Carcinogenesis最新文献

HS-10296 (Almonertinib) enhances radiosensitivity in EGFR-mutant NSCLC (including T790M) through inhibition of EGFR downstream signaling and DNA damage repair. HS-10296 （Almonertinib）通过抑制EGFR下游信号传导和DNA损伤修复，增强EGFR突变型NSCLC（包括T790M）的放射敏感性。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-10-15 DOI: 10.1093/carcin/bgaf070

Weiqi Liu, Yulian Liu, Yun Xie, Hui Huang, Mengzhi Wan, Ling Zhou, Fei Xu, Min Zhong

{"title":"HS-10296 (Almonertinib) enhances radiosensitivity in EGFR-mutant NSCLC (including T790M) through inhibition of EGFR downstream signaling and DNA damage repair.","authors":"Weiqi Liu, Yulian Liu, Yun Xie, Hui Huang, Mengzhi Wan, Ling Zhou, Fei Xu, Min Zhong","doi":"10.1093/carcin/bgaf070","DOIUrl":"https://doi.org/10.1093/carcin/bgaf070","url":null,"abstract":"Non-small cell lung cancer (NSCLC) harboring EGFR mutations, including the resistant T790M variant, continues to require improved therapeutic strategies despite the development of EGFR tyrosine kinase inhibitors (TKIs). This study evaluates the radiosensitizing potential of HS-10296 (Almonertinib), a third-generation EGFR-TKI, in EGFR-mutant NSCLC models. In vitro studies demonstrated selective growth inhibition in mutant cells (PC-9: half-maximal inhibitory concentration (IC₅₀) =2.62μM; H1975: IC₅₀=5.22μM at 48h) compared to wild-type A549 cells (IC₅₀=11.42μM). Clonogenic assays revealed significant radiosensitization in mutant cells (SER: PC-9=1.22; H1975=1.55) through multiple mechanisms including enhanced DNA damage (1.5-2.0-fold increase in comet tail moments with 4-10× persistent γH2A.X foci), marked suppression of RAD51-mediated DNA repair, and increased apoptosis (combination therapy: 19.53-20.71% vs monotherapies: 12.08-14.05%). Mechanistic investigation showed HS-10296 attenuated phosphorylation of EGFR and downstream effectors AKT and ERK, potentially disrupting DNA damage response pathways. In vivo validation using H1975 xenografts demonstrated superior tumor growth inhibition with combination of HS-10296 and radiotherapy, which correlated with reduced expression of p-EGFR, p-AKT, and RAD51, along with increased γH2A.X levels. These findings establish HS-10296 as a promising radiosensitizer for EGFR-mutant NSCLC through simultaneous targeting of oncogenic signaling via PI3K/AKT and MAPK/ERK pathways and critical DNA repair mechanisms. The study provides compelling preclinical evidence supporting clinical evaluation of HS-10296 combined with radiotherapy for EGFR-driven NSCLC, including tumors with T790M-mediated resistance.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polo-like Kinase 4 (PLK4) as a Therapeutic Target in Breast Cancer. polo样激酶4 （PLK4）作为乳腺癌的治疗靶点。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-10-14 DOI: 10.1093/carcin/bgaf067

