Early cancer detection and prophylactic intervention remain the primary strategies for reducing colorectal carcinoma incidence and mortality. Although the immune microenvironment and tumor-associated antigens have been shown to play a pivotal role in carcinogenesis, the factors shaping immune dynamics during the premalignant phase remain poorly understood. In this study, we performed a comprehensive multimodal characterization of the immune microenvironment in 258 longitudinal premalignant colorectal lesions. Using a discovery cohort of 135 lesions from 26 patients stratified by low versus high polyp development rate, we identified distinct immune states associated with polyp burden. These findings were validated in an independent cohort of 123 lesions from 43 patients. Lesions from patients with low polyp development rates exhibited signatures of robust immune surveillance characterized by enhanced adaptive immune infiltration, including defined T cell subsets, and a higher prevalence of mature tertiary lymphoid structures compared with lesions from patients with high polyp frequency. These immune features were accompanied by increased expression of noncoding RNAs. These transcripts were predicted to encode noncanonical antigens with high MHC-I (major histocompatibility complex class I) binding affinity, potentially increasing lesion immunogenicity. We propose that early carcinogenesis is shaped by the immune microenvironment in association with noncoding RNAs, revealing potential early biomarkers in individuals at high risk of developing colorectal cancer.
Human papillomavirus 33 (HPV33) is among the five most prevalent HPV genotypes in China and is commonly involved in co-infections. However, the synergistic effects of specific genotype combinations on cervical carcinogenesis remain incompletely understood. This study aimed to characterize HPV33 co-infection patterns and their associated genetic variations in relation to cervical lesion progression. We enrolled 1,770 HPV33-positive patients from the Obstetrics and Gynecology Hospital of Fudan University between 2018 and 2023, including 852 with HPV33 single infections and 918 with multiple infections. Logistic regression was used to assess associations between co-infection characteristics and cervical histopathological results. In a subset of 90 cases, the full-length L1 gene of HPV33 was sequenced and phylogenetically analyzed to evaluate genomic variation by infection status. The number of HPV33 co-infecting genotypes was positively correlated with cervical lesion severity (p < 0.05). HPV52, HPV16, and HPV58 were the most frequent co-infecting genotypes and were associated with an increased risk of cervical intraepithelial lesion progression: HPV16 (OR 1.97, 95% CI: 1.17-3.34), HPV52 (OR 2.07, 95% CI: 1.26-3.39), HPV58 (OR 2.83, 95% CI: 1.42-5.64). However, among HPV33 multiple infections (≥3 genotypes), only those that involved HPV16 were directly and significantly associated with an increased risk of cervical lesions, with ORs increasing from 1.72 (95% CI: 1.03-2.85) for LSIL to 3.16 (95% CI: 1.75-5.72) for HSIL or worse. Phylogenetic analysis classified most HPV33 sequences into sublineage A1, with no significant difference in L1 gene mutations between single and multiple infections. HPV33 co-infection patterns, particularly those involving HPV16, are consistently associated with an elevated risk of high-grade cervical lesions in this Chinese cohort. These findings underscore the differential risks associated with distinct HPV33 co-infection patterns and support genotype-specific risk stratification in cervical cancer screening programs.
Cutaneous squamous cell carcinoma (cSCC) represents a growing public health burden, with incidence projected to increase 23-29% over the coming decade. Topical immunoprevention strategies targeting the PD-L1 / PD-1 and TLR4 axes have demonstrated preclinical efficacy, yet optimal intervention timing in humans remains undefined. To address this gap, single-cell RNA sequencing was performed on matched sun-protected (SP), sun-damaged (SD), and actinic keratosis (AK) biopsies from the same individuals, along with independent cSCC cases. Immune checkpoint and innate inflammatory signals were detectable as early as SD skin, prior to histologically confirmed dysplasia. Monotonically increasing expression of CD274 ( PD-L1 ), CTLA4 , PDCD1 , CD27 , and STAT1 , alongside progressive TLR4 - MYD88 innate immune signaling, was revealed through pseudobulk data analysis, with earliest upregulation at the SD stage. Fuzzy c-means trajectory clustering identified cell-typespecific programs across dendritic cells, macrophages, T cells, fibroblasts, endothelial cells, and keratinocytes. Dendritic cells shifted from early inflammatory antigen-presenting programs toward late PD-L1 / IFN -regulatory states; macrophages showed monotonically increasing TLR4 -associated myeloid activation; and T cells defined a "hot but exhausted" microenvironment in established cSCC. These findings identify SD and AK as biologically active stages for topical immunoprevention and provide a cellular roadmap for PD-L1 / PD-1 and TLR4 blockade strategies.
