Carcinogenesis [JOURNAL]
Sun
200 papers
Mammary adipose dysfunction in the dual epidemic of obesity and breast cancer.
Jeyakumar E, Sundararaju S, Annett S … +1 more , Elrayess MA
Carcinogenesis · 2025 Sep · PMID 40899258 · Full text
Breast cancer (BC) is one of the leading causes of death among women, with obesity being a significant factor. Mammary adipose tissue (MAT) dysfunction in obesity creates a tumor-supportive environment, leading to increa...
Breast cancer (BC) is one of the leading causes of death among women, with obesity being a significant factor. Mammary adipose tissue (MAT) dysfunction in obesity creates a tumor-supportive environment, leading to increased risk. In obesity, MAT undergoes significant changes, including increased adiposity, chronic inflammation, aromatase overexpression, insulin resistance, and altered adipokine signaling, collectively fostering a protumorigenic microenvironment. The interaction between adipocytes and cancer cells further exacerbates BC progression through metabolic crosstalk and immune evasion. This review examines the role of MAT dysfunction in BC incidence and progression, in obesity. Interestingly, obesity appears to have a paradoxical effect on BC risk, offering a potentially protective role in premenopausal women, but increased risk in postmenopausal women, primarily due to differences in estrogen levels. Addressing the metabolic, inflammatory, and hormonal abnormalities in obese MAT can aid in enabling the development of precision therapies that reduce BC risk and improve treatment outcomes in obese patients.
Associations of prediagnostic serum liver enzyme levels with lung cancer risk in predominantly low-income African and European Americans.
Xu S, Cai H, Wu J … +7 more , Shi J, Courtney R, Yoon HS, Shu XO, Blot WJ, Zheng W, Cai Q
Carcinogenesis · 2025 Sep · PMID 40879454 · Full text
Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646...
Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646 matched controls with baseline serum alanine aminotransferase (ALT) and of 548 cases and 1032 matched controls with baseline serum alkaline phosphatase (ALP) nested within the Southern Community Cohort Study. Conditional logistic regression and generalized linear models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among all study participants and by stratification of potential effect modifiers. Most participants had clinically normal liver enzyme levels. Higher serum ALT levels were associated with reduced LC risk. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (Ptrend < .01), respectively. The inverse association was observed in African Americans (AAs) and European Americans, which was especially prominent among men, and was seen in both those diagnosed within [ORT3 versus T1 = 0.41 (0.19-0.88)] and beyond [ORT3 versus T1 = 0.35 (0.17-0.73)] a median follow-up time of 39 months. Higher serum ALP levels were associated with increased LC risk among AA men only [ORT3 versus T1 = 2.01 (1.19-3.39)] (Ptrend < .01). Our results indicate that in a predominantly low-income American population, higher serum ALT levels may be related to lower LC risk. Further studies are warranted to confirm our findings and elucidate the potential underlying biological mechanisms of the associations.
Δ133p53 isoform enhances TLR4 function to promote tumor growth.
Lekamlage SP, Boix De Jesus AN, Saraiva AM … +8 more , Drummond C, Dolan H, de Ribot FM, Royds JA, Mehta S, Braithwaite AW, Hung NA, Slatter TL
Carcinogenesis · 2025 Nov · PMID 40878805 · Full text
Tumor protein 53 (TP53) acts as a tumor suppressor and is often mutated in cancer. Isoforms of TP53, such as the Δ133p53 family, can promote tumor growth and metastasis. Therefore, targeting Δ133p53 function may represen...
Tumor protein 53 (TP53) acts as a tumor suppressor and is often mutated in cancer. Isoforms of TP53, such as the Δ133p53 family, can promote tumor growth and metastasis. Therefore, targeting Δ133p53 function may represent a new strategy for preventing tumor metastasis. To inform the identification of proteins to target in Δ133p53-expressing tumors, changes at the cell surface were characterized. Inhibition of cell surface trafficking in a mouse model syngrafted with tumors expressing proteins similar to Δ133p53 (Δ122p53) was associated with reduced tumor growth and metastasis. After confirming that changes at the cell surface were important for Δ133p53 tumor promotion, characterization of protein changes at the Δ133p53/Δ122p53 cell surface revealed increased expression of the toll-like receptor 4 (TLR4) and the TLR4 agonist, apoptosis inhibitor 5. Furthermore, inhibition of TLR4 was sufficient to reduce Δ122p53 tumor growth. Altogether, these results suggest a role for Δ133p53 in contributing to tumor progression by stimulating TLR4 function. Furthermore, targeting changes at the cell surface can reduce Δ133p53 tumor promotion.
A novel serum biomarker Enhancer RNA RASSF8-AS1 promotes the progression of gastric cancer.
Li X, Chen X, Chen B … +4 more , Gu X, Chu X, Shen X, Ju S
Carcinogenesis · 2025 Sep · PMID 40857618 · Publisher ↗
Gastric cancer (GC) is globally recognized as one of the most widespread malignant tumors. As the symptoms of patients with early GC are ambiguous, the majority of patients are given a diagnosis of advanced GC. Therefore...