Armen Parsyan, Harjot Athwal, Vasudeva Bhat, Alison L Allan

{"title":"Polo-like Kinase 4 (PLK4) as a Therapeutic Target in Breast Cancer.","authors":"Armen Parsyan, Harjot Athwal, Vasudeva Bhat, Alison L Allan","doi":"10.1093/carcin/bgaf067","DOIUrl":"https://doi.org/10.1093/carcin/bgaf067","url":null,"abstract":"Polo-like kinase 4 (PLK4) is a key kinase regulating centriole duplication, centrosome maturation, cytokinesis and other cellular processes. Growing evidence suggests a critical role of PLK4 in the development and progression of various cancers. In many cancer types, its upregulation leads to pro-oncogenic phenotypes, while its pharmacologic inhibition leads to anticancer effects. Functionally, PLK4 affects cancer cell proliferation, growth, motility, invasion, migration, epithelial-mesenchymal transition, apoptosis and other critical oncogenic processes. In breast cancer, PLK4 is associated with centrosome amplification, aneuploidy and chromosomal instability, promoting invasive phenotypes and resistance to cancer cell death. PLK4 shows great promise as a prognostic and predictive biomarker in breast cancer. It is commonly found to be overexpressed in primary human breast cancers and is associated with poor oncologic outcomes, clinicopathologic parameters, and high-risk subtypes. Various compounds, such as CFI-400945, centrinone B, and others have been developed to inhibit PLK4 activity. Preclinical studies have shown that PLK4 inhibitors lead to decreased proliferation, growth and migration and increased breast cancer cell death. Moreover, PLK4 inhibition can serve to enhance the effects of other treatments, including radiotherapy. Clinical studies have been initiated with some of these compounds in cancer patients, including those with breast cancer. This manuscript discusses the role of PLK4 as a promising therapeutic target in breast cancer, one of the most common causes of morbidity and mortality in women.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145298576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thrombospondin-4 from Cancer-associated Fibroblasts Downregulates ERBB2 Expression in Gastric Cancer Cells. 胃癌相关成纤维细胞血栓响应蛋白-4下调ERBB2的表达。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-10-07 DOI: 10.1093/carcin/bgaf064

Gen Tsujio, Masakazu Yashiro, Takashi Sakuma, Yurie Yamamoto, Daiki Imanishi, Canfeng Fan, Qiang Wang, Kyoka Kawabata, Hinano Nishikubo, Saki Kanei, Rika Aoyama, Koji Maruo, Masaichi Ohira, Kiyoshi Maeda

{"title":"Thrombospondin-4 from Cancer-associated Fibroblasts Downregulates ERBB2 Expression in Gastric Cancer Cells.","authors":"Gen Tsujio, Masakazu Yashiro, Takashi Sakuma, Yurie Yamamoto, Daiki Imanishi, Canfeng Fan, Qiang Wang, Kyoka Kawabata, Hinano Nishikubo, Saki Kanei, Rika Aoyama, Koji Maruo, Masaichi Ohira, Kiyoshi Maeda","doi":"10.1093/carcin/bgaf064","DOIUrl":"https://doi.org/10.1093/carcin/bgaf064","url":null,"abstract":"The intra-tumoral heterogeneity of HER2 expression is associated with resistance to anti-HER2 therapy in HER2-positive gastric cancers (GCs). We previously reported that thrombospondin-4 (THBS4) is overexpressed in cancer-associated fibroblasts (CAFs) in the GC microenvironment and is associated with GC remodeling. To clarify the relationship between CAFs and the intra-tumoral heterogeneity of HER2 in GC, the effect of CAFs on HER2 expression was investigated in GC cells. Two HER2-positive GC cell lines (NCI-N87 and OE19) and two pairs of gastric CAFs were used. The effect of fibroblasts on HER2 expression in cancer cells was analyzed by immunohistochemical staining and reverse transcription-polymerase chain reaction. THBS4 siRNA was used for knockdown assays. The effects of Herceptin or gabapentin, a THBS4 receptor inhibitor, on subcutaneous tumors were examined in nude mice. CAFs and THBS4 recombinant significantly downregulated HER2 (ERBB2) expression in GC cells. THBS4 siRNA and gabapentin significantly inhibited the HER2-decreasing activity in CAFs. In vivo, CAFs suppress HER2 expression of subcutaneous GC tumors and induce Herceptin resistance. Gabapentin overcomes CAF-induced Herceptin resistance. THBS4 from CAFs downregulated HER2 (ERBB2) expression in GC cells. Thus, THBS4 receptor inhibitors may be useful in preventing the acquisition of resistance to anti-HER2 therapy.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An update on the World Trade Center cancer tissue biobank: a scientific resource for molecular and mechanistic studies on WTC-related cancer. 世贸中心癌症组织生物库的最新进展：世贸中心相关癌症分子和机制研究的科学资源。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-10-03 DOI: 10.1093/carcin/bgaf063