Obesity contributes significantly to cancer development due to superfluous adipose tissue interfering with physiologic balance. The current narrative review outlines the molecular and physiological pathways linking obesity and cancer and highlights the role of natural products as preventive and therapeutic agents. Underlying processes intertwining obesity and cancer include chronic low-grade inflammation, insulin resistance, hormonal imbalance, adipokine dysregulation, oxidative stress, and changes in the gut microbiome. All of these are used to facilitate tumor-promoting microblood to increase tumor growth and help cancerous cells proliferate and metastasize. There are specific mediators that are important in the activation of oncogenic signalling pathways, such as tumor necrosis factor-alpha, interleukin 6, insulin-like growth factor-1, estrogen, leptin, and reactive oxygen species. Phytochemicals that have the potential to be used as natural anti-inflammatory, antioxidant, and anticancer agents include, but are not limited to, curcumin, resveratrol, epigallocatechin gallate (EGCG), quercetin, berberine, gingerol, and capsaicin. The compounds regulate major molecular pathways of the obesity-related cancers. A new method of delivery that automatically and involuntarily targets the delivery mechanism by use of nanotechnologies has demonstrated its capacity in increasing bioavailability and therapeutic effects of these bioactive agents. To reduce the burden of this impact of obesity on cancers, a strategy involving a blend of lifestyle changes, pharmacological treatment, and science-based natural solutions is required. We conclude that in order to increase the potential of natural products, there is a need to have clinical studies on oncology and public health, as well as regulatory advancement.
One of the most common soft-tissue sarcomas is LMS, a highly aggressive mesenchymal malignancy. LMS is characterized by significant molecular and clinical heterogeneity, arising from diverse anatomical sites and exhibiting distinct genomic alterations across subtypes. Among the key oncogenic drivers, the PI3K/AKT/mTOR signaling pathway plays a central role in regulating cell growth, proliferation, and survival. Dysregulation of this pathway, often through PTEN loss or upstream receptor activation, has been increasingly implicated in the pathogenesis of LMS, making it a critical therapeutic target. The MAPK pathway is among other intracellular signaling pathways and is significant in processes such as cell proliferation, differentiation, apoptosis, angiogenesis, and tumor metastasis. The important MAPK cascades found in eukaryotic cells include ERK, JNK/stress-activated protein kinase, p38 MAPK, and ERK5 signaling pathways. As these pathways are critical, they are promising areas for cancer therapy. In short, attention is on translating PI3K/AKT inhibitors into clinical practice to provide patients with new targeted therapy. This review summarizes the molecular mechanisms underlying LMS pathogenesis and discusses emerging therapeutic strategies to improve clinical outcomes.
Laryngeal squamous cell carcinoma (LSCC) frequently arises from premalignant dysplastic lesions, yet reliable predictors of malignant transformation remain limited. This study investigates the immune microenvironment of laryngeal dysplasia and its association with progression to invasive carcinoma. We conducted a retrospective cohort study of 110 patients with histologically confirmed laryngeal dysplasia excised between 2009 and 2022, reclassified according to the 2022 WHO two‑tier system. Clinical data, including tobacco and alcohol exposure, were collected, and outcomes included recurrence, progression to invasive carcinoma, and cancer‑free survival. Immunohistochemistry and digital image analysis were used to quantify intraepithelial and stromal immune markers (CD3+, CD4+, CD8+, CD68+, CD163+, PD-L1). High-grade dysplasia represented 68% of cases, and 33% progressed to invasive carcinoma. Intraepithelial T-cell and macrophage densities did not differ significantly between progressing and non-progressing lesions, whereas stromal immune characteristics showed prognostic value. In multivariate analysis, alcohol exposure, dysplasia grade, stromal CD8 + density, and PD-L1 expression were independently associated with progression. Former drinkers showed a higher risk than lifelong abstainers, while high-grade dysplasia carried a fourfold increased risk relative to low-grade lesions. Higher stromal CD8 + infiltration and lower stromal PD-L1 expression correlated with progression, though with modest effect sizes. Digital immune profiling validated distinct stromal immune signatures associated with progression in laryngeal dysplasia. These findings suggest that malignant transformation depends not only on histological grade and alcohol exposure but also on subtle immune alterations, supporting integration of stromal immune markers with WHO grading to refine risk stratification and guide surveillance strategies.
