Molecular Carcinogenesis最新文献_第3页

Adipose Secreted Slit2-C Suppresses Breast Cancer Invasion Through cAMP/PKA Transition. 脂肪分泌的Slit2-C通过cAMP/PKA转换抑制乳腺癌侵袭。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-07-01 Epub Date: 2025-04-01 DOI: 10.1002/mc.23915

Haolin Hu, Kexuan Li, Lifei Han, Yangyang Gu, Zhenling Ji

{"title":"Adipose Secreted Slit2-C Suppresses Breast Cancer Invasion Through cAMP/PKA Transition.","authors":"Haolin Hu, Kexuan Li, Lifei Han, Yangyang Gu, Zhenling Ji","doi":"10.1002/mc.23915","DOIUrl":"10.1002/mc.23915","url":null,"abstract":"Adipose tissue activation plays a positive role in breast cancer outcomes, consistent with the improved outcomes observed through exercise and weight loss mediated by brown and beige fat. However, the underlying mechanism of this process remains unclear. C-terminal fragment of Slit2 (Slit2-C), endogenously produced by brown or beige adipose cells could increase the thermogenic process of adipose cells in autocrine and paracrine manners. Here, we show that Slit2-C dominantly reduces breast cancer cell invasion through cAMP/PKA mediated inhibition of epithelial-mesenchymal transition. In the process, Slit2-C plays a vital role as a positive regulator of cAMP/PKA signaling in breast cancer. As a result, the overexpression of Slit2-C leads to a reduction in cancer cell invasion and an increase in both the epithelial phenotype and thermogenesis. Besides, inhibiting PKA phosphorylation with H89 reversed the reduced invasion process seen in human breast cancer cells overexpressing Slit2-C, which suggests that the effect of Slit2-C on reducing invasion is mediated through the activation of PKA signaling. Taken together, our study suggests that the modulation of the Slit2-C/cAMP/PKA axis might be a potential targeting therapeutic intervention in aggressive breast cancers.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1149-1159"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764490","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}

引用次数: 0

Differential Response and Resistance to KRAS-Targeted Therapy. kras靶向治疗的差异反应和耐药。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-07-01 Epub Date: 2025-04-21 DOI: 10.1002/mc.23908

Zhaojin Liu, Heinz-Josef Lenz, Jian Yu, Lin Zhang

{"title":"Differential Response and Resistance to KRAS-Targeted Therapy.","authors":"Zhaojin Liu, Heinz-Josef Lenz, Jian Yu, Lin Zhang","doi":"10.1002/mc.23908","DOIUrl":"10.1002/mc.23908","url":null,"abstract":"KRAS is the most frequently mutated oncogene. In epithelial malignancies such as lung, colorectal, and pancreatic tumors, KRAS is mutated in 25 to above 90% cases. KRAS was considered undruggable for over three decades until the recent development of covalent inhibitors targeting the KRAS G12C mutant. The recent approval of the KRAS G12C inhibitors sotorasib and adagrasib has ushered in a new era of KRAS-targeted therapy. Despite this success, a major challenge in KRAS-targeted therapy is intrinsic and acquired resistance to KRAS inhibitors. Clinical studies have shown that many patients with KRAS G12C cancers did not respond to sotorasib and adagrasib. Colorectal cancer, in particular, has a markedly lower response rate to KRAS G12C inhibitors compared to non-small cell lung cancer. Furthermore, the therapeutic response to KRAS G12C inhibition was short-lived, with quick emergence of acquired resistance. In this review, we summarize several major themes that have emerged from recent clinical and preclinical studies on the mechanisms of intrinsic and acquired resistance to KRAS-targeted therapy in colorectal, lung, and pancreatic cancers. We also discuss various combination strategies for targeting these mechanisms to overcome resistance to KRAS inhibitors.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":"1135-1148"},"PeriodicalIF":3.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971770","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}