Wiley M Turner, Angelo Zegarelli, Tara Ivic-Pavlicic, Rachel Brody, Stephanie Tuminello, Emanuela Taioli

{"title":"An update on the World Trade Center cancer tissue biobank: a scientific resource for molecular and mechanistic studies on WTC-related cancer.","authors":"Wiley M Turner, Angelo Zegarelli, Tara Ivic-Pavlicic, Rachel Brody, Stephanie Tuminello, Emanuela Taioli","doi":"10.1093/carcin/bgaf063","DOIUrl":"https://doi.org/10.1093/carcin/bgaf063","url":null,"abstract":"World Trade Center (WTC) responders were exposed to a complex mixture of toxins and carcinogens through dust, fumes, and smoke at ground zero. Since then, studies have indicated that WTC responders have elevated cancer rates compared to the general population. While studies have detailed the overarching connection between WTC exposure and cancer, a tissue biobank is needed to enable molecular and mechanistic studies on WTC-related cancers. The cohort includes responders involved in rescue, recovery, or cleanup enrolled in the World Trade Center Health Program (WTCHP) who consented to participate in research. Responders with cancer were identified through WTCHP certification. WTCHP provided data with patients' demographic information, contact details, and cancer diagnoses. Potential participants were contacted by mail, email, or phone for consent and procedure location. If consented, samples were requested from pathology departments. A biobank of cancer tissues from WTC responders has been established with 551 distinct primary cancers from 521 patients. Of these, prostate makes up 39.0%, thyroid 9.8%, melanoma 8.9%, kidney 6.5%, bladder 6.0%, colorectal 5.8%, breast 5.6%, lung 4.7%, head and neck 4.7%, and other cancers 9%. An additional 343 patients have consented for biobank projects and their samples are being requested. To date, we have created a valuable tissue biobank available to the scientific community for high-impact oncology studies in the unique population of WTC responders. By studying links between carcinogenic exposure and cancer sites, exposure signatures, and markers of cancer aggressiveness, this biobank offers an unprecedented opportunity to advance cancer research in an exposed population.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Oncogenic Role of AURKA in Gastric Cancer: Mechanisms, Pathways, and Clinical Relevance. AURKA在胃癌中的致癌作用：机制、途径和临床相关性。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-09 DOI: 10.1093/carcin/bgaf054

Caixia Lv, Yan Liu, Huanhu Zhang

{"title":"The Oncogenic Role of AURKA in Gastric Cancer: Mechanisms, Pathways, and Clinical Relevance.","authors":"Caixia Lv, Yan Liu, Huanhu Zhang","doi":"10.1093/carcin/bgaf054","DOIUrl":"https://doi.org/10.1093/carcin/bgaf054","url":null,"abstract":"Aurora kinase A (AURKA) is a serine/threonine kinase that plays a critical role in cell cycle regulation, particularly during mitosis. Recent studies have identified AURKA as an oncogene overexpressed in various cancers, including gastric cancer (GC). This review summarizes the molecular mechanisms by which AURKA contributes to GC pathogenesis, including its roles in cell proliferation, apoptosis inhibition, epithelial-mesenchymal transition (EMT), and cancer stemness. AURKA regulates key signaling pathways such as PI3K/Akt, Wnt/β-catenin, NF-κB, and JAK2/STAT3, promoting tumor growth, metastasis, and therapy resistance. Additionally, AURKA interacts with critical tumor suppressors like p53 and PTEN, further enhancing its oncogenic potential. Clinical studies have demonstrated that AURKA overexpression correlates with poor prognosis in GC patients, highlighting its potential as a diagnostic and therapeutic target. This review also discusses the efficacy of AURKA inhibitors in preclinical settings, offering insights into their therapeutic potential. By elucidating the multifaceted roles of AURKA in GC, this review aims to provide a comprehensive understanding of its mechanisms and implications for future research and treatment strategies.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longitudinal single-cell RNA model aids prediction of EGFR-TKI resistance. 纵向单细胞RNA模型有助于预测EGFR-TKI耐药性。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf038