Papillary thyroid carcinoma (PTC) is the most prevalent subtype of thyroid cancer; however, the regulatory mechanisms by which mitophagy influences its progression remain inadequately elucidated. This study sought to examine the role of myoferlin (MYOF) in mitophagy and its molecular basis during PTC development. Utilizing three paired PTC and adjacent normal tissues, we observed elevated MYOF expression at both protein and mRNA levels through western blot and qRT-PCR analyses. Stable MYOF knockdown cell lines were established in PTC (TPC-1, KTC-1) and normal thyroid (Nthy-ori 3-1) cells using lentiviral shRNA. Functional assays, including CCK-8, wound healing, transwell, flow cytometry, immunofluorescence, and mitophagic flux analysis, along with a xenograft mouse model, were employed. Subsequent evaluations involved hematoxylin and eosin staining, immunohistochemistry, western blot, and qRT-PCR. As a result, MYOF was significantly upregulated in PTC tissues and TPC-1 cells. Knockdown of MYOF inhibited PTC cell proliferation, invasion, migration, and colony formation, while promoting apoptosis. Mechanistically, MYOF was found to regulate PTC progression through the PINK1/Parkin-mediated mitophagy pathway. In vivo xenograft experiments demonstrated that MYOF silencing suppressed tumor growth and increased the expression of mitophagy-related proteins BNIP3 and NIX. In conclusion, MYOF drives PTC progression by repressing mitophagy. Targeted inhibition of MYOF activates tumor-suppressive mitophagy via the PINK1-Parkin axis, indicating MYOF as a potential therapeutic target in PTC.
Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse cardiometabolic outcomes. But the molecular mechanism is still unexplored. The purpose of our study is to investigate the relationship between exposure to PAHs and cardiometabolic dysfunction, and to explore the mechanism and molecular pathways. We combined National Health and Nutrition Examination Survey (NHANES) data with multiple toxicological databases. Mendelian randomization (MR) was used to evaluate the causal contribution of immune factors to cardiovascular diseases (CVD) and metabolic disorders. Network toxicology and molecular docking were conducted to identify candidate molecular targets and signaling pathways involved in PAHs-related cardiometabolic dysfunction. Higher PAHs exposure was associated with increased cardiometabolic index (CMI) in adults, and this association was partially mediated by monocyte percentage and white blood cell count. MR analyses supported a causal role of these immune-related factors in CVD and metabolic disorders. Network toxicology and molecular docking involved pathways including chemical carcinogenesis-receptor activation, chemical carcinogenesis- DNA adduct formation, cytochrome P450 metabolism, and steroid hormone biosynthesis. CYP1A1, ESR1, and MAO were identified as potential key targets. Changes in monocyte percent and white blood count may help explain how PAH exposure is linked to cardiometabolic dysfunction. The implicated pathways and targets provide potential mechanisms. Our findings provide epidemiological and mechanistic evidence suggesting that PAH exposure may be linked to adverse cardiometabolic outcomes, potentially through immune-related pathways.