引用次数: 0

KIAA1429 and AlkB Homolog 5 Regulate Bladder Cancer Progression via N⁶-Methyladenosine-Dependent Modulation of Sonic Hedgehog Signaling. KIAA1429和AlkB同源物5通过n6 -甲基腺苷依赖的Sonic Hedgehog信号调节膀胱癌的进展。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-26 DOI: 10.1002/mc.70004

Zhimin Jiao, Xiaowu Liu, Xiaoliang Yuan, Xugang Wang, Qinyu Xu, Haoran Wu

{"title":"KIAA1429 and AlkB Homolog 5 Regulate Bladder Cancer Progression via N6-Methyladenosine-Dependent Modulation of Sonic Hedgehog Signaling.","authors":"Zhimin Jiao, Xiaowu Liu, Xiaoliang Yuan, Xugang Wang, Qinyu Xu, Haoran Wu","doi":"10.1002/mc.70004","DOIUrl":"https://doi.org/10.1002/mc.70004","url":null,"abstract":"N6-methyladenosine (m6A) modification plays a pivotal role in cancer progression, yet its regulatory mechanisms in bladder cancer (BCa) remain poorly understood. This study investigates the functions of two key m6A regulators-α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) and KIAA1429-in modulating BCa cell behavior. Expression levels of ALKBH5, KIAA1429, and Sonic Hedgehog (SHH) were examined in BCa tissues and adjacent normal tissues. Functional assays, including methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and RNA stability assessments, were performed in J82 BCa cells to explore the underlying mechanisms. Results revealed that KIAA1429 was significantly upregulated in BCa and promoted cell proliferation, migration, and invasion by enhancing m6A modification and stabilizing SHH mRNA, leading to activation of the Hedgehog signaling pathway. In contrast, ALKBH5, which was downregulated in BCa, acted as an m6A demethylase that destabilized SHH mRNA and attenuated Hedgehog pathway activity, thereby counteracting the oncogenic effects of KIAA1429. Moreover, overexpression of SHH reversed the inhibitory effects induced by KIAA1429 knockdown, confirming its role as a downstream effector. In conclusion, ALKBH5 and KIAA1429 exert opposing regulatory effects on BCa progression via m6A-mediated modulation of SHH expression and Hedgehog signaling. These findings highlight SHH mRNA methylation as a central mechanism in BCa malignancy and identify ALKBH5 and KIAA1429 as potential therapeutic targets.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497529","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}

引用次数: 0

CDKL3 Targets ATG5 to Exacerbate the Progression of Malignant Melanoma. CDKL3靶向ATG5加速恶性黑色素瘤的进展

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-26 DOI: 10.1002/mc.70002

Qi Chen, Wenyuan Yu, Yifei Gu, Shikun Cao, Xiaoming Xie, Lijun Wu

{"title":"CDKL3 Targets ATG5 to Exacerbate the Progression of Malignant Melanoma.","authors":"Qi Chen, Wenyuan Yu, Yifei Gu, Shikun Cao, Xiaoming Xie, Lijun Wu","doi":"10.1002/mc.70002","DOIUrl":"https://doi.org/10.1002/mc.70002","url":null,"abstract":"Melanoma is a type of skin cancer originating from melanocytes with a high risk of gastrointestinal tract metastasis. The abnormal expression of cyclin-dependent kinase-like 3 (CDKL3) is involved in several tumor progression. However, the role of CDKL3 in malignant melanoma has never been reported and remains unknown. In this study, the expression of CDKL3 was revealed using clinical human malignant melanoma tissues and normal skin tissues. The effects of CDKL3 on malignant melanoma cell phenotypes was evaluated in vitro and in vivo via establishing CDKL3 deficiency cell models. Our results indicated that CDKL3 was highly expressed in malignant melanoma tissues, especially in advanced malignant melanoma tissues, in comparison with normal skin tissues. Moreover, CDKL3 knockdown significantly suppressed the proliferation, migration and invasion of malignant melanoma cells, and induced cell apoptosis. The indispensable role of CDKL3 on tumorigenesis was confirmed through in vivo experiments. Finally, we showed that CDKL3 promoted malignant melanoma progression via targeting autophagy related 5 (ATG5). CDKL3 induced melanoma cell autophagy through an ATG5-dependent manner. In conclusion, these results showed the promoting role of CDKL3 in proliferation and migration of malignant melanoma cells. The CDKL3 may be a novel biomarker for malignant melanoma progression and the potential therapeutic target for patients with malignant melanoma.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497528","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}

