G protein-coupled receptor 87 (GPR87) has been implicated in the growth and progression of several malignancies, but its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Here, we found that GPR87 was aberrantly upregulated in murine and human skin tumors and in TPA-stimulated HaCaT keratinocytes. Using a DMBA/TPA-induced mouse skin tumor model, we demonstrated that GPR87 knockout significantly delayed epidermal hyperplasia, tumor initiation, and malignant progression. Consistently, GPR87 knockdown suppresses TPA-induced keratinocyte proliferation, migration, stemness, and epithelial-mesenchymal transition in keratinocytes and cSCC cells. Mechanistically, GPR87 deficiency markedly reduced SOX2 expression in cultured cells and skin lesions. GPR87 knockdown also enhanced MST1/2 and LATS1/2 phosphorylation, increased inhibitory YAP phosphorylation, and suppressed YAP nuclear localization and downstream transcriptional activity. Importantly, activation of YAP by either YAP(S127A) expression or XMU-MP-1 treatment restored SOX2 expression in GPR87-depleted cells, whereas verteporfin-mediated inhibition of YAP-TEAD activity attenuated TPA-induced SOX2 upregulation. Together, these findings identify GPR87 as a key positive regulator of skin tumor initiation and progression and demonstrate that its tumor-promoting effects are mediated, at least in part, through the YAP-SOX2 axis. GPR87 may therefore represent a potential therapeutic target for cSCC.
Non-coding RNAs (ncRNAs) regulate gene expression through transcriptional, post-transcriptional, and epigenetic mechanisms, shaping hallmarks of cancer, including metastasis, therapy resistance, and relapse. Carcinogenesis arises when aberrant ncRNA networks initiate malignant transformation and sustain oncogenic changes through epigenetic modifications, shifts in cell identity, failures in genome protection, metabolic changes, and alterations in the tumour microenvironment. Environmental exposures, combined with chronic inflammation, reorganise these networks early on, leading to the formation of premalignant fields and persistent epigenetic changes. The four major ncRNA classes, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI-interacting RNAs (piRNAs) function as either oncogenes or tumour suppressors depending on the specific cancer type. Their stability, cell-type-specific expression, and presence in biofluids make them suitable candidates for biomarker discovery and liquid biopsy applications. Therapeutic strategies now include antisense oligonucleotides, small interfering RNAs, synthetic miRNA mimics, RNA aptamers, and aptamer-siRNA conjugates, which can either inhibit oncogenic ncRNAs or restore tumour-suppressive regulatory networks. CRISPR-based ncRNA modulation, including Cas9-mediated locus editing, CRISPR interference/activation, and Cas13-mediated transcript targeting, remains largely investigational because delivery, off-target activity, and an incomplete understanding of ncRNA context dependence continue to limit translation. High-throughput sequencing, single-cell transcriptomics, and computational modelling have accelerated the identification of cancer-related ncRNAs and elucidated their biological functions. This review examines how different types of ncRNAs contribute to cancer initiation, progression, and treatment resistance, and assesses their potential as diagnostic markers, prognostic factors, and therapeutic targets.
SCF (Skp1-Cullin1-Fbox protein) is a multi-subunit RING-type E3 ligase and plays critical roles in various pivotal physiological and pathological processes by mediating the ubiquitination and degradation of key proteins. F-box proteins directly bind substrates, thereby determining their specificity, stability, and function. However, the regulatory mechanisms of FBXO21 degradation in human cancers remain largely elusive. In this study, we demonstrated that Neddylation-ROC1 E3 ligase regulates the protein level of FBXO21. Mechanistic studies revealed that Neddylation-ROC1 targeted FBXO21 for ubiquitination and degradation. Moreover, we found that FBXO21 depletion increased p53 protein stability by delaying its degradation, followed by increasing the transcriptional level of p21. Taken together, our findings reveal a previously unrecognized mechanism by which FBXO21 is regulated by Neddylation modification and regulates the p53-p21 signaling pathway.
