Molecular Carcinogenesis最新文献

{"title":"Wogonin Inhibits Ovarian Cancer by Activating the AMPK-TET2-5hmC Axis.","authors":"Shu-Yi Yang, Jing-Siang Jhang, Wen-Long Huang, Leah H J Tsai, Min-Chia Tsai, Chin-Pui Chan, Ru-Inn Lin, Hon-Yi Lin, Chin Li, Chia-Chou Yeh, Michael W Y Chan","doi":"10.1002/mc.23856","DOIUrl":"10.1002/mc.23856","url":null,"abstract":"<p><p>Ovarian cancer is one of the most common gynecologic cancers. In the quest for effective anti-cancer agents, this study explores the effects of wogonin, a naturally occurring flavonoid, on the viability and migration of A2780 and Kuramochi ovarian cancer cells. A2780 and Kuramochi human ovarian cancer cell lines were utilized. Cytotoxicity and migration were evaluated using the CCK8 assay and the wound-healing assay, respectively. The effect of wogonin on the growth of A2780 ovarian cancer cells in vivo was assessed using a nude mouse model. The phosphorylation and half-life of AMPK were determined by western blot analysis. The level of 5hmC was assessed using dot blot analysis. The impact of wogonin on gene expression was examined through RNA-Seq. Our results show that wogonin not only impedes cancer cell growth and mobility both in vitro and in vivo but also significantly increases the cytotoxicity of cisplatin. Investigations of the mechanism underlying these effects reveal that wogonin suppresses genes associated with cell proliferation and the EMT and upregulates metabolic pathways, particularly the AMPK signaling pathway, which is crucial for increasing 5hmC levels. These results indicate that wogonin promotes DNA demethylation by stabilizing TET2. In conclusion, our findings highlight not only the therapeutic potential of wogonin but also its preventative capability against ovarian cancer in individuals with metabolic disorders, such as diabetes, who are at increased risk of ovarian cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"440-449"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M2 Macrophage-Derived Exosomal circ_0088494 Inhibits Ferroptosis via Promoting H3K4me1 Modification of STEAP3 in Cutaneous Squamous Cell Carcinoma.","authors":"Jun Yin, Zhigang Pei, Chunrong Wu, Jie Liu, Jianxiang Huang, Rui Xia, Debing Xiang","doi":"10.1002/mc.23862","DOIUrl":"10.1002/mc.23862","url":null,"abstract":"<p><p>Cutaneous squamous cell carcinoma (cSCC) is a common type of cutaneous cancer globally. M2 macrophage-derived exosomes (M2 exosomes) facilitate the development of cancer. Ferroptosis, a newly uncovered form of cell death, is linked to cancer progression. The present research planned to study the function and potential mechanism of M2 exosomes on ferroptosis in cSCC. Patients with cSCC were recruited to gather adjacent noncancerous specimens and cSCC tissues. Mononuclear macrophage (THP-1) cells were differentiated into M2 macrophages before exosome extraction, and then the exosomes were added into cSCC cells (A431 and SCL-1). Erastin was applied to induce ferroptosis. Cell viability, mitochondrial superoxide, lipid-ROS, malondialdehyde (MDA), and iron level were detected to validate ferroptosis in cSCC cells. Proteins and RNAs were tested by applying western blot and RT-qPCR. The combination between molecules was validated by ChIP and RIP. Six-transmembrane epithelial antigen of the prostate 3 (STEAP3) was elevated in cSCC specimens, which correlated to reduced ferroptosis. cSCC tissues presented an increase in the number of M2 macrophages. Erastin-elicited ferroptosis was repressed by M2 macrophages, while exosome inhibitor GW4869 neutralized the outcome of M2 macrophages. Furthermore, M2 exosomes repressed ferroptosis of cSCC cells via circ_0088494, which might be related to the upregulation of STEAP3. M2 exosomes-derived circ_0088494 promoted histone 3 lysine 4 monomethylation (H3K4me1) modification of STEAP3 by recruiting histone-lysine N-methyltransferase 2D (KMT2D). The effect of circ_0088494-silenced M2 exosomes on ferroptosis was antagonized by STEAP3 overexpression. M2 exosomes-derived circ_0088494 recruited KMT2D to promote H3K4me1 modification of STEAP3, thereby inhibiting ferroptosis in cSCC. This study might provide a novel target for cSCC treatment.