Carcinogenesis [JOURNAL]
Sun
200 papers
Somatic p53 mutations that are markedly overrepresented in lung cancer confer resistance to reactive oxygen species-induced cell death.
Tracewell MA, Karlin JE, Barnada SM … +4 more , McDuffie EL, Scott CP, Barta JA, McMahon SB
Carcinogenesis · 2025 Apr · PMID 40458924 · Publisher ↗
Lung cancer is among the leading causes of cancer-related death in the US Cigarette smoking remains the leading risk factor for lung cancer and can cause somatic mutations in the critical tumor suppressor gene TP53, amon...
Lung cancer is among the leading causes of cancer-related death in the US Cigarette smoking remains the leading risk factor for lung cancer and can cause somatic mutations in the critical tumor suppressor gene TP53, among others. Mutations in TP53 not only cause loss of wild-type function but may also introduce oncogenic, gain-of-function (GOF) properties. The frequency of missense mutations at residues p.V157 and p.R158 in p53 increases dramatically in lung cancer relative to other cancers. These p53 mutants exhibit both loss of wild-type p53 function and GOF properties, including broadly rewiring gene expression programs in lung cancer cells. Several pan-cancer hotspot mutations in p53 impart GOF activities that reprogram cellular metabolism. To refine our understanding of the GOF properties conferred by the lung-enriched p53 mutants, the cellular metabolism of cells containing mutant p53 (V157F) was investigated. Untargeted metabolomics revealed that glutathione metabolism is among the top altered metabolic pathways related to mutant p53 (V157F). p53 mutants V157F and R158L provided resistance to oxidative stress induced by both menadione and cigarette smoke extract. The cell death experienced in the absence of mutant p53 (V157F; R158L) was due to the increase in reactive oxygen species (ROS). These findings suggest that the lung-enriched mutations in p53 (V157F; R158L) confer lung cancer cells with resistance to ROS, and ROS accumulation in the absence of mutant p53 causes cell death.
The impact of reproductive factors on breast tumor and normal-adjacent tissue immune profile from menarche to menopause.
Peng C, Liu Y, Heng YJ … +7 more , Bodelon C, Stover D, Chen WY, Holmes MD, Eliassen AH, Kraft P, Tamimi RM
Carcinogenesis · 2025 Apr · PMID 40443130 · Full text
Reproductive factors and sex hormones are tightly linked to systemic immunity. However, no studies have examined whether reproductive factors and hormone use modulate the immune microenvironment of breast tissue. We pros...
Reproductive factors and sex hormones are tightly linked to systemic immunity. However, no studies have examined whether reproductive factors and hormone use modulate the immune microenvironment of breast tissue. We prospectively evaluated the associations of reproductive factors and exogenous hormone use with breast tumor and normal-adjacent tissue immune cell markers among 935 breast cancer cases in the Nurses' Health Studies. We deconvoluted immune cell abundance using CIBERSORTx and derived gene expression signatures of markers for immune checkpoint (PD1, PDL1, and CTLA4), co-regulatory signal and antigen presentation (MHC class I/ II and T cell receptor), and mammary cytokine signaling. Linear regression was used adjusting for confounders. Patterns of associations between reproductive factors and immune profile differed between tumor and normal-adjacent tissues and by estrogen receptor (ER) status. Tumors from postmenopausal women had significantly higher pro-inflammatory cytokine signaling and antigen presentation compared with tumors from premenopausal women (FDR ≤ 0.05). Several reproductive factors were nominally associated with immune profiles of normal-adjacent tissues. For example, parous women had higher CD8 T cell infiltration, higher PDL1 expression, and lower cytokine signaling (P ≤ .05); women who ever breastfed showed higher infiltration of NK cells and T helper cells in normal-adjacent tissue of ER+ tumors but lower infiltration of CD8 T cell and monocyte, and higher expression of cytokine signaling in normal-adjacent tissue of ER- tumors (P ≤ .05). Our study demonstrates for the first time in a large epidemiologic study that reproductive factors may influence breast tumor immune microenvironment and sheds light on potential immune regulation for breast cancer prevention.
A novel tRNA-derived small RNA 5'-tiRNA-His is a promising biomarker for diagnosis of colorectal cancer.
Gu X, Yang X, Zhu D … +6 more , Liu X, Nie J, Xu T, Pan Y, Sun H, Wang S
Carcinogenesis · 2025 Apr · PMID 40401812 · Publisher ↗
Colorectal cancer (CRC) is one of the most serious gastrointestinal tumors. The survival rate of patients with advanced stages is meager, so it is urgent to identify new diagnostic biomarkers with high sensitivity and sp...