Gastric cancer (GC) is globally recognized as one of the most widespread malignant tumors. As the symptoms of patients with early GC are ambiguous, the majority of patients are given a diagnosis of advanced GC. Therefore, this necessitates the search for new biomarkers to be utilized in the early diagnosis and screening of GC. Enhancer RNA (eRNA) is a non-coding RNA in transcription by enhancers that is tumor-specific and has a critical function in cancer progression. Our research investigates new eRNAs as bio-diagnostic markers for GC. Four eRNAs with good differential expression in GC were screened by TCGA and University of California, Santa Cruz databases. Quantitative real-time PCR was utilized for testing the level of RASSF8-AS1. The diagnostic effect of RASSF8-AS1 was evaluated using the receiver operating characteristic (ROC). Functional experiments were used to detect the ability of RASSF8-AS1 to affect the metastasis and proliferation in GC cells. The expression of RASSF8-AS1 was obviously elevated in both GC tissues and serum, whereas it was decreased in the serum levels of postoperative GC patients. ROC showed that RASSF8-AS1 was more diagnostically efficient than common diagnostic biomarkers for GC and that diagnostic effectiveness could be better than combining them. The findings of in vitro experiments showed that knocking down the level of RASSF8-AS1 clearly suppressed the ability of growth and metastasis in GC cells. Studies have shown that serum RASSF8-AS1 has the potential to contribute to the progression of GC as a biomarker for diagnosis and prognostic monitoring of GC.
Expression profile of Claudins 3, 4, and 7 in breast tumors and its correlation with clinicopathological features.
Yadav R, Goel S, Kumari L … +3 more , Dahiya D, Bal A, Bhatia A
Carcinogenesis · 2025 Sep · PMID 40845151 · Publisher ↗
Claudins, integral components of tight junctions, play a pivotal role in maintaining cellular adhesion and polarity. Aberrant expression of claudins has been implicated in the progression of various malignancies, includi...
Claudins, integral components of tight junctions, play a pivotal role in maintaining cellular adhesion and polarity. Aberrant expression of claudins has been implicated in the progression of various malignancies, including breast cancer (BC). This study aims to elucidate the clinical relevance of claudins by studying the expression of Claudins 3, 4, and 7 in BC cell lines (CLs) and cancer tissues and correlating it with cellular properties and clinicopathological parameters. The transcriptional expression of Claudins 3, 4, and 7 was assessed in four BCCLs (MDA-MB-231, MDA-MB-468, T47D, and SKBR-3) and tumor tissues by using quantitative PCR. Correlations between claudin expression profiles and clinicopathological parameters, including tumor grade, lymph node involvement, and proliferative index, were evaluated in patient samples. Compared to normal breast tissue, all BCCLs exhibited downregulated expression of Claudins 3, 4, and 7. Differential expression was observed among CLs, with MDA-MB-231 exhibiting the lowest and MDA-MB-468 the highest levels. Among BC patient samples (n = 65), 97% demonstrated significant (P < 0.05) dysregulation in the expression of one or more of these claudins. Prevalence of Claudins 3, 4, 7-low and -high tumors was found to be 29.23% and 21.53% respectively, in our patients. The former correlated significantly with adverse prognostic factors, including higher grade, nodal metastasis, and elevated proliferative indices. The pharmacological induction of Claudin 4 by celecoxib was found to attenuate cell viability, proliferation, and migration in aggressive claudin-low BC cells. These findings underscore the potential utility of modulating claudins as a therapeutic strategy for managing claudin-low BCs.
HECTD3 E3 ligase mediates ubiquitination of AKT-phosphorylated CMTM3 in HER2-overexpressed breast cancer cells.
Wang J, Wang D, Zhang X … +1 more , Xu X
Carcinogenesis · 2025 Sep · PMID 40836897 · Publisher ↗
CKLF-like MARVEL transmembrane domain-containing (CMTM) proteins play pivotal roles in tumorigenesis and cancer progression across various malignancies. However, their expression profiles and regulatory mechanisms in dis...