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"513-525"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A-to-I-Edited miR-1304-3p Inhibits Glycolysis and Tumor Growth of Esophageal Squamous Cell Carcinoma by Inactivating Wnt5a/ROR2 Signaling.","authors":"Peng Chen, Hang Zhou, Xian Yang, Yuzhen Zheng, Yujie Chen, Peiyuan Wang, Hao He, Shuoyan Liu, Feng Wang","doi":"10.1002/mc.23867","DOIUrl":"10.1002/mc.23867","url":null,"abstract":"<p><p>A-to-I RNA editing is a pervasive mechanism in the human genome that affects the regulation of gene expression and is closely associated with the pathogenesis of numerous diseases. This study elucidates the regulatory mechanism of A-to-I edited miR-1304-3p in esophageal squamous cell carcinoma (ESCC). Western blot, immunohistochemistry, and RT-qPCR assays were employed to quantify protein and mRNA expression. Colony formation, Edu, wound healing, and Transwell assays were applied to determine miRNA function. Glycolysis was assessed using glucose uptake and lactate production assay. A dual-luciferase reporter assay confirmed the downstream targets of miRNA, and a xenograft assay demonstrated the efficacy of the miRNA. The A-to-I RNA editing level of miR-1304-3p was observed to increase in KYSE180 and KYSE140 ESCC cells following ADAR1 treatment. Following A-to-I editing, the function of miR-1304-3p in ESCC progression underwent a reversal, shifting from carcinogenic to inhibitory. Wild-type (WT) miR-1304-3p targets IRS1, whereas the edited version targets ROR2. The WT miR-1304-3p, but not the edited version, suppressed the expression and tumor-suppressive effect of IRS1 in ESCC. Conversely, ROR2, a specific downstream target of the edited miR-1304-3p, acted as a tumor promoter in ESCC. Furthermore, A-to-I editing of miR-1304-3p can inhibit glycolysis and inactivate the Wnt5a/ROR2 signaling pathway in ESCC. A-to-I RNA editing alters the function of miR-1304-3p in ESCC by changing its target gene. The edited miR-1304-3p hinders the development of ESCC by inhibiting glycolysis and inactivating the Wnt5a/ROR2 signaling pathway.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":"64 3","pages":"552-564"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"mRNA m5C Alteration in Azacitidine Demethylation Treatment of Acute Myeloid Leukemia.","authors":"Ziwei Chen, Yingyu Guo, Zaifeng Zhang, Chang Li, Lili Zhang, Ye Liu, Gaoyuan Sun, Fei Xiao, Ru Feng, Chunli Zhang","doi":"10.1002/mc.23864","DOIUrl":"10.1002/mc.23864","url":null,"abstract":"<p><p>The DNA demethylating therapy with azacitidine (AZA) is a promising therapeutic strategy for elderly patients with acute myeloid leukemia (AML). AZA primarily inhibits DNA methylation, promotes cell differentiation and apoptosis in AML. However, as a cytosine nucleoside analog, AZA also has the potential to be incorporated into RNA molecules. To assess the impact of AZA on RNA m5C methylation during demethylating therapy, we conducted Nanopore direct-RNA sequencing on samples from three AML patients pre and after demethylating therapy, as well as on HL-60 cells pretreated with AZA. We performed an integrated analysis of the transcriptome and the m5C methylome, contrasting the states of complete remission with those of active disease (AML). Our results revealed an extensive demethylation effect at the RNA level attributable to AZA and found that mRNA m5C modification may play a pivotal role in the progression of AML. Additionally, S100P was identified as a biomarker with significant prognostic implications. We also conducted a conjoint analysis of the transcriptome and the m5C methylome of the full-length transcripts, uncovering several dysregulated mRNA isoforms. Collectively, our findings indicate that mRNA m5C methylation is implicated during AML progression, and AZA exhibits an overall suppressive effect on this process.