Colorectal cancer (CRC) is one of the most serious gastrointestinal tumors. The survival rate of patients with advanced stages is meager, so it is urgent to identify new diagnostic biomarkers with high sensitivity and specificity. tRNA-derived small RNAs (tsRNAs) are an emerging class of small non-coding RNAs that are highly abundant in the blood of cancer patients and are associated with various physiological and pathological processes. Therefore, the clinical value of tsRNAs in diagnosing CRC requires further investigation. In this study, we identified the differential expression profiles of tsRNAs in CRC tissues via Pandora sequencing. We selected 5'-tiRNA-His that were significantly highly expressed in CRC plasma and tissues for further investigation. Interestingly, the expression level of 5'-tiRNA-His was increased dramatically in the plasma of CRC patients and correlated with various clinicopathologic parameters. ROC analysis revealed that 5'-tiRNA-His had good diagnostic value in diagnosing CRC patients, superior to that of CEA, CA199, and CA724, and could significantly differentiate patients with CRC from healthy donors and patients with intestinal polyps. Moreover, 5'-tiRNA-His still had good diagnostic efficacy in the diagnosis of patients with early-stage CRC, and the diagnostic efficacy was further elevated when combined with clinically used tumor markers. In conclusion, our study identified plasma 5'-tiRNA-His as a promising biomarker for diagnosing and screening CRC.
Current challenges and potential opportunities for interception and prevention of head and neck cancer.
El-Bayoumy K, Christensen N, Broach J … +11 more , Meyers C, Stairs D, Machtay M, Hu J, Bitzer ZT, Schell TD, Chen KM, Sun YW, Desai D, Walter V, Zhu J
Carcinogenesis · 2025 Apr · PMID 40382784 · Full text
Globally, the incidence of head and neck squamous cell carcinoma (HNSCC) has increased over recent decades and is projected to continue to rise, largely driven by increases in oropharyngeal squamous cell carcinoma (OPSCC...
Globally, the incidence of head and neck squamous cell carcinoma (HNSCC) has increased over recent decades and is projected to continue to rise, largely driven by increases in oropharyngeal squamous cell carcinoma (OPSCC), which is linked to HPV infection. HPV infection is also involved in the development of other cancers (anogenital and cervical), and almost 100% of cervical cancer patients are positive for HPV. OPSCC is the most common HPV-associated cancer in men and has exceeded the incidence of cervical cancer cases in women in the USA. Our knowledge of the carcinogenesis process from HPV infection to OPSCC development has been primarily extrapolated from cervical cancer models. While the cooperation of tobacco smoking and HPV infection is documented in cervical cancer, mechanistic studies to address this interaction in management and control of HNSCC are scarce and are also extrapolated from cervical cancer models. The molecular heterogeneity of HNSCC constitutes a tremendous challenge, and despite advances in several fronts in the management and control of HNSCC, short- and long-term treatment-associated morbidities remain substantial. In addition to deaths directly caused by this disease, survivors of this cancer have the second-highest rate of suicide compared with other cancers survivors. Given the existing gaps in our knowledge and the current clinical challenges, future studies including a number of new conceptual and methodological elements discussed in this review can lead to the discovery of biomarkers for early detection of the disease and novel strategies that will advance our knowledge to intercept and prevent HNSCC.
Delta 4-desaturase sphingolipid 2 enhances prostate cancer stem-like traits through phytoceramide-mediated PI3K-AKT signaling pathway.
Luo Y, Yu J, Li Q … +4 more , Wang X, Liu X, Xu G, Qin W
Carcinogenesis · 2025 Apr · PMID 40380873 · Publisher ↗
Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, metastasis, and recurrence and play a crucial role in androgen deprivation therapy resistance, yet how sphingolipid metabolism promotes CSC maintenance...
Cancer stem cells (CSCs) are the initiating cells of tumorigenesis, metastasis, and recurrence and play a crucial role in androgen deprivation therapy resistance, yet how sphingolipid metabolism promotes CSC maintenance remains exclusive. Here, we conducted gene expression profiling of sphere-derived castration-resistant prostate cancer stem cells (PCSCs) and identified enhanced sphingolipid de novo biosynthesis with upregulated DEGS2 expression in PCSCs. Silencing of DEGS2 significantly suppressed prostate cancer stem-like traits, cell growth, clonogenicity, and metastasis, while ectopic overexpression of DEGS2 showed the opposite effects. Mechanistically, DEGS2-synthesized phytoceramide activates PI3K-AKT signaling pathway to promote cancer stem-like characteristics, and activation of AKT reversed DEGS2-depletion-inhibited cancer stem-like properties. Clinically, prostate cancer tissues expressed higher levels of DEGS2 compared with adjacent normal tissue, and DEGS2 expression exhibits strong correlations with SOX2, CD133, and Snail expression in primary prostate carcinomas. Collectively, our data illustrate that DEGS2 dictates prostate cancer stem-like properties via the PI3K-AKT pathway, and disruption of this pathway provides potential therapeutic strategies for prostate cancer.
Mechanisms of tumor-associated macrophages promoting tumor immune escape.
Li S, Zhang M, Gao Y … +5 more , Zhao C, Liao S, Zhao X, Ning Q, Tang S
Carcinogenesis · 2025 Apr · PMID 40371816 · Publisher ↗
The phenomenon of tumor immune escape involves multiple mechanisms that enable tumor cells to evade recognition and assault by the host's immune system, facilitating their survival and growth within the organism. Further...