CKLF-like MARVEL transmembrane domain-containing (CMTM) proteins play pivotal roles in tumorigenesis and cancer progression across various malignancies. However, their expression profiles and regulatory mechanisms in distinct subtypes of breast cancer remain largely undefined. In this study, we systematically analysed the expression of all nine CMTM family members across major molecular subtypes of breast cancer, including Luminal A, Luminal B, HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Among these, CMTM3 was uniquely downregulated in Luminal B and HER2+ breast cancer cells and functioned as a tumor suppressor. Overexpression of HER2 in normal breast epithelial cell lines led to the phosphorylation of CMTM3. Molecular and biochemical analyses revealed that HER2 overexpression activated the downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (also known as RAC-Alpha Serine/Threonine-Protein Kinase, AKT) signaling pathway in Luminal B and HER2+ breast cancer cells. AKT1 directly phosphorylated CMTM3 at serine 181 (Ser181), a modification that facilitated its recognition and ubiquitination by the E3 ligase HECT domain E3 ubiquitin protein ligase 3 (HECTD3), ultimately targeting CMTM3 for proteasomal degradation. Functional assays demonstrated that either knockdown of HECTD3 or pharmacological inhibition of PI3K/AKT signaling stabilized CMTM3 protein levels. Moreover, reintroducing a nonphosphorylatable CMTM3 mutant (CMTM3S181A) into CMTM3 knockout breast cancer cells resulted in significantly reduced proliferation, colony formation, invasive capacity, and in vivo tumor growth compared with cells expressing wild-type CMTM3 (CMTM3WT). Collectively, these findings reveal a previously unrecognized posttranslational regulatory mechanism of CMTM3 and suggest that targeting the PI3K/AKT-HECTD3-CMTM3 axis may offer a promising therapeutic approach for treating HER2+ breast cancers.
Core transcriptional regulatory circuit-regulated IGF2BP3 stabilizes E2F2 mRNA via m6A modification in neuroblastoma.
Yang P, Wang J, Wu Z … +20 more , Zhuo R, Chen Y, Li G, Tao Y, Li X, Fang F, Wu D, Yang Y, Yin H, Qian G, Wang H, Li X, Yu J, Yang R, Xu Y, Li Z, Shi L, Zhang Z, Pan J, Wang J
Carcinogenesis · 2025 Sep · PMID 40823720 · Full text
Neuroblastoma (NB) is a pediatric tumor with diverse outcomes and unknown underlying mechanisms. The core transcriptional regulatory circuit (CRC) and N6-methyladenosine (m6A) are key factors that control cell identity a...
Neuroblastoma (NB) is a pediatric tumor with diverse outcomes and unknown underlying mechanisms. The core transcriptional regulatory circuit (CRC) and N6-methyladenosine (m6A) are key factors that control cell identity and fate. IGF2BP3 is an m6A reader protein that is transcriptionally regulated by CRC transcription factors (TFs). In NB, this molecule is abundantly expressed, and there is a clear correlation between its expression and a bad prognosis. We mechanistically demonstrated that IGF2BP3 promotes E2F2 mRNA expression through m6A, which is correlated with high risk and poor prognosis in NB patients. We showed that the CRC TF-IGF2BP3-E2F2 regulatory axis forms an oncogenic network that drives NB development and progression. Overall, we investigated the molecular mechanism by which IGF2BP3, a m6A-reading protein that is regulated by CRC TFs, regulates E2F2 mRNA expression in an m6A-dependent manner. This study highlights the therapeutic potential of disrupting this axis with m6A-targeted interventions.
FZD6 promotes 5-fluorouracil resistance through inhibiting pyroptosis in colorectal cancer.
He Z, Yang J, Zhang Y … +5 more , Zhang T, Guo T, Jin L, Mao Y, Wang T
Carcinogenesis · 2025 Sep · PMID 40810359 · Publisher ↗
Resistance to 5-fluorouracil (5-FU) causes treatment failure in most colorectal cancer (CRC) cases. Pyroptosis is associated with chemotherapy resistance, although its role in 5-FU resistance in CRC is not well understoo...
Resistance to 5-fluorouracil (5-FU) causes treatment failure in most colorectal cancer (CRC) cases. Pyroptosis is associated with chemotherapy resistance, although its role in 5-FU resistance in CRC is not well understood. To investigate this, we performed proteomic sequencing and bioinformatics analysis on wild-type and 5-FU-resistant CRC cell lines. Subsequently, Frizzled receptor 6 (FZD6) knockdown and overexpression cell lines were established using a lentiviral system. CCK-8, colony formation, and EdU assays were performed to assess the viability and proliferative potential of 5-FU-treated cells. The morphological changes associated with pyroptosis were examined by microscopic imaging and electron microscopy. The nuclear expression of β-catenin was examined by immunofluorescence and western blotting. These findings indicated that FZD6 protein was upregulated in the 5-FU-resistant CRC cells compared with the corresponding wild-type cell lines, an observation further validated through immunohistochemical analysis of clinical samples. Additionally, 5-FU treatment induced NLRP3/caspase-1/GSDMD-mediated classical pyroptosis in the wild-type CRC cells and decreased their viability, while the pyroptosis inhibitor Ac-FITD-CMK enhanced drug resistance. Furthermore, overexpression of FZD6 promoted nuclear translocation of β-catenin, reduced pyroptosis, and increased 5-FU resistance. In contrast, 5-FU treatment did not induce significant pyroptosis in drug-resistant cells, while pyroptosis inducers (nigericin or LPS + ATP) significantly reduced cell viability regardless of 5-FU. Moreover, knockdown of FZD6 decreased nuclear translocation of β-catenin, enhanced pyroptosis, and reduced 5-FU resistance. Finally, β-catenin knockdown enhanced pyroptosis and decreased 5-FU resistance. Thus, FZD6 promotes 5-FU resistance in CRC cells by inhibiting pyroptosis through increased nuclear translocation of β-catenin.