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"502-512"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11814907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142838177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXM1-Cx31 Axis Drives Pancreatic Cancer Stem Cell-Like Properties and Chemoresistance.","authors":"Yang Chen, Qihui Sun, Qi Zou, Xiaoqi Zhu, Tingting Wen, Xiaojia Li, Shu Li, Jie He, Fang Wei, Keping Xie","doi":"10.1002/mc.23870","DOIUrl":"10.1002/mc.23870","url":null,"abstract":"<p><p>Pancreatic cancer is a highly lethal malignancy with few effective treatment options. Connexin 31 (Cx31) is a membrane protein capable of forming hexameric channels to facilitate the exchange of metabolites and signaling molecules. Yet, the contribution of Cx31 to the onset and progression of pancreatic cancer remains to be understood. We analyzed Cx31 expression in pancreatic cancer tissues and cell lines using public databases and experimental models. The correlation between Cx31 expression and clinical outcomes was evaluated. The effects of Cx31 on pancreatic cancer cell proliferation, stemness, migration, chemoresistance, and immune infiltration were investigated. Transcriptome analysis and bioinformatics tools were employed to explore the underlying mechanisms. Cx31 was found to be upregulated in pancreatic cancer tissues compared to normal tissues, and its high expression correlated with shorter overall survival and higher mortality risk. Cx31 promoted acinar-to-ductal metaplasia (ADM), stemness, proliferation, migration, metastasis, and chemoresistance in pancreatic cancer cells. Bioinformatics analysis suggested a positive correlation between Cx31 and stemness-related genes. Cx31 knockdown altered the expression of genes involved in stemness and chemoresistance pathways, such as Wnt and Notch. Additionally, Cx31 was identified as a direct target of the transcription factor FOXM1, which upregulated its expression. Cx31 plays a multifaceted role in pancreatic cancer, influencing processes from initiation to metastasis and chemoresistance. It may serve as a potential therapeutic target to combat the aggressive nature of pancreatic cancer. The FOXM1-Cx31 axis could be a promising target for overcoming treatment resistance in pancreatic cancer.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"565-579"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"circEIF3I Promotes Colorectal Cancer Metastasis by Regulating the miR-328-3p/NCAPH Axis.","authors":"Yali Zhao, Yan He, Zhiyuan Xiao, Le Xin, Mingjing Deng, Mingxia Yao, Guan Huang","doi":"10.1002/mc.23860","DOIUrl":"10.1002/mc.23860","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is the most common gastrointestinal malignancy, with its recurrence and metastasis significantly affecting patient survival. Circular RNAs (circRNAs), a novel class of noncoding RNAs, have emerged as crucial contributors to CRC pathogenesis. However, the role of circEIF3I in CRC metastasis remains unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to assess circEIF3I, microRNA (miR)-328-3p, and NCAPH expression. CRC cell migration and invasion were determined via Transwell assays. Western blot analysis was utilized to define the protein expression of epithelial-mesenchymal transition (EMT) markers and NCAPH. Xenograft tumor was established for exploration into the function of circEIF3I in CRC metastasis to the liver and lung. The binding between miR-328-3p and circEIF3I or NCAPH was predicted through ENCORI or TargetScan platform and ascertained through dual-luciferase reporter assays. circEIF3I and NCAPH expression were found to be elevated in CRC tissues and cells, while miR-328-3p was downregulated. Functionally, circEIF3I knockdown inhibited CRC cell migration, invasion, EMT, and tumor metastasis. Mechanistic analyses revealed that circEIF3I can target miR-328-3p, while NCAPH was targeted by miR-328-3p. Furthermore, circEIF3I facilitated NCAPH expression in CRC cells by sequestering miR-328-3p. Notably, miR-328-3p inhibitor or NCAPH overexpression negated the effects of circEIF3I knockdown on preventing CRC progression in vitro. Taken together, circEIF3I elevated NCAPH expression by sponging miR-328-3p, thereby promoting CRC metastasis. These findings suggest that the circEIF3I/miR-328-3p/NCAPH axis represents a novel therapeutic target for CRC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"450-462"},"PeriodicalIF":3.