The phenomenon of tumor immune escape involves multiple mechanisms that enable tumor cells to evade recognition and assault by the host's immune system, facilitating their survival and growth within the organism. Furthermore, tumor immune escape represents a critical mechanism in tumor progression and significantly contributes to the unsuccessful outcomes of immunotherapy. Tumor-associated macrophages (TAMs) are recruited into the tumor microenvironment, serving a pivotal role in modulating tumor immune escape. An increasing body of research has demonstrated that TAMs are linked to unfavorable cancer prognosis and drug resistance. They suppress immune cell activity, hinder antigen presentation, and inhibit T cell activation, thereby helping tumor cells evade immune attacks. Consequently, elucidating the mechanisms by which TAMs promote tumor immune escape is crucial for developing novel immunotherapeutic strategies and improving the efficacy of cancer immunotherapy. In terms of clinical relevance, studies on TAMs have revealed their significant roles in various types of cancer. In recent years, transformational therapies such as CSF-1R inhibitors and CD40 agonists targeting TAMs have entered clinical trials and are expected to reverse immunosuppression and enhance immunotherapy response. These studies provide new directions for improving the effectiveness of existing immunotherapies and overcoming drug resistance.
B vitamins and colorectal cancer: exploring research hotspots and frontiers from a bibliometric and visual analysis (1994-2024).
Li M, Meng L, Gu H … +6 more , Tian Y, Qu B, Ao Y, Chen X, Song Y, Cui W
Carcinogenesis · 2025 Apr · PMID 40243145 · Publisher ↗
Most studies suggest that B vitamins can reduce the risk of colorectal cancer (CRC), and research in this field has been growing. Focusing on 2617 articles in the field, this study used CiteSpace and VOSviewer software t...
Most studies suggest that B vitamins can reduce the risk of colorectal cancer (CRC), and research in this field has been growing. Focusing on 2617 articles in the field, this study used CiteSpace and VOSviewer software to evaluate the contributions of various countries/regions, institutions, authors, and journals. The United States and Harvard University were identified as the most productive nation and institution, respectively, with Edward L. Giovannucci (Harvard) being the top contributor. Cancer Epidemiology Biomarkers & Prevention was recognized as the leading journal. Through the analysis of keywords and citations, we found that the potential of B vitamins (B1, B2, B6, B9, and B12) in the prevention and treatment of CRC and their mechanisms including regulation of gene expression, anti-inflammatory and antioxidant, and modulation of gut microenvironment are hot topics of research in this field. Burst detection analysis further revealed that the application of nanoparticle-based targeted drug delivery systems (such as folate-conjugated nanocarriers) in the treatment of CRC represents both a current hotspot and a future trend. This study offers a comprehensive overview of the field, highlights research hotspots and trends, and offers valuable information for researchers to further grasp the research direction.
Genetic determinants and clinical significance of circulating and tumor-specific levels of insulin-like growth factor binding protein 7 (IGFBP7) in a Swedish breast cancer cohort.
Godina C, Rosendahl AH, Gonçalves de Oliveira K … +6 more , Khazaei S, Björner S, Jirström K, Isaksson K, Pollak MN, Jernström H
Carcinogenesis · 2025 Apr · PMID 40230015 · Full text
Previous research indicates that insulin-like growth factor binding protein 7 (IGFBP7) protein levels in breast cancer tissue and blood are prognostic. However, genetic determinants of IGFBP7 in breast cancer remain larg...
Previous research indicates that insulin-like growth factor binding protein 7 (IGFBP7) protein levels in breast cancer tissue and blood are prognostic. However, genetic determinants of IGFBP7 in breast cancer remain largely unexplored. We examined IGFBP7 in a cohort of 1701 patients with first breast cancer from Sweden, enrolled prior to surgery 2002-16 and followed for up to 15 years. Genotyping was performed on blood samples using OncoArray. Tumor-specific protein levels of IGFBP7, insulin receptor (InsR), and IGF-I receptor (IGFIR) were assessed on tumor tissue microarrays in 964 patients. Furthermore, 275 patients had plasma IGFBP7 levels measured. A genetic proxy marker for circulating IGFBP7 levels was constructed from five candidate single-nucleotide polymorphisms (SNPs) (rs6852762, rs1714014, rs9992658, rs10004910, and rs4865180) based on number of recessive genotypes. Age-adjusted linear regression was used to evaluate SNPs and tumor-specific IGFBP7 levels in relation to circulating IGFBP7 levels. Cox regression adjusted for age, tumor characteristics, and adjuvant treatments was used to assess associations with clinical outcomes. Circulating and tumor-specific IGFBP7 levels were significantly positively correlated. High circulating and genetically predicted IGFBP7 levels were associated with increased risk for distant metastasis and all-cause mortality. A significant interaction between high tumor-specific IGFBP7 levels and membrane-bound InsR resulted in a four-fold increased risk of breast cancer events and distant metastases. Both measured and genetically predicted IGFBP7 levels were independent prognostic biomarkers in breast cancer.