The ATP-gated P2X7 receptors are abundantly expressed in immune cells, neurons, glial cells, and cancer cells. The P2X7 receptor performs distinct functions, depending on the extracellular ATP concentration and the duration of exposure to ATP. With brief ATP stimulation, the P2X7 receptor acts as an ion channel, and the movement of ions is associated with the regulation of cell proliferation and differentiation. Prolonged ATP exposure induces a conformational change in P2X7, allowing large molecules to pass through the membrane via the formation of macropores, thereby contributing to cell death. A novel function of P2X7 as a scavenger receptor was recently reported in the absence of both serum and ATP. However, the discovery of non-functional P2X7 in cancer reveals that this group of isoforms of P2X7 fails to form macropores upon ATP stimulation and cannot initiate ATP-induced cell death, allowing malignant cells to evade this regulatory mechanism and continue proliferating. We discuss the multifaceted functions of the P2X7 receptor in regulating diverse cell types, including cell growth, death, and clearance, and how the non-functional form of P2X7 disrupts this balance in cancer. Furthermore, the review explores the potential targeting of this aberrant isoform of P2X7 in the development of novel cancer therapies.
Androgen receptor splice variant 7 (AR-V7) is associated with resistance to androgen receptor-targeting therapies in prostate cancer, but its prevalence and clinical relevance in non-prostatic cancers remain incompletely characterized. A systematic review was conducted in accordance with PRISMA guidelines. Thirty-four studies, including 4855 clinical cases and 60 cell lines, were included. Overall, AR-V7 positivity was reported in 948/4855 clinical cases (19.5%); however, this represents a descriptive estimate across heterogeneous tumor types, study designs, and detection methods. Breast cancer accounted for 4057 of 4855 clinical cases (83.6%) and 815 of 948 AR-V7-positive cases (86.0%), with a within-cancer prevalence of 20.1%. However, after excluding the TCGA cohort in which AR-V7 was inferred through splice-junction analysis, the prevalence of AR-V7-positive breast cancer decreased to 9%. Higher tumor-specific proportions were observed in salivary duct carcinoma (55.2%), hepatocellular carcinoma (57.1%), and non-muscle-invasive bladder cancer (82.6%), but these estimates were based on smaller cohorts and should be interpreted cautiously. AR-V7 was present in several treatment-naive non-prostatic cancers, suggesting that it may represent a preexisting molecular feature in selected contexts. Current evidence suggests that AR-V7 warrants further investigation as a candidate biomarker. Standardized detection methods and prospective studies are needed before its clinical utility can be established.
Hepatocellular carcinoma (HCC), accounting for nearly 90% of primary liver cancers, remains a major global health challenge due to late diagnosis and therapy resistance. Up to 50% of cases exhibit aberrant activation of the canonical Wnt/β-catenin pathway, driven by CTNNB1 mutations or inactivating alterations in AXIN1, adenomatous polyposis coli, or ZNRF3, which are mutually exclusive. This hyperactivation has complex implications: it has been associated with drug resistance, larger tumors, epithelial-mesenchymal transition, vascular invasion, cancer stemness, and immune evasion, yet in some contexts, it correlates with a less aggressive, well-differentiated phenotype and improved survival. This heterogeneity highlights the need for further research to clarify its prognostic significance. This review explores recent mechanisms by which aberrant nuclear β-catenin accumulation fosters resistance to frontline tyrosine kinase inhibitors like sorafenib and lenvatinib through ferroptosis evasion, cancer stemness, and β-catenin stabilization. It also highlights how hyperactivated Wnt/β-catenin promotes an immunosuppressive "cold" tumor microenvironment, impairing immunotherapy efficacy. These include cytokine profile alterations, CD8+ T-cell exclusion, dendritic cell repression, and recruitment of immunosuppressive cells such as myeloid-derived suppressor cells, tumor-associated neutrophils, macrophages, and regulatory T cells. Recent preclinical studies show that combining Wnt inhibitors with immunotherapy or tyrosine kinase inhibitors can reprogram the tumor microenvironment, restore ferroptosis sensitivity, eradicate cancer stem cells, enhance CD8+ T-cell infiltration, boost antitumor immunity, and overcome resistance with minimal side effects. Targeting the Wnt/β-catenin pathway offers a promising strategy to transform HCC treatment and improve outcomes by exploiting this pathway as a key therapeutic vulnerability.
