Carcinogenesis
· 2026 Jun · PMID 42237887
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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...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, APC, 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, M2 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 anti-tumor 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.
Castven D, Pereira S, Rodriguez LZ
… +10 more, Fischer ME, Marini F, Dooley S, Salié H, von Felden J, Jegodzinski L, Meindl-Beinker NM, Lee JS, Galle PR, Marquardt JU
Carcinogenesis
· 2026 Jun · PMID 42236301
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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 r...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.
You S, Li C, Sun W
… +6 more, Wang X, Huang L, Li L, Guo W, Xiang M, Zhou L
Carcinogenesis
· 2026 Jun · PMID 42236296
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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...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 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.
Carcinogenesis
· 2026 May · PMID 42217254
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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...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 (OR [95%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 = 0.008). ORs by genotype combination did not differ significantly across screening-year periods or by invasive status. Multiple cancers 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.
Campolo J, Annoni G, Borghini A
… +10 more, Peretti A, Papa M, Ait-Ali L, Bernier MO, Rage E, Dabin J, Thierry-Chef I, Haghdoost S, Picano E, Andreassi MG
Carcinogenesis
· 2026 May · PMID 42179267
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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 catheterizat...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.
Freeman B, Bian T, Xu G
… +9 more, Wheeler M, Fujioka N, Malaty J, Orlando FA, Braithwaite D, Salloum RG, Bruijnzeel AW, Zhang W, Xing C
Carcinogenesis
· 2026 Apr · PMID 42142878
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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 indu...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.
Aggison J, Medina C, Wu S
… +7 more, Li N, Molina-Pelayo F, Ji J, Gergeis MF, Raj R, Xu Y, Ripley RT
Carcinogenesis
· 2026 May · PMID 42141786
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Pleural mesothelioma (PM) usually occurs many years after asbestos fiber exposure; yet the mechanisms that convert chronic damage into malignancy remain unclear. Asbestos fibers induce persistent oxidative and genomic st...Pleural mesothelioma (PM) usually occurs many years after asbestos fiber exposure; yet the mechanisms that convert chronic damage into malignancy remain unclear. Asbestos fibers induce persistent oxidative and genomic stress that should activate apoptosis via mitochondrial outer membrane permeabilization (MOMP). MOMP normally triggers cytochrome c (cyt c) release as well as mitochondrially derived damaged-associated molecular patterns (DAMPs) resulting in downstream caspase activation which leads to DNA damage and cell death. With sublethal activation, a phenomenon known as a 'Incomplete or Minority MOMP (mMOMP)' occurs in which the cell survives the damage enabling retention and propagation of somatic mutations. We tested whether prolonged asbestos fiber exposure drives mMOMP in the mesothelial cells, MeT-5A. After culturing the cells for six months with chrysotile asbestos fibers (Chry-Asb) or crocidolite asbestos fibers (Croc-Asb), we observed an increase in clonogenicity, migration, and invasion, suggesting that transformation to a malignant-like phenotype was occurring. Next, we found increases in ROS production, cyt c release, and γH2AX phosphorylation without activation of caspase-3 and apoptotic induction. These cellular features are consistent with mMOMP. Additionally, an anti-apoptotic, mitochondrial protein, Myeloid Cell Leukemia (MCL)-1 was upregulated by asbestos and enabled mMOMP by preventing MOMP. Furthermore, we observed that asbestos-induced mMOMP was associated with features of drug-tolerant persister cells (DTPs). mMOMP facilitates avoidance of apoptosis by mesothelial cells while acquiring malignant traits. Our study indicates that mMOMP is a mechanism that promotes carcinogenesis, mitochondrial changes, and metabolic reprogramming. These findings offer a foundation for future therapeutic investigations.
Liu Y, Li S, Li W
… +8 more, Zhou M, Liang J, Liu X, Wang X, Guo Y, Li Z, Zhang B, Wang L
Carcinogenesis
· 2026 May · PMID 42093103
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Tumor-associated macrophages (TAMs) are the core innate immune cells in the tumor microenvironment (TME), and their phenotypic polarization and functional reprogramming determine the orientation of the tumor immune micro...Tumor-associated macrophages (TAMs) are the core innate immune cells in the tumor microenvironment (TME), and their phenotypic polarization and functional reprogramming determine the orientation of the tumor immune microenvironment and the efficacy of immunotherapy. As a key intracellular second messenger, cyclic adenosine monophosphate (cAMP) acts as a central hub regulating TAM function by activating two major downstream effector pathways: protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). This article systematically reviews the molecular mechanisms by which the cAMP-PKA/Epac signaling pathway regulates TAMs, the upstream regulatory factors in the TME, and targeted tumor immunotherapy strategies for this pathway. Studies have shown that cAMP mainly induces TAMs to polarize toward a pro-tumor "M2-like phenotype" through two classical pathways: cAMP-PKA-CREB and cAMP-PKA-STAT3/6. Meanwhile, it enhances the immunosuppressive, pro-angiogenic, and pro-fibrotic functions of TAMs via the cAMP-Epac pathway, inhibition of NF-κB signaling, and attenuation of M1 polarization. Furthermore, lactate and hypoxia-inducible factor-1α (HIF-1α) in the TME can further activate the intracellular cAMP signaling pathway in TAMs by activating G protein-coupled receptors and regulating the expression of adenylate cyclase, forming a cascade regulatory network with cAMP that exacerbates tumor immunosuppression. In addition, targeting the cAMP metabolic process, the downstream PKA pathway, and key molecules such as CREB/STAT/NF-κB can effectively reverse the "M2-like phenotype" of TAMs and restore their anti-tumor functions. Combination with immune checkpoint inhibitors can also significantly enhance the efficacy of tumor immunotherapy. By summarizing the core mechanisms of the cAMP-TAM regulatory axis and targeted intervention strategies, this article provides theoretical references and potential target directions for the development of novel tumor immunotherapy regimens based on TAM reprogramming.