NUF2 and NEK2 promote malignant progression of gallbladder cancer by remodeling the extracellular matrix.
Gao M, Ye P, Zhang Y … +2 more , Guo Y, Xu J
Carcinogenesis · 2025 Apr · PMID 40220284 · Full text
Gallbladder cancer (GBC) ranks as the most common malignant tumor of the biliary tract, which has been characterized by late diagnosis, low excisional rate, and poor prognosis. Recent studies exploring the roles of malig...
Gallbladder cancer (GBC) ranks as the most common malignant tumor of the biliary tract, which has been characterized by late diagnosis, low excisional rate, and poor prognosis. Recent studies exploring the roles of malignant progression-associated genes in GBC remain limited. Our study aims to identify significant hub genes involved in its pathogenesis, which may serve as novel potential therapeutic targets for GBC. Here, we employed RNA-seq analysis to identify differentially expressed genes (DEGs) of seven GBC samples and five matched adjacent samples. After screening the DEGs in clinical sequencing data and GSE139682, we further obtained 549 genes with consistent expression trends in two datasets, including 155 upregulated and 394 downregulated genes. Gene Ontology (GO) enrichment analysis revealed that these genes were significantly enriched in extracellular matrix (ECM)-related processes, such as organization, structure, and composition, which hint to us that remodeling of ECM may be the main driving factor for the malignant progression of GBC. In addition, we screened 17 candidate hub genes through protein-protein interaction (PPI) network analysis and Cytoscape, subsequent GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the remodeled ECM mainly functions by affecting cell division. Moreover, we found that NEK2 and NUF2 were overexpressed in GBC tumor tissues and validated their function in the pro-proliferation of GBC cells. Our results highlight that NEK2 and NUF2 may be hub genes promoting the malignant progression of GBC and are expected to be reliable new therapeutic targets for GBC.
Genetic variants in glycosylation pathways are associated with colorectal cancer risk.
Wu H, He X, Wang H … +4 more , Xu J, Ding J, Hua D, Wang H
Carcinogenesis · 2025 Apr · PMID 40207991 · Publisher ↗
The glycosylation pathway serves as a vital regulatory mechanism in colorectal cancer. However, how genetic variants in these pathways may affect the risk of colorectal cancer is still unknown. To examine the relationshi...
The glycosylation pathway serves as a vital regulatory mechanism in colorectal cancer. However, how genetic variants in these pathways may affect the risk of colorectal cancer is still unknown. To examine the relationships between the risk of colorectal cancer and the presence of selected single-nucleotide polymorphisms (SNPs), 1150 patients and 1342 controls were included in this case-control study. We found that GALNT2 rs76000797 and rs11576324, GALNT6 rs67726586, FUT8 rs117497405, FUT2 rs111311275, and B4GALT5 rs6125695 were strongly correlated with the risk of colorectal cancer. Moreover, rs111311275 exhibited an expression quantitative trait locus effect on FUT2 in colorectal cancer tissues, which could increase the risk of colorectal cancer by influencing FUT2 expression. GEPIA research and microarray data revealed that FUT2 expression was higher in colorectal cancer tissues than in normal tissues and that individuals with colon cancer with high expression of FUT2 had longer overall survival times. Our study highlights the significant impact of genetic variants on glycosylation pathways and offers novel insights into potential biomarkers for colorectal cancer risk.
Genetic susceptibility to lung squamous cell carcinoma: new insights on 9q33.2 variants and tobacco smoking.
Ma H, Wang G, Miao S … +7 more , Jin C, Cai J, Ge W, Zhang C, Zhang E, Ma H, Zhu M
Carcinogenesis · 2025 Apr · PMID 40168134 · Publisher ↗
Genome-wide association studies (GWAS) have identified over 60 susceptibility loci for lung cancer, yet the biological mechanisms underlying these associations remain largely unknown, particularly for lung squamous cell...
Genome-wide association studies (GWAS) have identified over 60 susceptibility loci for lung cancer, yet the biological mechanisms underlying these associations remain largely unknown, particularly for lung squamous cell carcinoma (LUSC). Here, we integrated data from 3890 LUSC cases and 13 328 controls of Chinese descent, and performed a conditional analysis to explore independent genetic variants and analyzed the interaction between the genetic variants and smoking. Our study was the first to identify a specific association between genetic variants in the 9q33.2 region and increased risk of LUSC in smokers. After adjusting for the tag SNP rs4573350 in 9q33.2, no additional significant genetic variants were found. However, significant additive (RERI = 1.66, 95% CI: 1.17-2.22, AP = 0.26, 95% CI: 0.19-0.33) and multiple interactions (OR = 1.30, 95% CI: 1.08-1.56, P = 5.40 × 10-3) were observed between rs4573350 and smoking. Compared to nonsmokers with the CC genotype, smokers with the CT/TT genotype showed an increased risk of 6.29-fold (95% CI: 5.46-7.23, P = 2.00 × 10-16). Functional annotation identified rs4573350 as the strongest functional variant within the linkage disequilibrium block. Biological experiments confirmed that the combined exposure to the T allele of rs4573350 and cigarette smoke extract promotes the expression of the ZBTB26 by modulating the binding ability of the transcription factor FOXA1. Furthermore, ZBTB26 was found to regulate tumorigenesis of LUSC both in vitro and in vivo by affecting the expression of PCNA, which is involved in cell cycle and promotes tumorigenesis of LUSC.
