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The β-catenin signaling pathway plays a key role in several cellular functions and is commonly deregulated in cancer, including melanoma. Malignant melanoma is a highly aggressive skin tumor that, due to its tendency to metastasize, and despite the recent development of targeted and immune therapies, is still the deadliest form of skin cancer. Activation of β-catenin signaling has been observed in deep penetrating naevi and human melanomas mainly through CTNNB1 (the gene encoding for β-catenin) and APC mutations, and non-genetic mechanisms.
Malignant melanoma is the most aggressive form of human skin cancer and shows an increasing incidence. The transformation from a normal melanocyte to a melanoma cell is a stepwise process and the complex mechanisms during early stages of tumor development remain incompletely understood. Based on the increased tumor incidence in Epidermolysis bullosa simplex (EBS), we hypothesize that keratinocytes affect early melanoma development through direct interactions or via indirect mechanisms involving cell-cell contacts, cytoskeletal proteins and by secretion of growth factors.
A transcriptomic analysis from vitiligo patient skins allowed us to discover that CLEC12B is selectively and strongly expressed by melanocytes. The objective of this study was to investigate the role of CLEC12B in melanoma. Expression of CLEC12B was assessed in melanoma cell lines, nevi and melanoma samples. Using a lentivirus construct we overexpressed (Ov) or downregulated (Sh) CLEC12B in melanoma cells lines to assess the effect of its modulation on proliferation and cell cycle. The signaling pathway involved was then studied.
Cutaneous SCC (cSCC) is the second most frequent type of human malignancy worldwide primarily caused by chronic long-term sun exposure. Somatic mutations in the tumor suppressor gene TP53 have been shown to occur frequently in aged sun-exposed skin and to favor clonal expansion. In contrast, p63, a p53 family member, is rarely mutated in cancer and rather is overexpressed and/or amplified in squamous cell carcinomas. Several studies have shown that p63 overexpression leads to higher proliferation rates and an increased ability to contrast differentiation, cellular senescence and apoptosis.
While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is less well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here we show that BRN2 haploinsufficiency is sufficient to promote melanoma initiation and metastasis formation, acting as a non-canonical tumor suppressor.
Plasmatic proteasomes (p-proteasomes) are a reliable marker for metastatic dissemination in melanoma patients. Recent works have suggested that p-proteasome partially originated from tumour cell secretion via exosomes, which are also considered as a new biomarker for metastatic melanoma. Our objectives were to investigate the origin, mechanism of secretion and functionality of the melanoma p-proteasomes. We show by proteasome purification either from culture supernatant of melanoma cell lines (A-375, SK-MEL-28) or from plasma of melanoma patients, that the extracellular proteasome is released essentially as an assembled 20S core particle, contrarily to proteasome analyzed from cell lysate, which presents additional 26S capped proteasome.
Squamous cell carcinomas (SCCs) and pre-malignant actinic keratoses (AKs) are thought to develop secondary to ultraviolet radiation (UV) damage. However, only ∼10% of AKs progress and become SCCs. We use RNA NanoString nCounter® analysis to validate a novel, 80-gene UV radiation-associated biomarker panel for stratification of skin cancer risk. Based on our previous study, we selected 80 of the 125 highly conserved UV-responsive genes to validate for clinical utility as a biomarker panel for detecting cancer-prone skin lesions.
Cutaneous squamous cell carcinoma (cSCC) is the second most frequent form of skin cancer showing a rapidly increasing incidence worldwide. cSCC originates from alterations in keratinocyte stem cells which, in turn, disrupt epidermal homeostasis. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk receptors) form a complex network with regulatory functions. CD271 is implicated in the switch between stem and early progenitors, thus playing a key role in keratinocyte differentiation.
We assessed the role of macrophages in squamous cell carcinoma (SCC) behavior. We used mouse SCC cells derived from tumors harboring a Kras12D activation mutation and Smad4 deletion in keratin 15 (K15)-positive stem cells, and a human SCC cell line, FaDu. SCC cells were transplanted into immune-compromised or -competent (syngeneic) recipients. After tumors were established, we profiled tumor infiltrating leukocytes using CyTOF. CD45+ leukocytes comprised 10-25% of the total tumor cells, and tumor-associated macrophages (TAMs) were 5-10% of the CD45+ cells.
The aim of the study was to assess safety and efficacy of two formulations with SPF 50+ in patients with dermatoses such as acne vulgaris, rosacea and skin affected by aesthetic treatments. Both tested formulas provide wide spectrum protection from sun radiation in UV, HEV and IR as well as alleviate symptoms of the respective dermatoses. Product 14004 contained hesperidin, an ingredient used in care of rosacea and dilated capillaries or hypersensitivity caused by aesthetic treatments (chemical peels, laser therapy).