BRINP3 promotes lung adenocarcinoma by enhancing CLOCK-mediated transcriptional regulation of CRYZL1 and activating the AKT pathway.
Zhang Y, Huang C, Chen Y … +2 more , Liu L, Li S
Carcinogenesis · 2025 Nov · PMID 40799124 · Publisher ↗
Lung cancer, particularly lung adenocarcinoma (LUAD), is the leading cause of cancer-related death globally. This study investigated the role of BRINP3 in LUAD. Immunohistochemical analysis revealed significantly upregul...
Lung cancer, particularly lung adenocarcinoma (LUAD), is the leading cause of cancer-related death globally. This study investigated the role of BRINP3 in LUAD. Immunohistochemical analysis revealed significantly upregulated BRINP3 expression in LUAD tissues compared to normal tissues, mainly located in the cytoplasm and positively correlated with tumor progression. RNA sequencing data from the TCGA-LUAD database corroborated these findings. Elevated BRINP3 expression was associated with advanced tumor stages, higher malignancy grades, and increased risk of lymphatic metastasis. Functional studies showed that BRINP3 knockdown inhibited cell proliferation, colony formation, and migration, while promoting apoptosis. Conversely, BRINP3 overexpression enhanced these malignant behaviors. Gene expression profiling identified CLOCK and CRYZL1 as potential BRINP3 targets, with BRINP3 interacting with CLOCK to regulate CRYZL1 transcription. Additionally, BRINP3 activated the AKT signaling pathway to promote LUAD progression. In vivo experiments validated the tumor-suppressing effects of BRINP3 knockdown, reducing tumor growth and metastatic potential. In conclusion, BRINP3 played a crucial role in LUAD development and progression by regulating CLOCK-mediated transcriptional regulation of CRYZL1 and activating the AKT signaling pathway. BRINP3 knockdown inhibited LUAD cell malignancy and might represent a potential therapeutic target.
Co-targeting KRASG12D and the HER family is efficacious in colorectal cancer.
Kilroy-Gehret MK, Wischmeier C, Park S … +4 more , Choi D, Feroz W, Mishra R, Garrett JT
Carcinogenesis · 2025 Apr · PMID 40755231 · Publisher ↗
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, with roughly 41% of CRC cases harboring a KRAS mutation. Acquired resistance to KRAS-targeted treatments has occurred with mechanisms includ...
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, with roughly 41% of CRC cases harboring a KRAS mutation. Acquired resistance to KRAS-targeted treatments has occurred with mechanisms including increased HER family expression among other receptor tyrosine kinases. HER3, a member of the HER family that is kinase impaired, has been shown to be a resistance mechanism upon inhibition of the HER family and downstream targets, including RAS/MEK/ERK and PI3K/AKT. We find that KRAS mutations tend to co-occur with HER3 alterations in a large panel of cancers and in CRCs. Our results show that both total and activated HER3 levels increase in CRC patient-derived organoids and cell lines after treatment with KRASG12D targeted agents, indicating that HER3 could be a potential adaptive response mechanism to KRAS-targeted therapy. Further, we found that genetic knock-down of KRAS and HER3 resulted in a reduction in the growth of CRC cells compared to a single knockdown of either KRAS or HER3. We observed that kinase-impaired HER3 binding partners, as assessed by immunoprecipitation, is cell dependent with EGFR binding HER3 in one cell line. After co-treating CRC cells with pan-HER inhibitors in combination with MRTX1133, a KRASG12D inhibitor, synergistic and additive effects in the reduction in cell growth were observed. Finally, we found that co-targeting KRASG12D mutant cells with a KRASG12D inhibitor and a HER3 antibody-drug conjugate further reduced cell viability. We posit that co-targeting both KRASG12D and HER3, whether directly or indirectly, is a potential therapeutic strategy in CRC patients.
Constitutive epidermal expression of osteopontin in osteopontin-null mice restores ultraviolet B-induced cutaneous squamous cell carcinomas to wild-type levels.
Chou CF, Huang Y, Foote JB … +8 more , Hsieh YH, Kuo HC, Crossman DK, Crowley MR, Janjetovic Z, Slominski AT, Elmets C, Chang PL
Carcinogenesis · 2025 Nov · PMID 40755224 · Full text
Studies of osteopontin (OPN)-null mice have supported the role of OPN as a critical factor in the promotion of skin tumorigenesis. OPN is a highly inducible integrin- and CD44-interacting acidic glycoprotein with pleiotr...