Amlodipine, an L-type Ca2+ channel inhibitor, regulates release of extracellular vesicles from tumor cells.
Mondal SK, Hong CS, Han J … +3 more , Diergaarde B, Zandberg DP, Whiteside TL
Carcinogenesis · 2025 Apr · PMID 40121518 · Full text
Tumor cells produce/release tumor-derived exosomes (TEX) which promote tumor growth, drive immune suppression, and interfere with immune therapies. Amlodipine, a calcium flux inhibitor, may block TEX release by tumor cel...
Tumor cells produce/release tumor-derived exosomes (TEX) which promote tumor growth, drive immune suppression, and interfere with immune therapies. Amlodipine, a calcium flux inhibitor, may block TEX release by tumor cells. Amlodipine's potential as a drug blocking TEX release was evaluated. We measured tumor growth, TEX numbers, phenotype, and molecular content in murine SCCVII and human cancer cell lines. Cell lysates and TEX were tested for expression of autophagy-related proteins by western blots (WBs). Tumor growth in mice, histopathology, T-cell infiltrations, and TEX production by SCCVII treated with amlodipine were measured. Numbers and protein content of TEX eluted from tumor explants were studied by flow cytometry and WBs. Amlodipine used in vitro at 0.5-5 µM was nontoxic, did not impair tumor cell viability, reduced cell proliferation, and decreased TEX production. It reduced PD-L1 and Rab11 content of TEX, altered tumor cell size/shape, induced vesicle accumulations in the cytosol, and upregulated expression levels of autophagy-related proteins, ATG7, Beclin-1, and LC3. In vivo, daily treatment of established SCCVII with amlodipine (10 mg/kg) inhibited tumor growth (P < 0.001), increased CD8+ T-cell infiltration into tumor, decreased TEX production, and altered PD-L1, Rab11, and FasL content of TEX. Amlodipine delivered in vitro to tumor cells or in vivo to tumor-bearing mice interferes with tumor growth and TEX production, induces tumor autophagy, reduces circulating TEX numbers, and alters the TEX immunosuppressive signature. Amlodipine emerges as a potentially promising drug for removing immunosuppressive TEX in cancer subjects who are candidates for immune therapies.
The influence of homologous recombination repair on temozolomide chemosensitivity in gliomas.
Zeng B, Shi H, Liu T … +4 more , Tang J, Lin J, Lin X, Zeng T
Carcinogenesis · 2025 Apr · PMID 40120126 · Publisher ↗
Gliomas represent a prevalent form of primary brain tumors, with temozolomide (TMZ) serving as the established first-line therapeutic option. Nevertheless, the effectiveness of TMZ is hindered by the development of chemo...
Gliomas represent a prevalent form of primary brain tumors, with temozolomide (TMZ) serving as the established first-line therapeutic option. Nevertheless, the effectiveness of TMZ is hindered by the development of chemoresistance. Recent investigations have underscored the correlation of homologous recombination repair (HRR), a pivotal mechanism responsible for mending DNA double-strand breaks, with TMZ resistance in glioma treatment. This review centers on elucidating the significance of HRR in the management of gliomas, with a particular emphasis on pivotal molecules implicated in the HRR process, including RAD51, ATM, ATR, and newly identified small molecules that impact HRR. Modulating the expression of these genes can effectively restrain pathways such as ATM/CHK2, ATR/CHK1, and PI3K/AKT, subsequently augmenting the sensitivity of gliomas to TMZ. Noteworthy efforts have been directed towards exploring inhibitors of these pathways in recent research endeavors, culminating in encouraging outcomes. In conclusion, the involvement of HRR in glioma resistance unveils novel therapeutic avenues, with targeting crucial molecules in the HRR pathway, holding promise for enhancing the effectiveness of TMZ therapy.
MACC1 is a potential prognostic biomarker for cancer immunotherapy in lung adenocarcinoma.
Pan C, Zhou Z, Cao J … +8 more , Zhang L, Cheng T, Li H, Jiang Z, Huang D, Zeng D, Luo Y, Wu J
Carcinogenesis · 2025 Apr · PMID 40117327 · Publisher ↗
Our team previously reported that MACC1 levels are closely related to a variety of tumors and the efficacy of immune checkpoint blockade (ICB) therapy. However, the predictive value of MACC1 levels for lung adenocarcinom...