Given a known incidence of photosensitivity reactions with the predecessor drug, Flutamide, we explore another interesting case of photosensitivity following Bicalutamide therapy. Case: A 74-year-old man started on bicalutamide for prostate cancer. Approximately 4-6 weeks after starting bicalutamide the patient developed diffuse, tender erythema spreading caudally from facial sites. The distribution is symmetrical and follows a sun-exposed pattern with erythema seen across the face, shoulders, upper torso and upper limbs.
The effect of ultraviolet (UV) radiation is well studied by increasing inflammatory response and oxidative stress leading to degradation of extracellular matrix (ECM) proteins such as collagen. Additionally, increasing numbers of studies have indicated the atmospheric pollution induces intracellular reactive oxygen species. Among various substances with potentials to prevent deleterious effect of environmental ageing, antioxidants are most representative and well studied, Especially, the combination formulation of L-ascorbic acid, vitamin E and Ferulic acid have shown it’s in vitro and in vivo effect in the prevention of photoaging.
Poliosis, an absence of functional melanocytes of affected hair follicle, is considered a poor prognostic factor in treatment of vitiligo because the melanocytes of hair follicles are the major source of repigmentation. We sought to evaluate the clinical outcome of poliosis in treatment of vitiligo. An open-label pilot study was performed between January 2016 and March 2018. Patients with vitiligo who have poliosis in head and neck were treated with the combination therapy of 308-nm excimer laser, topical tacrolimus, and intralesional triamcinolone injection for more than 3 months.
Disruption of the dermal matrix secondary to photoaging is one of the proposed etiologies for rosacea. Matrix metalloproteinase-1-mediated collagen degeneration has been shown to impact endothelial cells, leading to the formation of vascular tubes resembling telangiectatic lumina. We performed a case-control study to examine the relationship between clinical presentation, collagen degeneration, and microvascular changes between 5 patients with erythematotelangiectatic rosacea ages 47-83 and 5 controls matched by age ±5 years and race.
The pigmentation of human skin (nevi, senile lentigines, melasma, etc) is regulated by a complex process involving the synthesis and distribution of melanin. Overexpression of melanin is induced by the off-balance between the signals which regulates melanin synthesis, this can be caused due to a response to external or internal stimulus that often affects the genes related to melanogenesis. To date, many studies have focused on developing direct enzymatic inhibitors of tyrosinase in order to achieve a skin-lightening effect.
Congenital melanocytic nevus (CMN) is a hamartoma derived from neural crest appearing at birth. CMN has a dynamic course and may show various changes even spontaneous regression. CMN may grow in size during childhood and show pigmentary regression with increasing age and develop a hypopigmentation halo and regress spontaneously after halo formation, or undergo malignant transformation resulting in melanoma. A 9-year-old boy presented with solitary brownish to blackish patch on the right forearm which had appeared since birth.
Silymarin is a phytophenol extracted from the seeds of milk thistle (Silibum marianum). Silymarin has been studied in skin UV-protection due to its antioxidant and anti-inflammatory effects. However, its possible phototoxic potential was also shown. Based on these findings the dermatological application of this polyphenol is questionable. Our aim was to study the effects of silymarin on cell viability, ROS production and mutagenesis in UVA-irradiated epithelial cells. HaCaT immortalized keratinocyte and CHO (Chinese hamster ovary) cell lines were treated with silymarin for 30 min, then exposed to 10 or 20 J/cm2 UVA.
UVB-induced cyclobutane pyrimidine dimers (CPDs) are considered to be the main cause of acute sunburn and epidermal carcinogenesis. In humans, these lesions are repaired by nucleotide excision repair, but marsupials and lower organisms present photolyase enzyme which rapidly removes CPDs in a visible light-dependent process (photoreactivation). Previously we established an in vitro pseudouridin-modified mRNA encoding CPD-specific photolyase transfection on human keratinocyte cell lines, which was proved to be a proper method to avoid UVB-induced apoptosis.
PCE-DP (D-pantothenyl alcohol) is an active ingredient in pharmaceuticals and cosmetics that prevents inflammation and promotes hair growth. In our previous randomized double-blind placebo-controlled UVB irradiation-induced pigmentation study using healthy Japanese men and women, we found that topical PCE-DP has brightening effects when used for 4 weeks. In this study, we examined four studies to clarify the molecular mechanism of PCE-DP activity: (i) epidermal turnover, (ii) melanosomal uptake of keratinocytes, (iii) melanocyte activation by keratinocytes, or (iv) melanin production in melanocytes.
UVA1 phototherapy selectively uses the longer UVA1 wavelengths (340-400 nm), and does not include the shorter UVA2 wavelengths (320-340 nm) or UVB wavelengths (290-320 nm) that cause an erythema reaction. Several studies report the effectiveness of UVA1 phototherapy for various diseases such as atopic dermatitis, T-cell lymphoma, and systemic sclerosis. While UVA1 phototherapy has a high therapeutic effect, it also causes immediate pigment darkening (IPD) as a deleterious effect. IPD is a dull grayish-brown pigment enhancement observed during or immediately after UVA irradiation.