Overexpression of Krüppel-Like Factor 9 Enhances the Antitumor Properties of Paclitaxel in Malignant Melanoma-Derived Cell Lines.

Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response 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.

Skin cancer knowledge and photoprotective practices of organ transplant recipients.

BACKGROUND: Long-term use of immunosuppressive medications by organ transplant recipients (OTRs) leads to an increased risk of non-melanoma skin cancers (NMSCs). The objective of this study was to assess photoprotective knowledge and practices among OTRs and to identify predictors of poor sunscreen adherence and barriers to photoprotection. METHODS: A written survey was administered to 300 solid OTRs attending the Southern Alberta Transplant Program. Demographics, transplant and NMSC history, ultraviolet radiation (UVR) exposure, photoprotective knowledge and practices, and barriers to implementing photoprotection were collected. Relevant statistical analyses and univariate and multivariable regression models on sunscreen use were performed. RESULTS: One hundred and seventy-nine of the 300 respondents reported not using sunscreen most days despite 79.3% recalling have received photoprotection education. Of the surveyed OTRs, 45.7% reported no barriers to implementing photoprotective practices. On average, respondents scored 74.5% on a commonly used tool to assess photoprotective knowledge (SD 30.6%). In multivariable analyses, older age, male gender, and lack of post-secondary education were associated with lower rates of self-reported sunscreen use. The most commonly patient-reported barriers to photoprotection were "hassle/time consuming" (16.7%) and "sunscreen is uncomfortable or unpleasant" (10.0%). CONCLUSIONS: Despite OTRs self-reporting having received sufficient sun-protective knowledge and demonstrating reasonable recollection of photoprotective education on assessment, implementation of sun protection in the studied OTRs remains suboptimal.