Search Results (8)

Introduction: Melanoma, a malignant tumor arising from uncontrolled melanocytic proliferation, commonly found in the skin but capable of affecting extracutaneous sites, ranks fifth among diagnosed oncological entities and is a significant cause of cancer deaths, constituting over 80% of skin cancer mortality. Genetic factors and ultraviolet radiation (UVR) exposure, from both natural and artificial sources, are the primary risk factors. Case Presentation: We reported the case of a 25-year-old female with numerous pigmented nevi and notable changes attributed to extensive indoor tanning sessions. Dermatological examinations and dermoscopic evaluations revealed atypical features in two pigmented nevi, leading to surgical excision. Histopathological and immunohistochemical analyses confirmed a compound nevus in one lesion and superficial spreading melanoma in the other, emphasizing the importance of vigilant follow-up and the correct use of immunohistochemistry. Discussion: Indoor tanning significantly elevates the cutaneous melanoma risk, with initiation before age 35 amplifying the risk by up to 75%, especially in young women. The risk escalates with cumulative sessions, particularly exceeding 480, and individuals undergoing over 30 sessions face a 32% higher risk. UVR induces DNA damage, genetic mutations, and immunosuppression, contributing to oncogenesis. Genetic factors, like the PTCHD2 gene, may influence the tanning dependency. Legislation targeting minors has been enacted globally but only with partial efficacy. Tanning accelerators, though associated with minor side effects, correlate with high-risk behaviors. The case underscores the urgency of addressing indoor tanning risks, emphasizing targeted awareness efforts and legislative improvements. Conclusions: In conclusion, the reported case highlights the increased risk of cutaneous melanoma linked to indoor tanning, particularly among young women and specific sociodemographic groups. Despite legislative measures, challenges persist, suggesting the potential efficacy of online campaigns involving relatable influencers to raise awareness and discourage artificial tanning. Full article

PTCHD1 has been implicated in Autism Spectrum Disorders (ASDs) and/or intellectual disability, where copy-number-variant losses or loss-of-function coding mutations segregate with disease in an X-linked recessive fashion. Missense variants of PTCHD1 have also been reported in patients. However, the significance of these mutations remains undetermined since the activities, subcellular localization, and regulation of the PTCHD1 protein are currently unknown. This paucity of data concerning PTCHD1 prevents the effective evaluation of sequence variants identified during diagnostic screening. Here, we characterize PTCHD1 protein binding partners, extending previously reported interactions with postsynaptic scaffolding protein, SAP102. Six rare missense variants of PTCHD1 were also identified from patients with neurodevelopmental disorders. After modelling these variants on a hypothetical three-dimensional structure of PTCHD1, based on the solved structure of NPC1, PTCHD1 variants harboring these mutations were assessed for protein stability, post-translational processing, and protein trafficking. We show here that the wild-type PTCHD1 post-translational modification includes complex N-glycosylation and that specific mutant proteins disrupt normal N-link glycosylation processing. However, regardless of their processing, these mutants still localized to PSD95-containing dendritic processes and remained competent for complexing SAP102. Full article

Deleterious mutations in the X-linked Patched domain-containing 1 (PTCHD1) gene may account for up to 1% of autism cases. Despite this, the PTCHD1 protein remains poorly understood. Structural similarities to Patched family proteins point to a role in sterol transport, but this hypothesis has not been verified experimentally. Additionally, PTCHD1 has been suggested to be involved in Hedgehog signalling, but thus far, the experimental results have been conflicting. To enable a variety of biochemical and structural experiments, we developed a method for expressing PTCHD1 in Spodoptera frugiperda cells, solubilising it in glycol-diosgenin, and purifying it to homogeneity. In vitro and in silico experiments show that PTCHD1 function is not interchangeable with Patched 1 (PTCH1) in canonical Hedgehog signalling, since it does not repress Smoothened in Ptch1^−/− mouse embryonic fibroblasts and does not bind Sonic Hedgehog. However, we found that PTCHD1 binds cholesterol similarly to PTCH1. Furthermore, we identified 13 PTCHD1-specific protein interactors through co-immunoprecipitation and demonstrated a link to cell stress responses and RNA stress granule formation. Thus, our results support the notion that despite structural similarities to other Patched family proteins, PTCHD1 may have a distinct cellular function. Full article