Our team previously reported that MACC1 levels are closely related to a variety of tumors and the efficacy of immune checkpoint blockade (ICB) therapy. However, the predictive value of MACC1 levels for lung adenocarcinoma (LUAD) immunotherapy has not been studied. This study aimed to investigate the predictive effect of the oncogene MACC1 on ICB reactivity in patients with LUAD. First, the expression patterns and clinical features of MACC1 in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were comprehensively evaluated using R packages. We subsequently assessed the correlations between MACC1 and immunological characteristics in the LUAD tumor microenvironment (TME) using the CIBERSORT algorithm. The results revealed that MACC1 overexpression was significantly correlated with 3 immune checkpoints, 14 tumor-infiltrating immune cells (TIICs), 9 immunomodulators, 5 anticancer immune process activities, and 3 effector genes of TIICs in LUAD. Additionally, on the basis of the prognostic genes from LASSO analysis, we developed the MACC1-related Risk Score (MRRS), which can accurately predict the prognosis and response to cancer immunotherapy in LUAD patients (HR = 3.50, AUC at 1, 2, and 3 years = 0.737, 0.744, and 0.724, respectively). Finally, in vivo experiments revealed that the combination of MACC1 silencing and PD-L1 inhibitors significantly inhibits tumor progression. These findings increase our understanding of MACC1 as a potential prognostic biomarker and potential therapeutic target for cancer immunotherapy. The MRRS may play a critical role in predicting the response of LUAD patients to ICB therapy.
Multifaceted role of transgelin isoforms in cancer hallmarks.
Jimenez Jimenez AM, Haddad Y, Jemelikova V … +2 more , Adam V, Merlos Rodrigo MA
Carcinogenesis · 2025 Apr · PMID 40102702 · Publisher ↗
Transgelins (TAGLNs) are actin-binding proteins within the calponin family, playing a crucial role in modulating actin-myosin interactions and maintaining actin filament stability. These proteins are expressed in both sm...
Transgelins (TAGLNs) are actin-binding proteins within the calponin family, playing a crucial role in modulating actin-myosin interactions and maintaining actin filament stability. These proteins are expressed in both smooth and non-smooth muscle cells, contributing to the regulation of muscle contractility and cell migration. TAGLNs family has three isoforms that differ in their isoelectric point, namely: TAGLN1, TAGLN2, and TAGLN3. TAGLNs regulation is involved in the development of many diseases, such as pulmonary arterial hypertension, asthma, atherosclerosis, obstructive nephropathy, diabetes, and cancer. Recent research indicates TAGLNs involvement in carcinogenesis and chemoresistance. This review investigates TAGLNs as potential cancer biomarkers, exploring their versatile tissue-specific impact on patient outcomes. We also highlight their roles as, tumor suppressor agents and tumor progression oncogenes depending on the tumor type, tumor genetic variations, and TAGLNs expression profiles. Furthermore, emerging evidence suggests that the interplay between TAGLN2 and chemoresistance to anticancer drugs is mediated by its interaction with the chemoresistance double agent MT-2, with possible bidirectional implications. TAGLNs present a promising avenue for novel therapeutic strategies against cancer, owing to their tissue-specific duality in promoting/suppressing tumor growth and cell migration in cancer cells. Thus, they can serve as a potential prognostic/diagnostic biomarker. The focus should be on leveraging, in future therapeutics, the interplay between TAGLNs and MTs to reverse tumor progression and chemoresistance, transforming them into tumor suppression.
Chemoresistance and immune evasion in hepatocellular carcinoma: the role of miRNA-425-5p.
Pan X, Liu J, Zhang Y … +2 more , Sun C, Li Y
Carcinogenesis · 2025 Apr · PMID 40063719 · Publisher ↗
Hepatocellular carcinoma (HCC) represents a significant global health challenge, with chemoresistance severely limiting treatment efficacy. This study investigates the role of miRNA-425-5p in exosomes in modulating the t...
Hepatocellular carcinoma (HCC) represents a significant global health challenge, with chemoresistance severely limiting treatment efficacy. This study investigates the role of miRNA-425-5p in exosomes in modulating the tumor microenvironment (TME) and contributing to chemoresistance and immune evasion in HCC. Differentially expressed miRNAs were identified using TaqMan low-density array technology in serum samples from XELOX-resistant and -sensitive HCC patients. miRNA-425-5p expression was validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Exosomes from HCC cell lines were characterized by transmission electron microscopy and nanoparticle tracking analysis. Functional assays, including luciferase reporter assays and flow cytometry, elucidated the mechanisms of miRNA-425-5p. In vivo studies with mouse xenograft models evaluated the impact of miRNA-425-5p on tumor growth and chemosensitivity. miRNA-425-5p was significantly upregulated in the serum of XELOX-resistant HCC patients and correlated with poorer survival outcomes. Exosomes from chemoresistant HCC cells exhibited increased levels of miRNA-425-5p, which, when internalized by CD4+ T cells, promoted regulatory T cell (Treg) expansion by targeting phosphatase and tensin homolog (PTEN). In vivo, miRNA-425-5p overexpression enhanced tumor growth and chemoresistance, while its inhibition reduced tumor size and increased chemosensitivity. These findings indicate that miRNA-425-5p in exosomes plays a crucial role in HCC chemoresistance and immune evasion by modulating the TME and promoting Treg expansion through PTEN targeting. miRNA-425-5p serves as a potential biomarker for predicting chemoresistance and a therapeutic target for overcoming drug resistance in HCC.