Colorectal cancer (CRC) is an increasing health concern in low- and middle-income countries (LMICs), especially in Africa, driven by dietary shifts, urbanisation, infections, and limited treatment access. The gut microbiome plays a central role in CRC, while soil-transmitted helminths (STHs) exert complex effects that can promote or mitigate risk depending on species, infection intensity, and host context. This systematic review synthesised 17 human studies (2000-2026) examining helminth impacts on gut microbial diversity, revealing a dualistic pattern. Several studies reported that chronic or moderate helminth infections, such as Ascaris lumbricoides and Trichuris trichiura, were associated with increased bacterial richness and the expansion of beneficial taxa, including Paraprevotellaceae, Parabacteroides, Agathobacter, Ruminococcaceae, and Lactobacillus. These taxa are associated with the production of short-chain fatty acids (SCFAs), protection of the epithelial barrier, and regulation of the immune system, suggesting a potential buffering effect against inflammation-driven carcinogenesis. On the contrary, other studies demonstrated helminth-associated dysbiosis characterised by reduced diversity and enrichment of pro-inflammatory and oncogenic taxa. T. trichiura and Strongyloides stercoralis infections were associated with the expansion of Treponema succinifaciens, Streptococcus gallolyticus, Enterobacteriaceae, and Ruminococcus torques, which are linked to reduced gut microbiome diversity, pro-inflammatory states, and oncogenic processes. Furthermore, A. lumbricoides infections altered the host microbiome at the phylum level, with increased Proteobacteria and reduced Firmicutes and Bacteroidetes, alongside metabolome shifts in amino acid and lipid pathways that have been associated with tumourigenic processes. Collectively, the evidence shows that helminthiasis may either enrich potentially protective microbes or be associated with pro-tumourigenic dysbiosis, with outcomes shaped by species, infection intensity, and host context. Notably, none of the included studies directly assessed CRC, underscoring the fact that current evidence is indirect and mechanistic. Overall, helminths are associated with gut microbiome shifts in both potentially protective and potentially harmful directions. This systematic synthesis of human evidence provides an integrated understanding of how helminth-associated microbiome shifts may influence colorectal carcinogenesis and highlights the need for longitudinal mechanistic studies to clarify causality and inform biomarker discovery and prevention in endemic regions.
Chronic ultraviolet (UV) exposure drives the development of non-melanoma skin cancers (NMSCs), particularly cutaneous squamous cell carcinoma (cSCC), through persistent DNA damage and inflammation. However, how UV-induced epithelial damage is coupled to inflammatory signaling and tumor-stromal communication during skin carcinogenesis remains incompletely understood. Here, we identify CD70, a TNF superfamily member, as a UV- and DNA damage-inducible regulator that links epithelial stress responses to stromal activation and tumor-promoting signaling. Integrative analyses of transcriptomic (GTEx, GSE2503, GSE42677), proteomic (RPPA), and immunostaining datasets reveal robust upregulation of CD70 in sun-exposed skin, actinic keratoses, and cSCC lesions. Functionally, CD70 silencing suppresses cSCC proliferation and xenograft growth, whereas solar UV or DMBA exposure induces CD70 expression. CD70 depletion disrupts cytokine-receptor signaling and MAPK/NF-κB pathways and alters inflammatory gene expression in UV-irradiated keratinocytes. In dermal fibroblasts, CD70 enhances NF-κB activation and secretion of IL-6 and MCP3 in TGF-β-activated fibroblasts, thereby reinforcing paracrine inflammatory loops that support cSCC spheroid expansion and tumor progression. CD70 knockdown in fibroblasts abrogates these effects and reduces tumor proliferation and cytokine expression in vivo. Mechanistically, E2F1 directly binds and activates the CD70 promoter, linking the DNA damage response to CD70 upregulation. Collectively, our findings identify CD70 as a stress-inducible signaling hub that links DNA damage, inflammation, and tumor-stromal communication in skin carcinogenesis. Targeting CD70 may disrupt this feed-forward inflammatory circuit and provide a therapeutic strategy for UV-driven and inflammation-associated cSCC.
This paper is part of a series of publications developed by the Latin America-Comet assay (LA-COMET) group, which emerged in 2021, during the Asociacion Latinoamericana de Mutagenesis, Carcinogenesis y Teratogenesis Ambiental Congress, to organize the LA-COMET initiative. A total of 104 alkaline comet assay publications in animal (aquatic and terrestrial) and plant models, authored by members of this group, were analyzed to determine how DNA damage under experimental and environmental exposure conditions is assessed. The manuscript reflects the broad use and versatility of the comet assay in diverse taxonomic groups (invertebrates and vertebrates), in vivo research models, and cell types (e.g., erythrocytes, branchia cells, retinal epithelial cells, peripheral blood, liver, kidney, lung, bone marrow, testicle and nasal cells). Application of the comet assay in diverse biological systems requires careful methodological standardization to ensure reproducibility and allow for comparability of results. In order to unify the evaluations of the papers, a quality score system was developed, the 'quality score comet assay' (QSca), providing values reflecting the methodological rigor of the execution of the assay. The group identified key elements when performing the comet assay and uses them as the focus for the QSca score. The LA-COMET initiative will provide opportunities to strengthen collaborative networks among Latin American countries, promoting more integrative and regionally connected research where the comet assay can be used as a reliable and reproducible tool for the assessment of DNA damage in diverse biological models.