Emerging evidence suggests that perturbation of TGF-β signaling in parenchymal cells drives malignant transformation and cancer progression in a subset of patients with primary liver cancer (PLC). TGF-β plays a crucial role in liver pathophysiology with diverse effects on various processes and cell types. In liver homeostasis, TGF-β signaling exerts tumor-suppressive functions that are often lost during carcinogenic transformation, when downstream signaling rebranches from tumor-suppressive to pro-tumorigenic, facilitating invasiveness and metastasis. In this study, primary patient-derived and established liver cancer cell lines were exposed to TGF-β1 and TGF-β2, and effects on tumor-initiating potential, invasion, and migration were assessed by in vitro analyses including colony/sphere formation and wound healing assays. RNA sequencing and reverse-phase protein array (RPPA) were employed to analyze differential gene and protein expression across treatments. Our findings demonstrate that TGF-β1 and TGF-β2 reduced proliferation, colony and spheroid formation in investigated cell lines. Notably, TGF-β1 increased migratory and invasive properties of both HCC and CCA cell lines, whereas TGF-β2 had no such effect. Transcriptome profiling revealed activation of gene sets associated with cell cycle regulation by both ligands. Pro-migratory effects of TGF-β1 were linked to epithelial-mesenchymal transition (EMT), including enrichment of matrix metalloproteinase (MMP) and actin cytoskeleton pathways. Specifically, TGF-β1 downregulated epithelial marker E-cadherin and upregulated mesenchymal markers Vimentin and SNAIL. RPPA indicated p21 induction by both ligands, causing cell cycle arrest, while TGF-β1 specifically upregulated MMP14, promoting EMT-related properties. In conclusion, targeting TGF-β1-MMP14-EMT pathway could complement TGF-β-based therapies in PLC management.
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which is difficult to diagnose and treat due to lack of biomarkers, high metastasis, and recurrence. Ribosomal protein S6 kinase (RSK2) is frequently overexpressed and hyperactivated, thereby regulating proliferation and metastasis in many solid cancers, including breast cancer. However, the underlying mechanisms of RSK2 in TNBC metastasis are poorly understood. Here, we explored the role of RSK2 in the migration and invasion of TNBC. Our findings revealed that overexpression of RSK2 promoted Epithelial-mesenchymal transition (EMT) to induce migration and invasion of TNBC cells MDA-MB-231 and 4T1, whereas RSK2 knockdown decreased them. Mechanically, our results showed that RSK2 positively regulated the MEK/ERK pathway and enhanced GALNT5 mRNA expression and stability by RNA-seq analysis and experimental validation. Furthermore, knockdown of GALNT5 attenuated the MEK/ERK pathway. Finally, the in vivo results found that RSK2 promoted growth and EMT of TNBC. Collectively, our findings indicated that the MEK/ERK/RSK2 positive feedback loop promoted EMT to induce migration and invasion of TNBC via enhancing GALNT5 mRNA stability, and it was suggested that RSK2 may provide a novel therapeutic target for TNBC patients.
We analyzed initial endoscopic screening results, including esophageal iodine staining and oropharyngolaryngeal inspection, from 10 073 Japanese alcohol-dependent men (30-79 years) between 1993 and 2025. After adjustment for age, drinking and smoking habits, and screening year, using ADH1B*2 (rs1229984) plus ALDH2*1/*1 as the reference, the cancer risk (odds ratio (OR) [95% confidence interval (CI)]) associated with slow-metabolizing ADH1B*1/*1 plus ALDH2*1/*1, ADH1B*2 plus inactive ALDH2*2 (rs671), and ADH1B*1/*1 plus ALDH2*2 increased synergistically: 3.06 (2.13-4.39), 10.2 (7.33-14.2), and 21.0 (14.5-30.3) for esophageal squamous cell carcinoma (ESCC; n = 309, detection rate 3.1%); 4.34 (2.24-8.41), 11.3 (5.99-21.4), and 27.4 (14.3-52.5) for head and neck squamous cell carcinoma (HNSCC; n = 95, 0.9%). ADH1B*2 plus ALDH2*2 increased the OR for gastric adenocarcinoma (GA) to 3.71 (2.19-6.30; n = 91, 0.9%). ESCC and HNSCC were already detected at ages 30-39 (ESCC 0.3%, HNSCC 0.6%) and 40-49 (ESCC 1.3%, HNSCC 0.5%), and the corresponding ORs were markedly high in the 30-49 age group: 12.1 (2.62-56.0), 20.5 (4.09-103), and 166 (37.9-730) for ESCC; and 11.8 (1.36-102), 26.4 (2.92-238), and 95.0 (11.5-786) for HNSCC. The age-gradient difference in ORs was significant for ESCC (P = .008). ORs by genotype combination did not differ significantly across screening-year periods or by invasive status. Multiple cancers were detected in 39.8% of ESCC, 52.6% of HNSCC, and 30.8% of GA. Inactive ALDH2*2 was consistently linked with cancer multiplicity: ESCC OR 2.96 (1.77-4.95), HNSCC OR 14.0 (3.93-49.8), and GA OR 5.41 (1.63-18.0). These results support genotype-informed public health interventions in heavy-drinking East Asian populations.
