tubulin induced G2/M cell cycle arrest, impaired MTs dynamics, and reduced spontaneous MVs release. Additional studies are therefore required to elucidate the pathophysiologic and therapeutic role of ß3-tubulin in melanoma.

Corynebacterium tuberculostearicum, a human skin colonizer, induces the canonical nuclear factor-κB inflammatory signaling pathway in human skin cells.

INTRODUCTION: Corynebacterium tuberculostearicum (C. t.) is a ubiquitous bacterium that colonizes human skin. In contrast to other members of the genus Corynebacterium, such as toxigenic Corynebacterium diphtheriae or the opportunistic pathogen Corynebacterium jeikeium, several studies suggest that C. t. may play a role in skin health and disease. However, the mechanisms underlying these effects remain poorly understood. METHODS: To investigate whether C. t. induces inflammatory pathways in primary human epidermal keratinocytes (HEKs) and human cutaneous squamous carcinoma cells (SCCs), cell culture, reverse transcription-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay, immunofluorescence microscopy, Western blot, chromatin immunoprecipitation-PCR, small interfering RNA knockdown and luciferase reporter expression system were used. RESULTS: Herein, we demonstrate that C. t. upregulates the messenger RNA (mRNA) and protein levels of inflammatory mediators in two human skin cell lines, HEKs and SCCs. We further show activation of the canonical nuclear factor-κB (NF-κB) pathway in response to C. t. infection, including phosphorylation of the inhibitor of κB (IκB), the nuclear translocation of NF-κB subunit (NF-κB-P65 ) and the recruitment of NF-κB-P65 and RNA polymerase to the NF-κB response elements at the promoter region of the inflammatory genes. Lastly, the data confirm that C. t.-induced tumor necrosis factor mRNA expression in HEKs is toll-like receptor 2 (TLR2 ) dependent. CONCLUSION: Our results offer a mechanistic model for C. t.-induced inflammation in human keratinocytes via TLR2 and activation of IκB kinase and downstream signaling through the canonical NF-κB pathway. Relevance to chronic inflammatory diseases of the skin and cutaneous oncology is discussed.

Tobacco and the skin.

Smoking negatively impacts the health of the skin as it does every organ system. This contribution reviews the effect of cigarette smoking on wound healing, wrinkling, and aging of the skin, skin cancer, psoriasis, and other inflammatory skin diseases, hidradenitis suppurativa, acne, alopecia, lupus erythematosus, polymorphous light eruption, and tobacco-associated oral lesions. Dermatologists need to encourage their patients to discontinue this deleterious habit.

A population-based study of cutaneous melanoma in Alberta, Canada (1993-2002).

BACKGROUND: There is evidence to suggest that melanoma incidence rates continue to rise in Canada and the United States. OBJECTIVE: Our objective was to determine cutaneous melanoma trends from 1993 to 2002 in the province of Alberta and to compare the results to previously published provincial analyses for the decade of 1967-1976. METHODS: A retrospective study of 3479 patients with cutaneous melanoma diagnosed in Alberta between 1993 and 2002 was conducted. Estimates of relative survival compared the survival of melanoma patients with the Alberta population to derive the likelihood of surviving melanoma in the absence of other causes of death. Further comparison to published Canadian data was also conducted. RESULTS: For the period 1993-2002, the annual melanoma age-standardized incidence rates per 100,000 person-years ranged between 11.1 and 15.9 and between 9.8 and 14.1 among men and women, respectively. These rates are considerably higher than the previously reported (1976) highest Alberta incidence rates of 4.1 and 4.8 in men and women, respectively. The rates increased slightly for the period 1993-1999 with an average annual percentage change of +3.5%, but appeared to decrease for the interval 1999-2002 with an average annual percentage change of -6.4%. The majority of the tumors were less than 1.0 mm in thickness for both genders. On univariate analysis the following parameters were associated with decreasing patient survival: male gender, increasing age, head and neck tumors, Clark level of invasion, and Breslow tumor thickness. Multivariate analysis demonstrated that the strongest determinant of survival was Breslow tumor thickness. LIMITATIONS: Melanomas in-situ were not included in this study. CONCLUSIONS: Although melanoma incidence rates in Alberta are higher than previously reported, the incidence rates over the study period of 1993 to 2002 appear to have leveled and may in fact be declining over the past several years.