The involvement of certain adipokines link to carcinogenesis, development, and prognosis. However, the roles of adipokines in lung cancer and its histological subtypes remains indistinct. Therefore, the aims of this study are to explore the causal relationship between adipokines and lung cancers. Summary-level data for exposures (six adipokines) and outcomes (lung cancer and its histological subtypes) were collected from the IEU OpenGWAS, International Lung Cancer Consortium (ILCCO) and lectures. Two-sample mendelian randomization (MR) was conducted to estimate the causality by employing single nucleotide polymorphisms (SNPs) as instrument variables (IVs). Human tissue microarray and immunohistochemistry (IHC) analysis validated the adipokines expression. Functional effects of LEPR in LUSC were assessed in vitro using NCI-H2170 and SK-MES-1 cell lines via siRNA-mediated knockdown, followed by assays for cell proliferation, invasion, and apoptosis. Leptin receptor (LEPR) was associated with risk of lung squamous cell carcinoma (LUSC, OR: 1.05, 95% CI: 1.01-1.08; P < 0.0125), and no other adipokines associated with lung cancer and its histological subtypes (P > 0.05). Experimental results revealed that high expression of LEPR in LUSC tumor samples compared to adjacent normal samples, and associated with unfavorable survival status. In vitro, LEPR knockdown significantly inhibited proliferation and invasion while promoting apoptosis in LUSC cells. These findings suggest that LEPR may play a critical role in the development and progression of LUSC, providing a potential target for therapeutic intervention.
Polycyclic aromatic hydrocarbons (PAHs) are well-known for their mutagenic and carcinogenic effects. Benzo[b]fluoranthene (BbF) is one of 16 PAHs prioritized by the US Environmental Protection Agency for toxicological evaluation due to pervasive human exposure. As part of a multi-stakeholder consortium, the genotoxic effects of BbF were evaluated in MutaMouse males exposed to five doses of BbF or a vehicle control via repeated oral gavage for 28, 60, 90, 120, or 180 days, with dose ranges adjusted by duration of exposure. Mutagenesis was evaluated in lung tissue (n = 4) at 28, 90, and 180 days using Duplex Sequencing (DS), and chromosomal damage (n = 8) was evaluated using the micronucleus assay in peripheral blood at all time points. Dose- and time-dependent increases in total mutation frequency (MF) and C:G > A:T mutations were observed in lung tissue after 28, 90, and 180 days of exposure. By 28 days, BbF exposure produced lung cancer-associated mutational signatures linked to tobacco smoking. Mutations accumulated over time in lung, whereas chromosomal damage in peripheral blood erythrocytes reached a steady state by 28 days. Benchmark dose (BMD) confidence intervals (CIs) narrowed with extended exposure only for MF. Collectively, the data demonstrate that BbF is a potent mutagen capable of inducing cancer-relevant mutations in lung, supporting its potential role in human lung carcinogenesis. By distinguishing early mutagenic responses from cumulative mutation effects over time, these findings highlight the value of integrating mutagenicity assessment into extended-duration studies to better inform the potential health effects of chronic genotoxic exposures.
Breast cancer remains the most frequently diagnosed malignancy among women worldwide, while metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease, reflecting a global burden of metabolic dysfunction. Increasing evidence suggests that MASLD is associated with breast cancer development and progression; however, whether this relationship reflects an independent effect of hepatic metabolic dysfunction or the broader metabolic environment remains uncertain. This review synthesizes current epidemiological, clinical, and mechanistic data linking hepatic metabolic dysfunction to breast carcinogenesis. Population-based studies consistently demonstrate an association between hepatic steatosis and increased breast cancer incidence, particularly in postmenopausal and metabolically vulnerable populations, as well as poorer oncological outcomes. Mechanistically, MASLD promotes a systemic pro-tumorigenic environment through interconnected pathways, including insulin resistance, hormonal dysregulation with increased estrogen bioavailability, chronic inflammation, oxidative stress, lipid metabolic reprogramming, and gut-liver axis disruption. Hepatokines, particularly fibroblast growth factor 21 (FGF21), emerge as key mediators of tumor progression and potential biomarkers of metabolic vulnerability, while Fetuin-A and angiopoietin-like protein 8 (ANGPTL8) further support the liver's endocrine role in oncogenic signaling. Preclinical evidence highlights fatty acid oxidation as a metabolic dependency in aggressive breast cancer subtypes, suggesting novel therapeutic targets. Despite consistent associations, causality remains unproven. Future prospective studies are needed to determine whether targeting metabolic dysfunction can improve breast cancer prevention and outcomes.