The risk of cancer from medical exposure to ionizing radiation (IR) in pediatric patients-particularly those with congenital heart disease (CHD)-is a concern, given the need for repeated X-ray-guided cardiac catheterization (CC) procedures throughout their lives. To better understand the effects of low-dose IR, this study-part of the European HARMONIC project-investigated changes in blood miRNA expression following CC in CHD patients. Small RNA sequencing was performed on a discovery cohort of 10 CHD patients at three time points: before CC (T0), immediately after (T1), and one year later (T2). Differentially expressed miRNAs were validated in an independent group of 15 patients using qRT-PCR. KEGG pathway annotation analysis was carried out to determine the biological pathways involving target genes regulated by the dysregulated miRNAs. At the discovery stage, 74 miRNAs were significantly differentially expressed between the T1 and T0 groups, 69 between the T2 and T0 groups, and 41 between the T2 and T1 groups (q-value < 0.05 and |log2(fold change)|>1). Sixteen miRNAs (9 up-regulated and 7 down-regulated) were found dysregulated in both T1 and T2 compared to T0. Additionally, seven known miRNAs were uniquely dysregulated at T2. qRT-PCR analysis of six selected miRNAs partially validated the sequencing results, confirming consistent expression patterns for four miRNAs across cohorts. Pathway enrichment analysis indicated that predicted miRNA target genes were overrepresented in several pathways, including those annotated as cancer-related (enrichment p<0.0001). These findings suggest potential associations with radiation exposure, but their biological significance and health implications remain uncertain and require further investigation.
4-(Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its major metabolite 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are tobacco-specific lung carcinogens. NNK is widely used in preclinical models to induce lung tumorigenesis for elucidating carcinogenesis mechanisms and developing preventive agents, because of the high tumour burden in a cost-effective manner. Typical NNK doses employed in these models substantially exceed levels in humans and the routes of administration (e.g. intraperitoneal injection, oral gavage, or delivery via drinking water) differ fundamentally from inhalational exposure through cigarette smoke. At the molecular level, NNK and NNAL undergo metabolic bioactivation by cytochrome P450 enzymes, generating reactive intermediates capable of covalently modifying DNA and proteins, thereby initiating carcinogenesis. NNK and NNAL are also subject to competing metabolism. Their portion undergoing carcinogenic bioactivation is expected to vary as a function of dose and route of exposure, raising concerns about the physiological relevance of these preclinical models. Systematic comparison of NNK and NNAL bioactivation profiles in humans with these preclinical models can help assess their physiological relevance and inform translational application. Using LC-MS/MS methods, this study quantified 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB, an NNK-derived bioactivation hydrolysis product) and 1-(3-pyridyl)-1,4-butanediol (PBD, an NNAL-specific bioactivation hydrolysis product) in lung, liver, and serum samples from two mouse models and in human lung and plasma samples. Marketed differences were observed between NNK intraperitoneal preclinical models and human samples; in contrast, the tobacco smoke-based preclinical model better recapitulates human NNK and NNAL bioactivation. These results provide guidance for the future use of these models in investigating lung carcinogenesis and developing preventive agents.