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 wi...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.
Chen KM, Krebs NM, Sun YW
… +5 more, Sun D, Liao J, Reinhart L, Mallery SR, El-Bayoumy K
Carcinogenesis
· 2026 Apr · PMID 42063384
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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...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.
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 stud...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.
Wang Y, Wu Y, Zheng S
… +11 more, Yan X, Yu X, Gao Y, Xie S, Jiang Z, An R, Li G, Yang J, Tong Q, Xie X, Zhang J
Carcinogenesis
· 2026 Apr · PMID 41913584
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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)....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.
Stewart BW, Marshall H, Bonevski B
… +8 more, Griffin HJ, Hopkins AM, Itchins M, Mazza CJ, Modi ND, Ryan M, Varlow M, Sitas F
Carcinogenesis
· 2025 Dec · PMID 41910510
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This review involves a qualitative carcinogenic risk assessment of nicotine-based e-cigarettes. Though direct epidemiological evidence of cancer causation takes time to accumulate, carcinogenicity of e-cigarettes is evid...This review involves a qualitative carcinogenic risk assessment of nicotine-based e-cigarettes. Though direct epidemiological evidence of cancer causation takes time to accumulate, carcinogenicity of e-cigarettes is evident from different types of investigation including, with respect to studies in humans, some case reports but mainly involving monitoring of biomarkers of exposure and biomarkers of harm implicating tumorigenesis. Complementary laboratory investigations of e-cigarette aerosols and constituent chemicals include rodent bioassays and a range of approaches to elucidate mechanism(s). In respect of e-cigarettes, each of these types of investigation have been subject to successive reviews, sometimes more than once per year. Consequently, this over-arching review is restricted to publications since 2017 to avoid possible selection bias. Physiological evidence of exposure using biomarkers reveals DNA damage correlated with vape-derived metabolites attributable to carcinogens including nicotine-derived nitrosamines, volatile organic compounds, flavour-derived agents, and certain metals. Biomarkers also indicate vaping-attributable oxidative stress, epigenetic change and inflammation in oral and respiratory tissue often specified in comparison with smoking. Rodent bioassays include inhalation exposure of mice to e-cigarette aerosol described as causing lung adenocarcinomas. Mechanistic data are presented using the key characteristics of carcinogens and taken together implicate a complex mixture mediating carcinogenicity via genotoxic and other processes. From 2017 to 2025, the conclusions in e-cigarette reviews addressing different avenues of investigation moved from describing a need for more evidence to notifying concern about e-cigarette carcinogenicity. Nicotine-based e-cigarettes are likely to be carcinogenic to humans who use them causing an indeterminate burden of oral cancer and lung cancer.
Cell division cycle 20 homolog (CDC20), a critical substrate-recruiting subunit of the anaphase-promoting complex/cyclosome (APC/C), binds to APC/C to form the active APC/C-CDC20 complex, which regulates the degradation...Cell division cycle 20 homolog (CDC20), a critical substrate-recruiting subunit of the anaphase-promoting complex/cyclosome (APC/C), binds to APC/C to form the active APC/C-CDC20 complex, which regulates the degradation of key cell cycle substrates to ensure accurate and timely mitotic progression. Accumulating evidence demonstrates that CDC20 functions as an oncogenic factor, with its overexpression observed in various malignancies. Its dysregulation is closely associated with tumor initiation, progression, drug resistance, and poor clinical outcomes, underscoring its potential as a therapeutic target in anti-cancer strategies. In this review, we describe the biological functions of CDC20 in cancers, discuss its role and underlying mechanisms in solid tumors and hematological malignancies, and elucidate currently reported CDC20-targeted inhibitors along with their clinical benefits and challenges. By emphasizing the oncogenic significance of CDC20, we propose that the development of specific, safe, and potent CDC20 inhibitors could provide a promising therapeutic approach for cancer patients exhibiting CDC20 overexpression.