Smoking behavior-related genetic variants and lung cancer risk in Japanese: an assessment by mediation analysis.
Yamamoto S, Koyanagi YN, Iwashita Y … +31 more , Shinozaki T, Fujiwara Y, Sakakura N, Hara M, Nishida Y, Otonari J, Ikezaki H, Tanoue S, Koriyama C, Kasugai Y, Oze I, Koyama T, Tomida S, Michihata N, Nakamura Y, Suzuki S, Nakagawa-Senda H, Nagayoshi M, Kubo Y, Kato Y, Wakai K, Watanabe T, Ishizu M, Takashima N, Kadota A, Momozawa Y, Nakatochi M, Tamura T, Niimi A, Ito H, Matsuo K
Carcinogenesis · 2025 Apr · PMID 40059777 · Publisher ↗
Cigarette smoking is one of the most important risk factors for lung cancer. Genetic studies have shown that smoking behavior-related genetic variants are directly associated with lung cancer, independent of smoking beha...
Cigarette smoking is one of the most important risk factors for lung cancer. Genetic studies have shown that smoking behavior-related genetic variants are directly associated with lung cancer, independent of smoking behavior, mainly in European populations. A recent genome-wide association study in Japan identified five loci associated with the number of cigarettes smoked per day. This study aimed to evaluate whether these loci are associated with lung cancer risk directly or indirectly through changing smoking behavior. Here, we conducted a case-control study (1427 cases and 5595 controls) and a prospective cohort study (128 incident cases in 10 520 subjects). Using mediation analysis, we decomposed the total effect of the lead single nucleotide polymorphism (SNP) at each locus on lung cancer risk into direct and indirect effects. The results of the two studies were pooled using a random-effects model to estimate summary relative risks (RRs) and their 95% confidence intervals (CIs). Two studies showed that: (i) rs78277894 (EPHX2-CLU, G > A) had a protective direct effect (RR: 0.84; 95% CI: 0.77-0.93) on lung cancer risk; and (ii) rs56129017 (CYP2A6, C > T) had carcinogenic direct and indirect effects on lung cancer risk (RR: 1.26; 95% CI: 1.15-1.39 and RR: 1.01; 95% CI: 1.00-1.01, respectively). This mediation analysis revealed that two smoking behavior-related SNPs, EPHX2-CLU rs78277894 and CYP2A6 rs56129017, were associated with lung cancer risk through pathways independent of changing smoking behavior. Our findings may contribute to our understanding of lung carcinogenesis pathways that cannot be addressed by changes in smoking behavior.
Olfactomedin 4 promotes gastric cancer cell G2/M progression and serves as a therapeutic target in gastric adenocarcinoma.
Liu W, Li H, Botos I … +3 more , Kumkhaek C, Zhu J, Rodgers GP
Carcinogenesis · 2025 Apr · PMID 40056162 · Full text
Olfactomedin 4 (OLFM4) is a member of the olfactomedin domain-containing olfactomedin glycoprotein family and plays important roles in innate immunity, inflammation, and cancer. It exhibits increased expression in gastri...
Olfactomedin 4 (OLFM4) is a member of the olfactomedin domain-containing olfactomedin glycoprotein family and plays important roles in innate immunity, inflammation, and cancer. It exhibits increased expression in gastric cancer patient tissues and has been shown to regulate proliferation and apoptosis in gastric cancer cells. However, the molecular mechanism(s) underlying OLFM4's role in gastric cancer remain unknown. In this study, we found that OLFM4 knockdown significantly inhibited YCC3 gastric cancer cell proliferation and induced G2/M cell cycle arrest. Yeast two-hybridization screening revealed that OLFM4 directly interacts with cyclin B1 interacting protein 1 (CCNB1IP1), an E3 ubiquitin protein ligase. In YCC3 cells, OLFM4 co-immunoprecipitated and colocalized with CCNB1IP1 and underwent cell cycle phase-specific nucleo-cytoplasmic shuttling. OLFM4 knockdown decreased both cyclin B1 protein levels and CDK1 activity in YCC3 cells. Screening of a cohort of OLFM4-targeted microRNAs (miRNAs) for their impact on cell proliferation identified several that significantly downregulated OLFM4 protein levels and inhibited YCC3 cell proliferation in vitro. Rescue experiments demonstrated that these miRNAs' inhibitory effect on cell proliferation was partially related to their downregulation of OLFM4. When three of these miRNAs were individually administered intratumorally to nude mice bearing YCC3 cell xenografts, tumor growth was significantly inhibited when compared with tumors treated with a negative control miRNA. These results suggest that OLFM4 promotes cell cycle progression and cell proliferation in gastric cancer cells and may have utility as a therapeutic target in gastric adenocarcinoma.