Studies of osteopontin (OPN)-null mice have supported the role of OPN as a critical factor in the promotion of skin tumorigenesis. OPN is a highly inducible integrin- and CD44-interacting acidic glycoprotein with pleiotropic functions. In various cancers, elevated levels of OPN from cancer and inflammatory cells are secreted into the microenvironment and the bloodstream. To determine whether OPN expressed by keratinocytes without contribution from activated resident and infiltrating inflammatory cells promotes cutaneous tumorigenesis, transgenic mice with constitutive epidermal expression of OPN in an OPN-null background (tg(K14-OPN)) were generated. In photocarcinogenesis studies, tumor multiplicity and the incidence of cutaneous squamous cell carcinoma (cSCC) were similar in the tg(K14-OPN) and wild-type (WT) mice. The incidence of cSCC was significantly higher in the WT than in OPN-null mice. This incidence did not reach significance in tg(K14-OPN) and OPN-null mice, likely due to fewer mice. Tg(K14-OPN) mice exhibited reduced keratinocyte apoptosis but not enhanced epidermal hyperplasia after ultraviolet B (UVB) exposure compared to OPN-null mice. Additionally, tg(K14-OPN) and OPN-null mice irradiated with long-term low-dose UVB had significantly lower numbers of mutated p53 keratinocytes than WT mice. RNA-sequencing data from the epidermis of acute UVB-irradiated tg(K14-OPN) versus OPN-null mice compared to UVB-irradiated WT versus OPN-null mice suggest the importance of inflammation, Wnt, integrin, and gonadotropin-releasing hormone receptor signaling in cutaneous tumorigenesis and implicates UVB irradiation and its induction of OPN in driving those pathways. In summary, the constitutive epidermal expression of OPN in OPN-null mice facilitates the development of cSCC comparable to WT mice.
Genome-wide association study of early-stage non-small cell lung cancer prognosis: a pooled analysis in the International Lung Cancer Consortium.
Dong M, Thakral A, Byrne KS … +37 more , Bosse Y, Zhou H, Zhang Y, Atkins J, Haycock P, Brown MC, Murison K, Timens W, Sin DD, Kothari J, Gabriel AAG, Zaridze D, Savic M, Lissowska J, Świątkowska B, Janout V, Holcatova I, Mukeria A, Fernandez-Tardon G, Davies MPA, Triplette M, Schabath MB, Andrew AS, Chen C, Taylor F, Field JK, Tardon A, Shete SS, Brennan P, Landi MT, McKay J, Amos CI, Lin X, Christiani DC, Hung RJ, Liu G, Xu W
Carcinogenesis · 2025 Apr · PMID 40746155 · Full text
Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale gen...
Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale genome-wide association prognostic study using data from the International Lung Cancer Consortium (ILCCO) through a two-phase analysis. Phase 1 includes the discovery of genome-wide association studies analysis using a multivariable Cox PH model on 3428 NSCLC patients of European ancestry from 10 ILCCO participating studies to identify genetic variants associated with overall survival and validation analysis for genome-wide significant variants (P-value ≤5 × 10-8) using the Cancer Genome Atlas (TCGA). Phase 2 aims to identify causal variants using functional analyses of genome-wide significant and suggestive variants (P-value ≤1 × 10-5), including variant-epigenetic functional annotation (FAVOR), CHIP-seq data, variant-gene expression association, and colocalization analysis. We identified two significant variants; of those, a locus at 9q21.31 (rs117979484) was significant at the genome-wide level (P = 3.67 × 10-8) and validated in TCGA (P = 0.03). Three suggestive variants were found to have a putative epigenetic function: intronic variants rs149281784 (BCL7B gene) and rs148031766 (POM121 gene) both located at 7q11.23 and in moderate linkage disequilibrium with each other; and variant rs2471630 (SRCIN1 gene; 17q12). Specifically, variants rs149281784 and rs148031766 have potential regulatory roles in the transcriptional activation of the BCL7B gene and POM121 gene. Exploratory survival analyses in the squamous cell carcinomas subgroup also identified a significant variant, rs138467404 (GRHL-2 gene; 8q22.3) at a genome-wide level (P = 4.75 × 10-8) and validated by TCGA (P = 0.02). These new findings indicate potential novel pathways associated with early-stage NSCLC prognosis. Future research may validate additional genome-wide suggestive variants as being relevant for lung cancer outcomes.
Longitudinal single-cell RNA model aids prediction of EGFR-TKI resistance.
Hou G, Lu Z, Zeng D … +3 more , Chen Q, Cheng S, Song B
Carcinogenesis · 2025 Sep · PMID 40739818 · Publisher ↗
Resistance is inevitable and a major challenge in treating lung adenocarcinoma (LUAD) patients with EGFR mutations. This study aimed to investigate the mechanism of EGFR-TKI resistance in LUAD using longitudinal single-c...