引用次数: 0

M1 Macrophage Extracellular Vesicles and TLR3 Agonist Nanoparticles Down-Regulate Immunosuppression and Metastasis via AKT/TAM in Triple-Negative Breast Cancer. M1巨噬细胞胞外泡和TLR3激动剂纳米颗粒通过AKT/TAM下调三阴性乳腺癌的免疫抑制和转移

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-24 DOI: 10.1002/mc.70003

Shirley V de Paiva Souza, Andreza Conceição Veras Aguiar, Elizabeth Costa S de Albuquerque, Christina Eich, Luis J Cruz, Pablo Lara, Carla Jorquera-Cordero, Raelle Ferreira Gomes, Regina Célia Monteiro de Paula, Rosemayre S Freire, de Araújo Júnior Raimundo Fernandes de AraújoJúnior

{"title":"M1 Macrophage Extracellular Vesicles and TLR3 Agonist Nanoparticles Down-Regulate Immunosuppression and Metastasis via AKT/TAM in Triple-Negative Breast Cancer.","authors":"Shirley V de Paiva Souza, Andreza Conceição Veras Aguiar, Elizabeth Costa S de Albuquerque, Christina Eich, Luis J Cruz, Pablo Lara, Carla Jorquera-Cordero, Raelle Ferreira Gomes, Regina Célia Monteiro de Paula, Rosemayre S Freire, de Araújo Júnior Raimundo Fernandes de AraújoJúnior","doi":"10.1002/mc.70003","DOIUrl":"https://doi.org/10.1002/mc.70003","url":null,"abstract":"Metastasis induced by tumor immune escape has been implicated as one of the factors contributing to the aggressiveness of triple-negative breast cancer. Macrophage type 1-derived extracellular vesicles were isolated and combined with PLGA nanoparticles loaded with the TLR3 agonist poly I:C as a therapeutic strategy to investigate their antitumor activity by downregulating tumor immune escape in the tumor microenvironment (TME) of breast cancer in a murine model of orthotopic tumor growth. Tumors were evaluated by qRT-PCR and immunohistochemistry. Cellular uptake and polarization of murine macrophages (RAW 264.7 cells) were analyzed In Vitro by immunofluorescence and flow cytometry, respectively. Furthermore, mouse survival, lymph node involvement, and metastasis were also evaluated. In the animal model, the combination therapy inhibited tumor progression through TME immunomodulation, leading to a reduction in primary tumor size (p < 0.0001) and metastasis, along with an extension in survival of 11 days. Importantly, both innate and adaptive immune responses were enhanced, as indicated by increased CD8 expression (p < 0.0001) and reduced PD-L1 levels in the TME, as well as elevated CD11c expression in lymph nodes (p < 0.0001). Likewise, the combination therapy suppressed tumor progression by reducing AKT1 expression (p < 0.001) and increasing E-cadherin expression (p < 0.01). Based on these findings, the combination therapy functioned as a \"vaccine-like immunomodulatory strategy,\" promoting TME immunomodulation and suppressing metastasis in a murine model of triple-negative breast cancer.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476105","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}

引用次数: 0

Mitochondrial Energy Metabolic Reprogramming Facilitates the Malignant Progression of Intrahepatic Cholangiocarcinoma. 线粒体能量代谢重编程促进肝内胆管癌的恶性进展。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-22 DOI: 10.1002/mc.23930