Endometrial cancer is the most common gynaecological malignancy in developed countries. One of the largest risk factors for endometrial cancer is obesity. The aim of this study was to determine whether there are differences in the transcriptome of endometrial cancers from obese vs. lean women. Here we investigate the transcriptome of endometrial cancer between obese and lean postmenopausal women using rRNA-depleted RNA-Seq data from endometrial cancer tissues and matched adjacent non-cancerous endometrial tissues. Differential expression analysis identified 12,484 genes (6370 up-regulated and 6114 down-regulated) in endometrial cancer tissues from obese women, and 6219 genes (3196 up-regulated and 3023 down-regulated) in endometrial cancer tissues from lean women (adjusted p-value < 0.1). A gene ontology enrichment analysis revealed that the top 1000 up-regulated genes (by adjusted p-value) were enriched for growth and proliferation pathways while the top 1000 down-regulated genes were enriched for cytoskeleton restructure networks in both obese and lean endometrial cancer tissues. In this study, we also show perturbations in the expression of protein coding genes (HIST1H2BL, HIST1H3F, HIST1H2BH, HIST1H1B, TTK, PTCHD1, ASPN, PRELP, and CDH13) and the lncRNA MBNL1-AS1 in endometrial cancer tissues. Overall, this study has identified gene expression changes that are similar and also unique to endometrial cancers from obese vs. lean women. Furthermore, some of these genes may serve as prognostic biomarkers or, possibly, therapeutic targets for endometrial cancer. Full article

Over the last one and a half decades, copy number variation and whole-genome sequencing studies have illuminated the considerable genetic heterogeneity that underlies the etiologies of autism spectrum disorder (ASD) and intellectual disability (ID). These investigations support the idea that ASD may result from complex interactions between susceptibility-related genetic variants (single nucleotide variants or copy number variants) and the environment. This review outlines the identification and neurobiological characterization of two such genes located in Xp22.11, Patched domain-containing 1 (PTCHD1), and its antisense lncRNA PTCHD1-AS. Animal models of Ptchd1 disruption have recapitulated a subset of clinical symptoms related to ASD as well as to ID. Furthermore, these Ptchd1 mouse knockout studies implicate the expression of Ptchd1 in both the thalamic and the hippocampal brain regions as being crucial for proper neurodevelopment and cognitive function. Altered kynurenine metabolic signalling has been postulated as a disease mechanism in one of these animal studies. Additionally, ASD patient-derived induced pluripotent stem cells (iPSCs) carrying a copy number loss impacting the antisense non-coding RNA PTCHD1-AS have been used to generate 2D neuronal cultures. While copy number loss of PTCHD1-AS does not affect the transcription of PTCHD1, the neurons exhibit diminished miniature excitatory postsynaptic current frequency, supporting its role in ASD etiology. A more thorough understanding of risk factor genes, such as PTCHD1 and PTCHD1-AS, will help to clarify the intricate genetic and biological mechanisms that underlie ASD and ID, providing a foundation for meaningful therapeutic interventions to enhance the quality of life of individuals who experience these conditions. Full article

Background: The incidence of lung cancer differs between men and women, suggesting the potential role of sex-specific influences in susceptibility to this cancer. While behavioural differences may account for some of the risk, another possibility is that X chromosome susceptibility genes may have an effect. Little is known about genetic variants on the X chromosome that contribute to sex-specific lung-cancer risk, so we investigated this in a previously characterized cohort. Methods: We conducted a genetic association reanalysis of 518 lung cancer patients and 844 controls to test for lung cancer susceptibility variants on the X chromosome. Annotated gene expression, co-expression analysis, pathway, and immune infiltration analyses were also performed. Results: 24 SNPs were identified as significantly associated with male, but not female, lung cancer cases. These resided in blocks near the annotated genes DMD, PTCHD1-AS, and AL008633.1. Of these, DMD was differentially expressed in lung cancer cases curated in The Cancer Genome Atlas. A functional enrichment and a KEGG pathway analysis of co-expressed genes revealed that differences in immune function could play a role in sex-specific susceptibility. Conclusions: Our analyses identified potential genetic variants associated with sex-specific lung cancer risk. Integrating GWAS and RNA-sequencing data revealed potential targets for lung cancer prevention. Full article

Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis. Full article

Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response. Full article