Guoxin Hou, Zhimin Lu, Dongqiang Zeng, Qican Chen, Subing Cheng, Binbin Song

{"title":"Longitudinal single-cell RNA model aids prediction of EGFR-TKI resistance.","authors":"Guoxin Hou, Zhimin Lu, Dongqiang Zeng, Qican Chen, Subing Cheng, Binbin Song","doi":"10.1093/carcin/bgaf038","DOIUrl":"10.1093/carcin/bgaf038","url":null,"abstract":"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.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted sequencing and functional interrogation identified novel variant at 12q14.2 associated with risk of ovarian cancer in Han Chinese women. 靶向测序和功能询问鉴定了中国汉族女性卵巢癌风险相关的12q14.2新变异。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf037

Yanrui Zhao, Wei Geng, Wei Liu, Lei Liu, Changcai Teng, Yuxin Chen, Dong Yang, Linqing Chai, Wei Wang, Xinlei Chu, Caiyun Huang, Ben Liu, Kexin Chen, Hong Zheng, Lian Li

{"title":"Targeted sequencing and functional interrogation identified novel variant at 12q14.2 associated with risk of ovarian cancer in Han Chinese women.","authors":"Yanrui Zhao, Wei Geng, Wei Liu, Lei Liu, Changcai Teng, Yuxin Chen, Dong Yang, Linqing Chai, Wei Wang, Xinlei Chu, Caiyun Huang, Ben Liu, Kexin Chen, Hong Zheng, Lian Li","doi":"10.1093/carcin/bgaf037","DOIUrl":"10.1093/carcin/bgaf037","url":null,"abstract":"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.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mammary adipose dysfunction in the dual epidemic of obesity and breast cancer. 肥胖和乳腺癌双重流行中的乳腺脂肪功能障碍。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf053

Elvina Jeyakumar, Sathyavathi Sundararaju, Stephanie Annett, Mohamed A Elrayess

{"title":"Mammary adipose dysfunction in the dual epidemic of obesity and breast cancer.","authors":"Elvina Jeyakumar, Sathyavathi Sundararaju, Stephanie Annett, Mohamed A Elrayess","doi":"10.1093/carcin/bgaf053","DOIUrl":"10.1093/carcin/bgaf053","url":null,"abstract":"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.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to: p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis. 修正：p62/SQSTM1与vimentin相互作用促进乳腺癌转移

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf042

引用次数: 0

HECTD3 E3 ligase mediates ubiquitination of AKT-phosphorylated CMTM3 in HER2-overexpressed breast cancer cells. 在her2过表达的乳腺癌细胞中，hector 3 E3连接酶介导akt磷酸化的CMTM3泛素化。

IF 2.9 3区医学

Carcinogenesis Pub Date : 2025-09-04 DOI: 10.1093/carcin/bgaf048

Jun Wang, Delong Wang, Xinxing Zhang, Xiaoyang Xu

{"title":"HECTD3 E3 ligase mediates ubiquitination of AKT-phosphorylated CMTM3 in HER2-overexpressed breast cancer cells.","authors":"Jun Wang, Delong Wang, Xinxing Zhang, Xiaoyang Xu","doi":"10.1093/carcin/bgaf048","DOIUrl":"10.1093/carcin/bgaf048","url":null,"abstract":"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.","PeriodicalId":9446,"journal":{"name":"Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0