Jun-Long Wang, Yu-Chen Pei, Qi-Zhi Liang, Xi Yu, Jia-Yi Cai, Nian-Dong Yi, Wei-Gen Wu, Yu-Ze Wang, Qi Liu, Wei Chen

{"title":"Mitochondrial Energy Metabolic Reprogramming Facilitates the Malignant Progression of Intrahepatic Cholangiocarcinoma.","authors":"Jun-Long Wang, Yu-Chen Pei, Qi-Zhi Liang, Xi Yu, Jia-Yi Cai, Nian-Dong Yi, Wei-Gen Wu, Yu-Ze Wang, Qi Liu, Wei Chen","doi":"10.1002/mc.23930","DOIUrl":"https://doi.org/10.1002/mc.23930","url":null,"abstract":"Mitochondrial function plays a crucial role in cancer development, with mitochondrial energy metabolism-related genes (MEMRGs) contributing to carcinogenesis. This study investigates the role of MEMRGs in intrahepatic cholangiocarcinoma (ICC) by analyzing RNA-seq data from TCGA and GEO databases to identify differentially expressed MEMRGs. Functional enrichment and KEGG pathway analyses revealed their significant involvement in metabolic pathways. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, two distinct ICC subtypes were identified. Tumor mutational burden (TMB), immune cell infiltration, and immune escape potential were assessed, highlighting the importance of the Hippo/YAP pathway. Cox regression analyses pinpointed key prognostic genes, including ADH1A, ADH1B, and CYP4A11. A MEMRG-based nomogram was developed that accurately predicted 1- and 3-year survival outcomes. Experimental validation showed that ADH1B suppresses ICC malignancy through the Hippo/YAP pathway. These findings suggest that MEMRGs are vital in ICC progression and immune regulation, serving as promising prognostic biomarkers and therapeutic targets, though further validation is required.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369089","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}

引用次数: 0

Spatial Transcriptomic Landscape of Canine Oral Squamous Cell Carcinoma. 犬口腔鳞状细胞癌的空间转录组学研究。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-17 DOI: 10.1002/mc.23932

Stephanie Goldschmidt, Clifford G Tepper, Jack Goon, Maria Soltero-Rivera, Robert Rebhun, Andrew C Birkeland, Xiao-Jing Wang, Ryan R Davis, Stephenie Y Liu, Iris Rivas, Brian Murphy, Natalis Vapniarsky

{"title":"Spatial Transcriptomic Landscape of Canine Oral Squamous Cell Carcinoma.","authors":"Stephanie Goldschmidt, Clifford G Tepper, Jack Goon, Maria Soltero-Rivera, Robert Rebhun, Andrew C Birkeland, Xiao-Jing Wang, Ryan R Davis, Stephenie Y Liu, Iris Rivas, Brian Murphy, Natalis Vapniarsky","doi":"10.1002/mc.23932","DOIUrl":"https://doi.org/10.1002/mc.23932","url":null,"abstract":"Canine oral squamous cell carcinoma (COSCC) is the second most common oral tumor in dogs and the most relevant for comparative human trials as a spontaneous large animal model of disease. Historical genomic work has focused primarily on bulk sequencing. The present study describes the complete transcriptomic landscape of COSCC with spatial distinction between the surface tumor, deep invasive tumor, peritumoral dysplastic epithelium, and tumor microenvironment compared to matched normal oral samples. Each region demonstrated distinct molecular signatures. Genes related to epithelial growth factor (EGFR) and epithelial-mesenchymal transformation (EMT) were upregulated in both peritumoral dysplasia and surface cancer. Additionally, the KRAS gene set, KRT17, and SSP1 were enriched in cancer. We identified five genes that represent dysplastic lesion with high potential for malignant transformation (FZD4, GAS1, HACD2, NOG, and SLC39A6). Also, three genes, SFRP4, FZD1, and IL34 represented a specific signature of the invasive portion of the COSCC that should be explored for prognostic value as a biomarker of malignancy. Lastly, we verified the immunomodulatory tumor microenvironment detecting an increase in macrophages and an abundance of IL-10 secretion. The other predominant leukocytes were T-cells, with CD4+ T-cells being the most prevalent. CD4+ T cells expressed transcripts for both stimulatory (Inducible T-cell Co-Stimulator (ICOS) and inhibitory molecules (CTLA4). The observed high CTLA4 suggests that this inhibitory signal may be preventing a robust antitumor immune response. Taken together, this study identified multiple targets to be explored for biomarkers of malignancy, prediction of tumor behavior, and potential targets for development of novel therapies.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317512","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}