High-linear energy transfer (LET) radiation is thought to induce highly complex DNA damage compared with photon radiation such as X-rays, suggesting a characteristic mechanism for the development of cancers associated with high-LET radiation exposure. However, few studies have investigated the carcinogenic mechanisms that are dependent on radiation quality or LET. This study analyzed mutations and gene expression in thymic lymphomas (TL) induced by high-LET carbon-ion irradiation to identify characteristic genetic alterations. The results revealed that TL arising after four-fractionated high-LET carbon-ion irradiation frequently exhibited loss of heterozygosity (LOH) in the region containing the TL-associated gene Ikzf1 on chromosome 11 owing to extensive genomic deletions in the paternal allele. Nevertheless, for carbon ion-induced TL, those with only LOH without Ikzf1 alterations were observed at a relatively high frequency (16/39, 41.0%). Comprehensive RNA sequencing and reverse-transcription PCR analysis of neighboring genes of Ikzf1 revealed highly upregulated expression of Grb10 (17/39, 43.6%), an imprinted gene that is barely expressed in the normal thymus. In TL expressing Grb10, enhanced interferon signaling and Pten mutations, along with activation of the PI3K-AKT-mTOR signaling pathway, were suggested to promote cell proliferation and survival. These results suggest that extensive genomic deletions caused by high-LET carbon-ion irradiation may contribute to carcinogenesis by altering the expression of multiple genes located in the deleted region.
The tobacco constituent, N'-nitrosonornicotine (NNN) is a potential etiological agent in the development of oral cancer. NNN is metabolically activated to form DNA adducts that release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) which was detected at higher levels in the oral cavity of smokers than non-smokers. Black raspberry (BRB) has been proposed as a preventive agent of oral cancer. In a phase 0 clinical trial, 40 active smokers (16 males, 24 females) consumed 5 g of BRB lozenges daily for 8 weeks. Each participant served as his/her own control. Buccal cells and urine were collected at baseline, during BRB administration, and washout period. In all smokers, BRB reduced, but not significantly, the levels of HPB-releasing DNA adducts (Baseline: 0.97 ± 0.51 and End-BRB: 0.61 ± 0.23 HPB/106 Guanine). A sex-specific response to BRB was observed: BRB had no effects in men, but in 16 of 24 women, BRB significantly reduced the levels of HPB. We further tested the hypothesis that detoxification of NNN via N-glucuronidation by BRB may, in part, account for the inhibition of HPB levels. The ratio of NNN-N-glucuronide to free NNN significantly increased (P = 0.028) from 1.29 ± 0.40 (baseline) to 2.77 ± 0.76 (End-BRB) in all 40 women as well as in female responders from 1.24 ± 0.60 (baseline) to 2.87 ± 1.00, but not in non-responders. The metabolic changes of NNN observed in our clinical trial indicate that BRB is a promising candidate for cancer interception and prevention of oral cancer in some, but not in all active smokers.
Neuroblastoma (NB), a common childhood solid tumor, is the leading cause of childhood cancer deaths. Transgelin (TAGLN) is an actin-binding protein of the calponin family, and it is involved in cell motility and migration. The TAGLN gene expression was induced in NB cell lines, such as GOTO, SK-N-SH, and TGW, by gene overexpression using a retroviral Tet-On inducible expression system, and was repressed by RNA interference (RNAi) treatment. TAGLN overexpression repressed cell growth and migration and induced cell arrest and differentiation. On the other hand, RNAi-mediated TAGLN repression activated cell growth. Cells overexpressing TAGLN showed decreased levels of undifferentiated cell markers, such as SOX2, OCT4, KLF4, and ID2. Single-cell analysis after TAGLN overexpression revealed a distinguishable cluster characterized by expression of POSTM, APOE, PDGFRA, IGFBP3, SMAD5, and IGFBP7. In TH-MYCN mice, which have a high frequency of NB development, Tagln overexpression by induction of the murine Tagln gene significantly reduced tumor formation and prolonged survival. In conclusion, these in vitro and in vivo analyses suggest that TAGLN is a candidate tumor suppressor gene in NB.