Resistance is inevitable and a major challenge in treating lung adenocarcinoma (LUAD) patients with EGFR mutations. This study aimed to investigate the mechanism of EGFR-TKI resistance in LUAD using longitudinal single-cell RNA sequencing (scRNA-seq) data. We collected tumour samples of LUAD patients before and after EGFR inhibitor treatment and performed single-cell RNA sequencing. We used machine learning models for cell annotation and classified cells into subgroups. The inferCNV algorithm was used for CNV score calculation and tumour cell identification, and metabolic analysis was done using a gene-scoring approach. EGFR resistance score (ERscore), a gene signature derived from resistant tumour cells, was established to evaluate the predictiveness to EGFR-TKI inhibitors. The investigation classified subgroups of cells and identified three tumour cell types as critical cells mediating EGFR-TKI resistance. Our data also analysed the metabolic aspects of EGFR-TKI resistance using a single-cell approach. It showed that some tumour cell subtypes had a consistent metabolic profile, significantly up-regulating purine metabolism, oxidative phosphorylation, glycogen, and lipid metabolism. An assessment system called ERscore was established to evaluate the association between EGFR-TKI resistance and tumour ecosystem. The analysis showed a significant correlation between the ERscore and EGFR-TKI resistance, lung cancer phenotype, and prognosis. The findings suggest that the molecular mechanisms driving EGFR-TKI resistance in lung cancer may also contribute to poorer prognosis, particularly in lung adenocarcinomas with high EGFR mutation rates. Overall, the study provides important insights into the mechanisms of EGFR-TKI resistance in lung cancer at the single-cell level.
Targeted sequencing and functional interrogation identified novel variant at 12q14.2 associated with risk of ovarian cancer in Han Chinese women.
Zhao Y, Geng W, Liu W … +12 more , Liu L, Teng C, Chen Y, Yang D, Chai L, Wang W, Chu X, Huang C, Liu B, Chen K, Zheng H, Li L
Carcinogenesis · 2025 Sep · PMID 40719211 · Publisher ↗
Chromosome 12q14.2 has been reported as a potential risk locus for epithelial ovarian cancer (EOC) in genome-wide association study (GWAS). We performed targeted sequencing around the rs11175194 at chromosome 12q14.2 and...
Chromosome 12q14.2 has been reported as a potential risk locus for epithelial ovarian cancer (EOC) in genome-wide association study (GWAS). We performed targeted sequencing around the rs11175194 at chromosome 12q14.2 and identified five potential risk variants. The association between these five variants and EOC risk was evaluated in 893 EOC cases and 1292 controls. We identified that rs11175195 (P = 1.94 × 10-6, OR = 1.36, 95% CI = 1.20-1.54) was significantly associated with EOC risk in validation study and after meta-analysis with previous GWAS data, rs11175195 reached genome-wide significant level (P < 5 × 10-8). Functional annotation and expression quantitative trait loci analysis prioritized rs11175194 as a causal variant at this locus. The presence of G-rs11175194 risk allele increased binding affinity of the transcription factor NR1H4 and upregulate SRGAP1 gene expression. Overexpression of SRGAP1 promotes the proliferation and invasion in ovarian cancer cell lines. In conclusion, we identified a novel susceptibility locus of ovarian cancer and revealed a potential molecular mechanism for ovarian cancer carcinogenesis. These results may provide a potential biomarker and therapeutic target for ovarian cancer.
GPS2 confers l-asparaginase resistance in acute lymphoblastic leukemia cells through ATF4/ASNS axis.
Chen J, Luo J, Liu Y … +3 more , Zhou J, Cui H, Deng L
Carcinogenesis · 2025 Apr · PMID 40693356 · Publisher ↗
l-asparaginase (l-ASP) is an important chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, resistance to l-ASP is an unfavorable prognostic factor, and the mechanism und...
l-asparaginase (l-ASP) is an important chemotherapeutic agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, resistance to l-ASP is an unfavorable prognostic factor, and the mechanism underlying l-ASP resistance is not fully understood. Here, we show that activation of the activating transcription factor 4 (ATF4) and induced expression of downstream target asparagine synthetase (ASNS) play a pivotal role in l-ASP resistance of ALL cells. In addition, the G protein pathway suppressor 2 (GPS2) binds to ATF4 and stabilizes ATF4 protein. Mechanistically, GPS2 inhibits ubiquitin-proteasome degradation of ATF4 through impairing the interaction between ATF4 and beta-transducin repeat-containing E3 ubiquitin protein ligase (BTRC), an E3 ligase that triggers proteasomal degradation of ATF4. Moreover, GPS2 knockdown sensitizes ALL cells to l-ASP treatment via repressing the ATF4/ASNS axis in vitro and increases l-ASP efficacy against xenografted ALL tumors in vivo. Taken together, these findings demonstrate that GPS2 positively regulates the ATF4/ASNS axis to confer l-ASP resistance in ALL cells, suggesting a therapeutic potential of targeting this pathway to overcome l-ASP resistance.
Macrophage migration inhibitory factor as a prognostic biomarker in multiple myeloma: clinical significance and in vitro effects.