引用次数: 0

LINC02562 Promotes Progression of Lung Cancer by Regulating NTHL1 Dependent DNA Damage Repair Mechanisms. LINC02562通过调节NTHL1依赖的DNA损伤修复机制促进肺癌进展

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-11 DOI: 10.1002/mc.23935

Limian Cao, Hui Xu, Aijie Zhang, Lei Gao, Qianru Li, Jiaqi Yan, Chencheng Feng, Min Shao, Hao Gu

{"title":"LINC02562 Promotes Progression of Lung Cancer by Regulating NTHL1 Dependent DNA Damage Repair Mechanisms.","authors":"Limian Cao, Hui Xu, Aijie Zhang, Lei Gao, Qianru Li, Jiaqi Yan, Chencheng Feng, Min Shao, Hao Gu","doi":"10.1002/mc.23935","DOIUrl":"https://doi.org/10.1002/mc.23935","url":null,"abstract":"Lung cancer poses a serious threat to public health due to its high morbidity and mortality rates. The mechanisms of lung cancer formation and progression are complex and involve regulation of various biomolecules. Long noncoding RNAs (lncRNAs) have emerged to be critical in tumorigenesis of various malignancies. In this study, we identified candidate lncRNAs associated with occurrence and development of lung cancer by analyzing the differentially expressed lncRNAs in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) cancer tissues and adjacent noncancerous tissues from UALCAN database. We found that LINC02562, which is highly expressed in LUAD and LUSC, can affect the occurrence and development of lung cancer in vivo and in vitro. Furthermore, LINC02562 competes with YBX1 to bind to the DNA repair protein NTHL1, which makes both the interaction between YBX1 and NTHL1, and the activity of NTHL1 in a balanced state, thereby promoting the progression of lung cancer. Additionally, the LINC02562/NTHL1/YBX1 axis represents a novel therapeutic target for lung cancer.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275385","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}

引用次数: 0

SPP1⁺ Venous Endothelial Cells and CRABP2⁺ Tumor Cells Contribute to Favorable Body and Tail Pancreatic Ductal Adenocarcinoma Tumor Microenvironment. SPP1+静脉内皮细胞和CRABP2+肿瘤细胞有助于机体和尾部胰腺导管腺癌肿瘤微环境的形成

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-11 DOI: 10.1002/mc.23936

Yueze Liu, Yifan Fu, Tao Liu, Jun Wang, Zeyu Zhang, Yanan Shi, Zhe Cao, Gang Yang, Hao Chen, Wenhao Luo, Jinxin Tao, Yuanyang Wang, Guihu Weng, Menggang Zhang, Liyuan Ye, Jianchun Xiao, Jiangdong Qiu, Taiping Zhang, Hua Huang