Pancreatitis is a significant risk factor for pancreatic cancer, with Kras mutations being the most common in this malignancy. Inflammation accelerates tumorigenesis driven by Kras mutations. However, the interactions between inflammation and Kras mutation in the context of pancreatic tumorigenesis remain unclear. In this study, we discovered that under pancreatitis conditions, the endoplasmic reticulum stress-related pathways are downregulated in Kras mutant mice compared to wild-type mice, while endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is abnormally upregulated. Kras mutation downregulates the ER-associated E3 ubiquitin ligase HRD1, resulting in reduced ubiquitination and degradation of HIF1α, which transcriptionally induces the expression of ERO1L. Inhibition of ERO1L activity or pancreas-specific knockout of the Ero1l gene can delay the progression of pancreatic carcinogenesis. Mechanistically, ERO1L enhances the protein expression of the chemokine CCL2 through its role in oxidative folding, thereby promoting the recruitment of macrophages. Thus, this study reveals that Kras mutation upregulates ERO1L to promote inflammation and pancreatic tumorigenesis, providing new insights and potential targets for the treatment of pancreatic cancer.
Oral squamous cell carcinoma (OSCC) is characterized by consistently high mortality rates (≤60%) despite therapeutic advances. This is attributable to diagnostic delays arising from the asymptomatic early stages and time-consuming protocols. Hence, the establishment of reliable biomarkers for the routine assessment of the oral mucosa is imperative. MicroRNAs (miRNAs), key epigenetic regulators of gene expression, represent ideal candidates given their characteristic dysregulation across different pathologies. Here, we aimed to identify novel OSCC-specific miRNAs for the saliva-based detection of OSCC from the presymptomatic stage of early invasion. Through a multistep bioinformatic workflow, four miRNAs (miR-20b-5p, miR-484, miR-185-5p and miR-181d-5p) were identified as disease-specific since they simultaneously regulated >65% of a panel encompassing the 15 primarily overexpressed oncogenes in OSCC and a stage-specific panel including the six upregulated genes that genetically define the malignant stages of sequential oral carcinogenesis. The salivary expression of the identified miRNAs was studied in 31 OSCC patients and 31 healthy controls, using quantitative real-time PCR, followed by statistical analysis and an evaluation of the diagnostic accuracy. All studied miRNAs were significantly downregulated in the saliva of OSCC patients compared to controls (miR-484, p < 0.001; miR-181d-5p, p < 0.001; miR-185, p = 0.008; miR-20b, p = 0.026) and exhibited combinatory diagnostic performance of 95.4% (p < 0.001) for OSCC detection. Their expression remained uninfluenced by lifestyle and clinicopathological parameters, including smoking/alcohol, tumor site, grade and disease stage. The proposed 4-miRNA panel exhibits high diagnostic performance for the early, saliva-based detection of OSCC, irrespective of histopathological and lifestyle confounders, highlighting its potential as a robust non-invasive screening tool.
β, β-Dimethylacrylshikonin (DMAS), a natural naphthoquinone derivative isolated from the root of a biennial herb belonging to the family Boraginaceae, has been demonstrated to exhibit anti-cancer and anti-inflammatory features. Yet, the effects of DMAS on restraining the progression of prostate cancer (PC) remain mostly elusive. Here, we attempted to examine whether DMAS hampers PC progression and subsequently explored the underlying mechanisms. Our results demonstrate that DMAS elicited cytotoxicity to PC cell lines, DU-145 and PC-3 cells, along with promotion of apoptosis and cell cycle arrest. Moreover, fluctuations in the levels of many potential apoptosis markers (upregulation of HO-1 and downregulation of cIAP-1 and XIAP) and activation of caspase pathways were observed in DMAS-treated PC cell lines. Furthermore, DMAS-induced caspase activations in PC cells were affected by silencing of HO-1 and the pretreatment with a selective ERK (U0126) or p38 inhibitor (SB203580), unveiling a functional linkage of HO-1, ERK, and p38 signalling to the responses of DMAS-treated PC cells. In conclusion, our results revealed that DMAS induced activation of caspase cascades to elicit cell apoptosis in PC, through HO-1 upregulation and ERK/p38 activation. These findings provide possible avenues for the use of a naturally occurring compound with therapeutic values in fighting prostate carcinogenesis.