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-505-5p/-3p Regulates the Proliferation, Invasion, Apoptosis, and Temozolomide Resistance in Mesenchymal Glioma Stem Cells by Targeting AUF1.","authors":"Souichi Oe, Rio Kakizaki, Sumika Sakamoto, Teruhide Sato, Mikio Hayashi, Haruna Isozaki, Masahiro Nonaka, Hikaru Iwashita, Shinichi Hayashi, Taro Koike, Ryohei Seki-Omura, Yousuke Nakano, Yuki Sato, Yukie Hirahara, Masaaki Kitada","doi":"10.1002/mc.23842","DOIUrl":"10.1002/mc.23842","url":null,"abstract":"<p><p>Mesenchymal glioma stem cells (MES-GSCs) are a major subtype of GSCs that reside within glioma tissues and contribute to metastasis, therapy resistance, and glioma recurrence. However, the precise molecular mechanisms governing MES-GSC functions remain elusive. Our findings revealed that expression levels of miR-505-5p/-3p are elevated in MES-GSCs compared with those in proneural (PN)-GSCs, glioma cell lines, and normal brain tissue and that miR-505-5p/-3p expression levels are decreased in differentiated MES-GSCs. We assumed that miR-505-5p/-3p would play distinctive roles in MES-GSCs and performed loss-of-function experiments targeting miR-505-5p/-3p. Knockdown of miR-505-5p/-3p increased proliferation and promoted differentiation in MES-GSCs while suppressing invasion, temozolomide resistance, and enhancing apoptosis in MES-GSCs. Mechanistically, miR-505-5p/-3p directly targets the 3' UTR of AUF1, leading to its repression in MES-GSCs. Notably, AUF1 expression levels were significantly lower in MES-GSCs compared with those in PN-GSCs, glioma cell lines, and normal brain tissues. Co-inhibition of AUF1 expression with miR-505-5p/-3p knockdown ameliorated the observed cellular phenotypes caused by miR-505-5p/-3p knockdown in MES-GSCs. These results suggest that miR-505-5p/-3p exerts MES-GSC-specific roles in regulating proliferation, differentiation, invasion, apoptosis, and temozolomide resistance by repressing AUF1 expression.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"279-289"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Value of Neutrophil Extracellular Traps in Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer.","authors":"Bingqing Shang, Zhilong Hu, Ruiyang Xie, Jie Wu, Wang Qu, Wen Zhang, Aiping Zhou, Lin Feng, Xingang Bi, Jianzhong Shou","doi":"10.1002/mc.23844","DOIUrl":"10.1002/mc.23844","url":null,"abstract":"<p><p>Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC). However, the efficacy of MIBC for chemotherapy is only about 40%. Therefore, predictors of therapy response are urgently needed. Neutrophils form neutrophil extracellular traps (NETs), a network structure, and growing evidence indicated that it could be a prognostic and predictive marker in cancer. In MIBC, the predictive role of NETs in chemotherapy resistance is unclear. We used the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression analyses to develop a NETs-associated signature score (NETs-score) for therapeutic response prediction in the discovery cohort (GSE169455). Then the NETs score-based risk stratification was verified in two validation cohorts (Taber et al.'s cohort, our institutional cohort). In the training cohort, high NETs-score was associated with poor chemotherapy response (AUC = 0.781) and reduced recurrence-free survival (RFS) (hazard ratio [HR] = 2.07, 95% confidence interval [CI]: [1.26-3.40], p = 0.003) in MIBC patients. The NETs-score was also demonstrated to be a predictive factor for the efficacy of neoadjuvant chemotherapy in the validation cohort (AUC = 0.731). The accuracy of the NETs-score was superior to other chemotherapy response predictors such as Ba/Sq expression subtype (AUC = 0.711), BRCA2 mutation (AUC = 0.692) and ERCC2 mutation (AUC = 0.548). Furthermore, in our center cohort, the expression level of H3Cit showed a significant difference between the response and no-response group (p = 0.01). Through immunohistochemical validation, NETs was an independent predictor of MIBC neoadjuvant chemotherapy efficacy as determined by the multivariate logistic regression analysis (OR = 5.94, 95% CI: 1.20-45.50, p = 0.045). Patients with high levels of NETs predicted poor response to neoadjuvant chemotherapy. This study was the first to reveal the correlation between the level of NETs in MIBC and the efficacy of chemotherapy, which may provide a theoretical basis regarding NETs inhibitors.