Stress is a risk factor for the development of various types of cancer. However, its impact and related underlying mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. Therefore, the present study aimed to investigate how chronic stress affects OSCC progression. We assessed mitochondrial metabolism by investigating tumor growth and performing behavioral analysis and molecular assessment, including non-targeted metabolomics and U-13C5-glutamine isotope metabolic flow analysis. We knocked down glutamate dehydrogenase 1 (GLUD1) using lentiviral vectors and investigated it both in vitro (HSC3 and HN6 cells) and in vivo (xenograft models). Our results indicated that chronic stress enhanced glutamate oxidative deamination and tricarboxylic acid cycle metabolism in OSCC cells. It also increased α-ketoglutarate (α-KG) levels, adenosine triphosphate synthesis, and oxygen consumption. Notably, GLUD1-knockdown suppressed these metabolic pathways and significantly inhibited tumor growth both in vitro and in vivo. Furthermore, under chronic stress, GLUD1 regulated OSCC progression through histone H3 trimethylation at lysine 4. However, α-KG supplementation partially reversed GLUD1-knockdown-induced OSCC progression inhibition. Collectively, our results indicate that the glutamate-dependent metabolic phenotype regulated by the GLUD1-α-KG metabolic axis is involved in the progression of OSCC under chronic stress.
This study investigated the expression profile and prognostic significance of nicotinamide N-methyltransferase (NNMT) in pan-cancer stroma, with focused validation in lung adenocarcinoma (LUAD) and breast carcinoma (BC). Integrated analysis of Genotype-Tissue Expression and The Cancer Genome Atlas databases revealed tumor-specific NNMT mRNA upregulation in these malignancies. Subsequently, the relationship between NNMT mRNA expression levels and clinical parameters across multiple cancer types was examined, with particular emphasis on LUAD, BC, and CRC. Single-cell RNA sequencing data further revealed elevated NNMT expression specifically within stromal compartments, with fibroblasts exhibiting the highest NNMT expression levels among stromal cell populations. Protein-level validation using the Human Protein Atlas database, the National Cancer Institute's Proteomics Data Commons, and the quantitative immunohistochemistry of our independent clinical cohorts demonstrated elevated stromal NNMT protein expression, particularly in cancer-associated fibroblasts. Cox regression analysis and survival curve analysis established stromal NNMT expression as an independent prognostic factor for overall survival in LUAD and BC patients (P < .05). In conclusion, high stromal NNMT levels correlated with poor prognosis, establishing it as a promising biomarker for risk stratification in LUAD and BC.
Many chemical carcinogens in tobacco smoke require bioactivation by cytochrome P450 enzymes. While the roles of P450 enzymes in carcinogenesis have been demonstrated in vivo using several individual carcinogens at relatively high doses, no data has been reported on their contributions to carcinogenesis induced by tobacco smoke, a complex mixture of >4000 compounds. The present study aims to address this important knowledge gap, using mice deficient in the expression of enzymes of the Cyp2abfgs gene subfamilies, which are known to bioactivate multiple chemical carcinogens in tobacco smoke. Male and female wild-type (WT) and Cyp2abfgs-null mice on the A/J genetic background were exposed to environmental tobacco smoke (ETS), a mixture of mainstream and sidestream smoke, for 6 hours/day, 5 days/week, for 5 months, at a target dose of 0 or 120 mg/m3 suspended total particulate matter. All mice were returned to filtered air (FA) for 4 months after cessation of ETS exposure. At approximately 11 months of age, mice were euthanized, and lungs were collected for tumor enumeration. ETS exposure increased tumor multiplicity (number of tumors per lung) in WT mice by 2.5-fold (p<0.0001), but only by 1.7-fold in Cyp2abfgs-null mice (p<0.001), compared to FA-exposed mice (n=∼180 per group, male and female). Multiplicity of ETS-induced tumors was significantly reduced (by 50%; p<0.01) in Cyp2abfgs-null relative to WT mice. These results demonstrate for the first time, in vivo, that bioactivation of ETS constituents by P450 enzymes, of the Cyp2abfgs gene subfamilies, play an important role in tobacco-smoke induced lung tumorigenesis in mice.