The body's microbiota plays a fundamental role in maintaining homeostasis and influences immune function, metabolism, and tissue integrity. A growing body of research suggests that fluctuations in the composition and abundance of individual microbiota populations may influence cancer development and the effectiveness of therapy. The condition of microbiota dysbiosis has been demonstrated to induce chronic inflammation, immune system dysregulation, and, most significantly, modulation of molecular pathways that promote tumorigenesis. The efficacy and toxicity of cancer treatment can be influenced by the composition of the microbiota. Bacteria can modify the effectiveness and toxicity of chemotherapy and immunotherapy by affecting drug metabolism and the body's immune response. In contrast, the development of anticancer therapies that utilize bacteria is gaining increasing interest. This alternative to conventional treatment utilizes the natural ability of certain bacterial species to selectively colonize hypoxic and necrotic environments. The exploration of natural and genetically modified bacteria as vectors for the delivery of cytotoxins, immunomodulators, or therapeutic genes in the combat of cancer is a current area of research. In addition, their capacity to stimulate an antitumor immune response is also exploited. Preclinical investigations in animals have demonstrated the efficacy of this therapeutic approach, underscoring the promise of bacterial therapies as either an adjunct to conventional treatment or as a standalone strategy for combating cancer. This article synthesizes the current knowledge regarding the role of microbiota in carcinogenesis in animals and discusses recent developments in the field of bacterial therapies. The text also addresses the challenges, safety considerations, and future perspectives associated with translating microbiota-targeted and bacterial therapies into veterinary and comparative oncology.
The aim of this study was to analyze the effect of concomitant use of cannabigerol (CBG) and 3-O-ethylascorbic acid (EAA) on changes in the proteome of UVA-irradiated skin melanocytes, with particular emphasis on adduct formation between lipid peroxidation products and metabolically important proteins. Proteomic analysis allowed the identification of 1248 proteins with statistically significantly changed expression following melanocytes irradiation and/or incubation with CBG/EAA. The top 25 proteins with the most strongly differentially abundant expression included proteins involved in cell protection/antioxidant response, as well as pro-inflammatory and proapoptotic signalization. Moreover, in melanocytes irradiated with UVA, the levels of lipid peroxidation product, 4-hydroxynonenal (4-HNE) and its protein adducts were increased, as well as significant changes in the profile of proteins modified by 4-HNE were observed. CBG and EAA, especially when used together, largely reverse these effects. This study for the first time demonstrated the combined effect of CBG and EAA on the proteome of melanocytes after their exposure to UVA radiation, which applies to both changes in protein expression and intracellular signaling based on proteins modified by 4-HNE. It can be suggested that CBG and EAA may provide melanocytes with effective protection against the effects of oxidative stress and perhaps even protect the skin from carcinogenesis.
CRC remains a major cause of cancer-related morbidity and mortality worldwide. In recent years, the gut microbiota has gained increasing attention in CRC research. Intestinal microbes are not passive bystanders in tumor development. They may promote persistent inflammation, disrupt epithelial barrier integrity, alter microbial metabolites, and affect host immune and signaling pathways. Emerging evidence also suggests that microbiota-related metabolites and microbial functional alterations may influence host epigenetic regulation, including DNA methylation and chromatin-associated signaling, thereby further shaping colorectal carcinogenesis. Together, these changes can create a microenvironment that favors tumor initiation and progression. Several bacterial species, including Fusobacterium nucleatum, Parvimonas micra, and Peptostreptococcus anaerobius, have been repeatedly associated with CRC. In contrast, beneficial commensal microbes and their metabolites, especially short-chain fatty acids, may help maintain intestinal homeostasis and limit tumor-promoting processes. Because the gut microbiota is strongly shaped by diet, lifestyle, and environmental exposure, regional differences are also relevant. This is particularly important in Sichuan, China, where distinctive dietary habits and environmental features may influence microbial patterns associated with CRC risk and disease behavior. This review summarizes the main mechanisms linking the gut microbiota to CRC, examines the regional context of Sichuan, China, and discusses current and emerging clinical strategies. These include dietary intervention, probiotics, fecal microbiota transplantation, and microbiome-informed approaches to prevention, diagnosis, and treatment.