Acneiform facial eruptions: a problem for young women.

OBJECTIVE: To summarize clinical recognition and current management strategies for four types of acneiform facial eruptions common in young women: acne vulgaris, rosacea, folliculitis, and perioral dermatitis. QUALITY OF EVIDENCE: Many randomized controlled trials (level I evidence) have studied treatments for acne vulgaris over the years. Treatment recommendations for rosacea, folliculitis, and perioral dermatitis are based predominantly on comparison and open-label studies (level II evidence) as well as expert opinion and consensus statements (level III evidence). MAIN MESSAGE: Young women with acneiform facial eruptions often present in primary care. Differentiating between morphologically similar conditions is often difficult. Accurate diagnosis is important because treatment approaches are different for each disease. CONCLUSION: Careful visual assessment with an appreciation for subtle morphologic differences and associated clinical factors will help with diagnosis of these common acneiform facial eruptions and lead to appropriate management.

Multiple keratoacanthomas arising post-UVB therapy.

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 resembles 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.

Cutaneous effects of smoking.

BACKGROUND: Cigarette smoking is the single biggest preventable cause of death and disability in developed countries and is a significant public health concern. While known to be strongly associated with a number of cardiovascular and pulmonary diseases and cancers, smoking also leads to a variety of cutaneous manifestations. OBJECTIVE: This article reviews the effects of cigarette smoking on the skin and its appendages. METHODS: A literature review was based on a MEDLINE search (1966-2004) for English-language articles using the MeSH terms cutaneous, dermatology, tobacco, skin, and smoking. An additional search was subsequently undertaken for articles related to smoking and associated mucocutanous diseases, with the focus on pathogenesis and epidemiologic data. Articles presenting the highest level of evidence and latest reports were preferentially selected. RESULTS: Smoking is strongly associated with numerous dermatologic conditions including poor wound healing, wrinkling and premature skin aging, squamous cell carcinoma, psoriasis, hidradenitis suppurativa, hair loss, oral cancers, and other oral conditions. In addition, it has an impact on the skin lesions observed in diabetes, lupus, and AIDS. The evidence linking smoking and melanoma, eczema, and acne is inconclusive. Anecdotal data exist on the possible protective effects of smoking in oral/genital aphthosis of Behçet's disease, herpes labialis, pyoderma gangrenosum, acral melanoma, and Kaposi's sarcoma in AIDS patients. CONCLUSIONS: An appreciation of the adverse cutaneous consequences of smoking is important. Dermatologists can play an integral role in promoting smoking cessation by providing expert opinion and educating the public on the deleterious effects of smoking on the skin.

Paying more than lip service to lip lesions.

OBJECTIVE: To review the epidemiology, etiology, diagnosis, management, and prognosis of the most common, potentially lethal, lip lesions: leukoplakia, actinic cheilitis, and squamous cell carcinoma (SCC). QUALITY OF EVIDENCE MEDLINE: was searched from 1966 to 2002 for English-language articles on prevalence of lip lesions. No articles for a family physician audience were found. MEDLINE was searched again using the terms "leukoplakia," "actinic cheilitis," and "squamous cell carcinoma." Randomized, controlled trials were selected; non-blinded trials, population-based studies, and systematic reviews were also used. MAIN MESSAGE: Leukoplakia, actinic cheilitis, and SCC of the lips are relatively common presentations that can cause substantial morbidity and, more rarely, mortality. Any abnormality of the lips can be an embarrassment. Because of the seriousness and frequency of lip disease, it is important to look for, diagnose, and treat lip lesions to prevent morbidity and mortality and also to maintain social acceptance and self-esteem. CONCLUSION: Knowledge of leukoplakia, actinic cheilitis, and SCC of the lips will aid family physicians in diagnosing and managing these lesions and in preventing associated morbidity and mortality.