For decades, there has been a strong epidemiological association between solar ultraviolet (UV) radiation and skin cancer. UVB and UVA are the major UV bands that can penetrate the atmosphere, playing vital roles in skin carcinogenesis. Our research group previously discovered that a specific dose of UVA can inhibit the increase of activator protein 1 (AP-1) activity caused by UVB. It is unclear whether UVA plays a particular role in UVB-induced skin cancer. Here, we report that UVA was protective in UVB-induced cutaneous squamous cell carcinoma (cSCC) by attenuating UVB-induced DNA damage. DNA repair chip array results showed that the mRNA level of X-ray cross-complementing protein 4 (XRCC4) significantly increased in the UVA/B group compared with the UVB group, and knockdown of XRCC4 partly blocked the protective effect of UVA in UVB-induced DNA damage. AP-1, the predicted transcriptional regulatory factor of XRCC4, exhibited no sensitivity to UVB radiation upon pretreatment with UVA. More importantly, the luciferase reporter assay showed that c-Fos, which is the critical component of AP-1, inhibited the transcription of XRCC4, and mutation of c-Fos (cys154 > serine) partly enhanced this effect and promoted keratinocyte transformation. UVA was protective in UVB-induced cSCC by interacting with the c-Fos/XRCC4 axis.
While the effect of hyperglycemia on cutaneous wound healing is well recognized, the impact of high-glucose (HG) environment on UVB-induced skin tumor formation remains inconclusive. Similar to impaired wound healing, skin tumor formation involves keratinocyte proliferation and migration. Intriguingly, SOX2 has been recognized to play an important role in both wound healing and UVB-induced skin tumor formation by modulating cell proliferation and migration. As hyperglycemia results in impaired cutaneous wound healing, we hypothesized that the HG environment also impacts UVB-induced tumor formation of the skin. This study aimed to explore the effects of HG environment on epidermal keratinocytes, focusing on the impact of UVB-induced cell proliferation and migration via SOX2 expression. In cultured keratinocytes, HG-cultivated keratinocytes showed reduced SOX2 levels compared to control with or without UVB treatment. SOX2 regulates keratinocyte migration and proliferation via modulation of AKT phosphorylation. Additionally, O-linked-N-acetylglucosamine glycosylation contributed to reduced SOX2 levels in HG-cultivated keratinocytes. Animal studies demonstrated that diabetic mice skin has significantly less UVB-induced tumor formation, epidermal thickening, SOX2, and pAKT expression than the control mice; mutant p53 expression was also lower in diabetic mice but did not reach statistical significance compared to control. In conclusion, HG environment reduces UVB-induced keratinocyte proliferation and migration, in association with decreased SOX2 expression and downstream AKT signaling. The current findings provide novel insights regarding UVB-induced skin tumor formation of skin in patients with diabetes.
Human exposure to toxicants and carcinogens occurs via polluted air, the diet, occupational settings, endogenous processes, and tobacco products. The glutathione-S-transferase detoxification pathway resulting in the excretion of mercapturic acids is one of the most important human systems for processing and excreting toxicants and carcinogens. Maximizing effectiveness of this pathway through dietary modifications can potentially decrease the impact of such exposures. We conducted a two-site clinical trial with a crossover, single blind (to participants) design, randomized to order of product receipt comparing levels of selected urinary mercapturic acids when participants consumed a drink made from freeze-dried watercress (3× daily, 2 weeks) naturally containing 2-phenethyl isothiocyanate (PEITC) vs. a placebo drink containing maltodextrin (3× daily, 2 weeks) with a 4-week washout between the treatment periods. Two hundred forty participants (157 F) were recruited and 188 (125 F, 152 non-smokers) were compliant and completed the study. Among compliant subjects, urinary mercapturic acid detoxification products of acrolein, acrylonitrile, benzene, crotonaldehyde, methacrolein, and methyl vinyl ketone increased significantly (P ≤ 0.002), with the largest increases being observed for the mercapturic acids of acrolein (65.6%) and benzene (37.3%), both P < 0.001. Consumption of a drink, three times daily, prepared from freeze-dried watercress containing PEITC (total of approximately 40 mg/day) significantly increased the detoxification of 6 of 7 environmental toxicants and carcinogens monitored. The results indicate that watercress consumption can ameliorate exposure to environmental toxicants and carcinogens. These results are particularly timely and relevant to exposures to atmospheric pyrolysis products resulting from wildfires. Clinical trial registration number: NCT03978117.