Li D, Qiao B, Cheng Q … +5 more , Chen L, Zhao F, Zuo L, Li Q, Sun C
Carcinogenesis · 2025 Apr · PMID 40628663 · Publisher ↗
Macrophage migration inhibitory factor (MIF) emerged in recent years as an important cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of inflammatory diseases and malignancies....
Macrophage migration inhibitory factor (MIF) emerged in recent years as an important cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of inflammatory diseases and malignancies. A growing body of research indicates that the overexpression of MIF is prevalent across a variety of solid tumors. Howbeit, there are fewer studies regarding the expression and clinical significance of serum MIF in multiple myeloma (MM) patients. In this study, we investigated the clinical significance of serum MIF in newly diagnosed MM (NDMM) patients and explored the effect of exogenous MIF on the proliferation, migration, and invasion of MM cells in vitro. Herein, our study revealed that NDMM patients exhibited markedly elevated serum MIF levels compared to healthy adults. High levels of MIF were associated with advanced International Staging System (ISS) stage and the Second Revision of the International Staging System (R2-ISS) stage. Besides, NDMM patients with high levels of MIF were prone to have a higher incidence of hypercalcemia, renal insufficiency, high tumor burden, and extramedullary lesions. Moreover, we found that serum MIF, creatinine, and lactate dehydrogenase levels were independent risk factors for predicting poor progression-free survival and overall survival in NDMM patients. Meanwhile, in vitro experiments revealed that MIF can promote the proliferation of MM cells and enhance their migration and invasion. Our study confirmed that NDMM patients with high serum MIF levels showed poor clinical characteristics and inferior prognosis. Therefore, MIF may serve as a promising biomarker in the clinical practice of MM.
Urinary metabolites in association with kidney cancer risk.
Al-Sayegh T, Song S, Lipworth L … +7 more , Cai H, Lan Q, Gao Y, Rothman N, Cai Q, Zheng W, Shu XO
Carcinogenesis · 2025 Apr · PMID 40576378 · Full text
Kidney cancer incidence has increased worldwide in recent decades. While metabolomic studies have shown promise in unveiling mechanisms underlying disease development, few studies have investigated prediagnostic urinary...
Kidney cancer incidence has increased worldwide in recent decades. While metabolomic studies have shown promise in unveiling mechanisms underlying disease development, few studies have investigated prediagnostic urinary metabolites and kidney cancer risk. We conducted a case-control study nested within the Shanghai Women's and Men's Health Studies to prospectively investigate the association between urinary metabolites and kidney cancer risk to understand its etiology and the underlying biological mechanisms. Two hundred primary kidney cancer cases and their individually matched controls were included. A total of 1301 metabolites were evaluated, and 67 metabolites were found nominally associated with kidney cancer using conditional logistic regression. After backward selection, 11 urine metabolites remained significantly associated with kidney cancer: lipids (e.g. picolinoylglycine, odds ratio [OR]; 95% confidence interval [CI]: 2.01 [1.44, 2.79], and pregnanediol-3-glucuronide, OR; 95% CI: 0.56 [0.39, 0.82]), xenobiotics (e.g. beta-guanidinopropanoate, OR; 95% CI: 1.75 [1.32, 2.32] and 4-vinylphenol sulfate, OR; 95% CI: 0.66 [0.49, 0.90]), and nucleotides (e.g. allantoic acid, OR; 95% CI: 0.71 [0.54, 0.92]). Time lag analysis showed that metabolite-kidney cancer associations were stronger for beta-guanidinopropanoate (OR; 95% CI: 8.22 [1.68, 40.18]) and picolinoylglycine (OR; 95% CI: 6.45 [1.28, 32.43]), but weaker for allantoic acid (OR; 95% CI: 0.87 [0.37, 2.06]) and 3-methylglutarate/2-methylglutarate (OR; 95% CI: 0.62 [0.19, 2.00]) when urinary samples were collected within 3 years between urine sample collection and cancer diagnosis (Pinteraction < .05 for all). Future metabolomics studies with large sample sizes, particularly from multiple ancestry populations, are needed to validate our findings.
Integrated functional genomics-identified DEAF1 in oxidative stress and hepatocellular carcinoma development.
Huang L, Yu X, Zhang Z … +4 more , Huo Y, Zhang L, Zhang N, Yang M
Carcinogenesis · 2025 Apr · PMID 40554679 · Publisher ↗
Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with an overall 5-year survival rate of only 16%. The molecular mechanisms leading to malignant progression of HCC pati...