{"title":"SPP1+ Venous Endothelial Cells and CRABP2+ Tumor Cells Contribute to Favorable Body and Tail Pancreatic Ductal Adenocarcinoma Tumor Microenvironment.","authors":"Yueze Liu, Yifan Fu, Tao Liu, Jun Wang, Zeyu Zhang, Yanan Shi, Zhe Cao, Gang Yang, Hao Chen, Wenhao Luo, Jinxin Tao, Yuanyang Wang, Guihu Weng, Menggang Zhang, Liyuan Ye, Jianchun Xiao, Jiangdong Qiu, Taiping Zhang, Hua Huang","doi":"10.1002/mc.23936","DOIUrl":"https://doi.org/10.1002/mc.23936","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy; however, no validated treatments are currently available. Clinically, the tumor position, head and uncinate process (HU), or body and tail (BT) of the pancreas are vital for surgical strategies; however, fundamental research has seldom revealed the heterogeneous tumor microenvironment (TME) among different types of PDAC. Here, we applied multicohort single-cell and spatial RNA-seq methods together with patient-derived organoid models to reveal the TME heterogeneity between HU and BT PDAC. Osteopontin, encoded by SPP1, is secreted by vessel endothelial cells in BT PDAC and is associated with increased tumor burden. The number of tumor cells marked by CRABP2 was lower in BT PDAC and was identified as a prognostic marker of overall survival, as well as CD8+ T-cell infiltration. The expression of CRABP2 was also validated to be downregulated in BT PDAC in patient-derived organoid models. Overall, we profiled the heterogeneous PDAC TME between HU and BT PDAC, which could provide novel insight into the relationships between clinical characteristics and TME molecular research.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275399","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}

引用次数: 0

GRPEL2 Modulates Apoptosis in Esophageal Squamous Cell Carcinoma via the JNK Signaling Pathway. GRPEL2通过JNK信号通路调控食管鳞状细胞癌的凋亡。

IF 3 2区医学

Molecular Carcinogenesis Pub Date : 2025-06-11 DOI: 10.1002/mc.23934

Lu Wen, Jiyu Pang, Jiaxin Yao, Rendan Zhang, Chunyan Zhao, Jiancai Tang, Chenwu Yang, Qin Liu, Jinyue Ma, Min Zhang, Bo Mu

{"title":"GRPEL2 Modulates Apoptosis in Esophageal Squamous Cell Carcinoma via the JNK Signaling Pathway.","authors":"Lu Wen, Jiyu Pang, Jiaxin Yao, Rendan Zhang, Chunyan Zhao, Jiancai Tang, Chenwu Yang, Qin Liu, Jinyue Ma, Min Zhang, Bo Mu","doi":"10.1002/mc.23934","DOIUrl":"https://doi.org/10.1002/mc.23934","url":null,"abstract":"Esophageal squamous cell carcinoma (ESCC) is a common malignancy worldwide with a low survival rate due to a lack of therapeutic targets. Here we found that the mitochondria-related gene GrpE-like 2 (GRPEL2) transcript levels are significantly upregulated in ESCC patient samples, and its high expression predicts poor prognosis. Knockdown of GRPEL2 aggravated suppressed cell proliferation and colony formation. Conversely, overexpression of GRPEL2 promotes ESCC cell proliferation both In Vitro and In Vivo. We delved deeper into the effects of GRPEL2 on mitochondrial function and found that the depletion of GRPEL2 induced mitochondrial dysfunction and cellular apoptosis. Mechanistically, our RNA-Seq analysis revealed that suppression of GRPEL2 expression triggers activation of the MAPK/JNK signaling pathway. Additionally, the apoptosis induced by GRPEL2 loss can be largely reversed by treatment with SP600125, a JNK inhibitor. To further enhance the feasibility of targeting GRPEL2 for inhibiting ESCC proliferation in practical applications, we conducted computer-based drug screening to identify potential GRPEL2 inhibitors. We identified Vandetanib, a known antitumor agent, as a promising molecule that not only exhibits robust binding activity but also effectively reduces GRPEL2 protein levels. In conclusion, the data presented herein implicate GRPEL2 as a pivotal regulator in ESCC, modulating the MAPK/JNK signaling cascade to potentiate apoptosis, thereby offering a specific therapeutic vulnerability for targeting ESCC.","PeriodicalId":19003,"journal":{"name":"Molecular Carcinogenesis","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275384","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}

引用次数: 0