LncRNA MEG3 suppresses prostate cancer progression by mediating macrophage polarization via the miR-148a-3p/ARRDC3 signaling axis.
Luo J, Tao H, Chen L … +3 more , Hu H, Mao L, Guan H
Carcinogenesis · 2025 Apr · PMID 40036590 · Publisher ↗
Long-chain noncoding RNA (LncRNA) MEG3 significantly influences tumor microenvironment (TME) dynamics and macrophage polarization. However, its specific involvement in prostate cancer (PCa) progression remains unclear. M...
Long-chain noncoding RNA (LncRNA) MEG3 significantly influences tumor microenvironment (TME) dynamics and macrophage polarization. However, its specific involvement in prostate cancer (PCa) progression remains unclear. MEG3 exhibited low expression in PCa, and immune infiltration analysis revealed a positive association with M1 macrophages infiltration and a negative association with M2 macrophages infiltration. Immunohistochemical analysis demonstrated increased MEG3 levels, corresponding with upregulated INOS (an M1 marker) and downregulated CD163 (an M2 marker). MEG3 expression was markedly elevated in LPS-induced M1 macrophages and notably reduced in IL-4-induced M2 macrophages. The overexpression of MEG3 significantly enhanced M1 macrophages polarization while suppressing M2 macrophages polarization. Using an online database and a dual luciferase reporter assay, miR-148a-3p was identified as a downstream target of MEG3. Reduced miR-148a-3p expression was observed in LPS-induced M1 macrophages, while an increase was noted in IL-4-induced M2 macrophages. Moreover, MEG3 overexpression's impact on macrophage polarization was nullified following miR-148a-3p mimic transfection. ARRDC3 was validated as a downstream target of miR-148a-3p. The upregulation of ARRDC3 triggered by MEG3 overexpression was effectively suppressed by miR-148a-3p mimics. Additionally, Knockdown of ARRDC3 effectively counteracted the MEG3 overexpression-induced increase in M1 macrophages polarization while simultaneously mitigating the reduction in M2 macrophages polarization. Collectively, MEG3 exhibits reduced expression in PCa and correlates with macrophage infiltration and polarization. Specifically, it drives M1 macrophages polarization while suppressing M2 macrophages polarization via the miR-148a-3p/ARRDC3 axis, thereby impeding tumor immune evasion and restricting PCa progression.
Reactions of [13C]-labelled tobacco smoke with DNA to generate selected adducts formed without metabolic activation.
Tang MK, Ostlund T, Dameh NF … +6 more , Alcheva A, Cohen JD, Hegeman AD, Carmella SG, Stepanov I, Hecht SS
Carcinogenesis · 2025 Apr · PMID 40036216 · Full text
DNA adducts are central in the carcinogenic process because they can cause miscoding leading to permanent mutations in important genes involved in carcinogenesis. While it is known that tobacco smoking leads to increased...
DNA adducts are central in the carcinogenic process because they can cause miscoding leading to permanent mutations in important genes involved in carcinogenesis. While it is known that tobacco smoking leads to increased levels of multiple DNA adducts, most DNA adducts detected to date in humans cannot be explicitly attributed to smoking but instead have various possible exogenous and endogenous sources. We plan to probe the tobacco source of DNA adducts by providing carbon-13 labelled ([13C]-labelled) cigarettes to smokers and analyzing [13C]-labelled DNA adducts in their oral cells to determine which adducts arise from smoking. Prior to conducting studies in humans, we first report here proof-of-principle machine smoking experiments to evaluate carbon isotopologues of (a) selected carbonyls and (b) DNA adducts resulting from direct exposure of cigarette smoke vapour-phase to calf-thymus DNA. The smoke of the study cigarettes, made from a 50:50 mixture of [13C]-labelled tobacco and a popular commercial tobacco, yielded similar concentrations of carbonyl compounds and their respective DNA adducts compared with the smoke of 1R6F reference cigarettes and the popular brand of cigarettes. We detected [13C]-isotopologues of DNA adducts such as 1,N6-etheno-dA, (8R/S)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxypyrimido[1,2-a]purine-10(3H)-one (γ-OH-Acr-dG), and (6S,8S and 6R,8R)-3-(2'-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-a]purine-10(3H)-one [(6S,8S)-γ-OH-Cro-dG and (6R,8R)-γ-OH-Cro-dG], proving that they have a direct source from tobacco smoke and providing important new insights regarding their mechanisms of formation. These unique results form the basis for further studies in cell culture and in cigarette smokers to establish how carcinogens in tobacco smoke cause DNA adduct formation.
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