Hepatocellular carcinoma (HCC) is the third most common cause of death for cancer patients globally, with an overall 5-year survival rate of only 16%. The molecular mechanisms leading to malignant progression of HCC patients remain largely unclear. Hepatocyte nuclear factor 4α (HNF4α) functions as a tumor-suppressive transcription factor (TF) in HCC. In this study, we aimed to identify functional HCC susceptibility single nucleotide polymorphisms (SNPs) in HNF4α-binding sites throughout the human genome. We identified 1274 HNF4α-binding site polymorphisms via a genome-wide screening using TUIFGA (the updated integrative functional genomics approach), which we previously developed to recognize cancer susceptibility SNPs within genome-wide TF-binding sites. Among these SNPs, the DEAF1 rs11246280 SNP was significantly associated with HBV-related HCC susceptibility in several case-control studies. Importantly, the rs11246280 SNP could interrupt HNF4α binding to the DEAF1 promoter and enhance DEAF1 expression. Oncogenic TF DEAF1 binds to the SLC38A3 promoter, elevates glutamine transporter SLC38A3 expression, enhances influx of glutamine and GSH production, leads to reduced ROS levels in cells and, thereby, promotes HCC progression. Our findings highlighted the role of DEAF1 during HCC development via maintaining redox balance, which sheds light on the development of novel cancer therapeutics.
Regulatory mechanisms of PFKFB2 in glycolysis and tumor metabolism: implications for cancer therapy.
Lou Q, Chang J, Pan Y … +5 more , Gong Y, Xu W, Tong M, Wang L, Jiang F
Carcinogenesis · 2025 Apr · PMID 40538377 · Publisher ↗
Glycolysis is a crucial metabolic process that facilitates the rapid proliferation of cancer cells. Phosphofructokinase-1 (PFK-1) is the key rate-limiting enzyme in glycolysis, with fructose-2,6-diphosphate (F-2,6-BP) ac...
Glycolysis is a crucial metabolic process that facilitates the rapid proliferation of cancer cells. Phosphofructokinase-1 (PFK-1) is the key rate-limiting enzyme in glycolysis, with fructose-2,6-diphosphate (F-2,6-BP) acting as its most effective regulator. The levels of F-2,6-BP are closely correlated with the activity of 6-phosphate fructose-2-kinase/fructose-2,6-diphosphatase (PFK-2/FBPase-2, PFKFB). The PFKFB family consists of four isoenzymes: PFKFB1-4. Most evidence suggests that PFKFB activity is essential for activating glycolytic and oncogenic properties in tumor cells. However, previous studies have focused predominantly on PFKFB3 and PFKFB4, with relatively few investigating PFKFB2. The role of PFKFB2 in cancer is complex and multifaceted, encompassing various aspects of tumor metabolism, cell migration, invasion, and the immune response. Consequently, this review aims to summarize the current understanding of the gene structure and biological function of PFKFB2 and to explore its pathogenic mechanisms in different cancers. Additionally, we highlight the metabolic signaling pathways associated with PFKFB2. This review seeks to provide insights into the current status of PFKFB2 and to assist in identifying new targets for cancer therapy.
Identification of HCAR1 as a ferroptosis-related biomarker of gastric cancer based on a novel ferroptosis-related prognostic model and in vitro experiments.
Zhang H, Zhan J, Zhou J … +7 more , Liu L, He Y, Le Y, Liu W, Zhou L, Liu Y, Xiang X
Carcinogenesis · 2025 Apr · PMID 40482015 · Publisher ↗
Currently, research on ferroptosis-related prognostic models for gastric cancer is limited, whereas traditional predictive models often have a narrow perspective and low accuracy. In this study, we systematically analyze...
Currently, research on ferroptosis-related prognostic models for gastric cancer is limited, whereas traditional predictive models often have a narrow perspective and low accuracy. In this study, we systematically analyzed the expression patterns of ferroptosis-related genes in patients with gastric adenocarcinoma and evaluated their prognostic value. Using data from The Cancer Genome Atlas (TCGA) and the FerrDb database, we developed a ferroptosis-related prognostic risk model based on four genes: hydroxycarboxylic acid receptor 1 (HCAR1), branched-chain amino acid transaminase 1 (BCAT1), ceruloplasmin (CP), and dickkopf-1 (DKK1). This model demonstrated strong prognostic value and potential clinical relevance in stratifying gastric cancer patients by overall survival outcomes. ferroptosis-related prognostic risk model. Compared to traditional clinicopathological features, the risk score derived from this model exhibited superior predictive accuracy for overall survival in patients with gastric cancer and served as an independent prognostic factor. Functional enrichment analysis revealed that the risk score was primarily enriched for extracellular matrix-related pathways. Additionally, the risk score was significantly correlated with TME signature genes, immune checkpoint expression, and immune cell infiltration in stomach adenocarcinoma (STAD). Mechanistic studies revealed that HCAR1 is abnormally overexpressed in gastric cancer tissues and is associated with a poor prognosis. It exerted its effects by regulating the GPX4/SLC7A11 axis to inhibit lipid peroxidation and malondialdehyde accumulation, thereby obstructing ferroptosis. Experimental validation demonstrated that the downregulation of HCAR1 promoted ferroptosis and suppressed malignant tumor phenotypes, suggesting that both the gene and its associated risk model hold significant clinical value as potential therapeutic targets and prognostic biomarkers.
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