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"305-316"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Novel RUNX1::STX2 Fusion in Mixed-Phenotype Acute Leukemia (MPAL) With BCR::ABL1.","authors":"Yuan Long, Qi Xu, Jing Li, Bei-Cai Liu, Peng Cheng, Jun Luo, Shengbin Zhao, Ping Chen, Zhen-Fang Liu","doi":"10.1002/mc.23850","DOIUrl":"10.1002/mc.23850","url":null,"abstract":"<p><p>Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia (AL), MPAL with BCR::ABL1 fusion is the main subtype of MPAL, mainly affecting adult males. It is an acute leukemia with unique clinical and biological characteristics that involve both the myeloid and lymphatic systems. Gene fusion plays a crucial role in the pathogenesis, diagnosis, prognosis assessment, and treatment of leukemia. We present the first discovery of a novel fusion of RUNX1::STX2 in this subtype, which is co-expressed with BCR::ABL1 fusion. RUNX1 is a crucial transcription factor for hematopoietic differentiation, frequently found to be abnormal in AML, while STX2 may play a role in cancer progression. The RUNX1::STX2 fusion protein may act as the primary negative regulator of wild-type RUNX1, influencing normal cell differentiation and proliferation, consequently elevating the risk of leukemia. The gene fusion status of this patient is unique and complex, requiring further exploration to understand its functional significance in leukemia progression and treatment response.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"221-225"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NEK2 Promotes ESCC Malignant Progression by Inhibiting Cellular Senescence via the FOXM1/c-Myc/p27 Signaling Pathway.","authors":"Jiachen Li, Yaojie Wang, Sisi Wei, Shi Xu, Suli Dai, Li Zhang, Ziqiang Tian, Lianmei Zhao, Huilai Lv","doi":"10.1002/mc.23839","DOIUrl":"10.1002/mc.23839","url":null,"abstract":"<p><p>Never in mitosis gene A (NIMA)-related kinase 2 (NEK2) is a crucial serine-threonine kinase involved in the process of cell mitosis. However, the precise relationship between NEK2 and esophageal squamous cell carcinoma (ESCC) remains inadequately understood. NEK2 expression in ESCC tissues was assessed through bioinformatics analysis, reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry, revealing a correlation with ESCC patient prognosis. Cultured ESCC cells and human normal esophageal epithelial cells (HEEC) were used to investigate the effects of NEK2 knockdown on the development and progression of ESCC by integrated confluence algorithm, colony formation, wound-healing, transwell, and ESCC xenograft tumor model, in vitro and in vivo. In ESCC tissues, NEK2 was found to be significantly upregulated, and its expression correlated with poor prognosis in ESCC patients. NEK2 may facilitate ESCC development by regulating cell proliferation, migration, and invasion. Additionally, results from in vivo experiments suggested that NEK2 knockdown can inhibit tumor growth. Moreover, forkhead box M1 (FOXM1) was identified as a potential downstream target of NEK2 in the regulation of ESCC, with its overexpression reversing the effects of NEK2 knockdown on ESCC. Mechanistic studies also indicated that NEK2 may promote the malignant progression of ESCC by inhibiting cellular senescence through the activation of the FOXM1/c-Myc/p27 signaling pathways, which may provide a novel perspective for the management of ESCC.</p>","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"244-259"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}