{"title":"靶向MTPN使野生型BRCA1/2胰腺癌对顺铂化疗增敏。","authors":"Zhuoxin Wang, Xinyang Huang, Tingting Bai, Yixun Jin, Tingting Gong, Wei Wu, Berik Kouken, Qi Wang, Lifu Wang","doi":"10.1038/s41417-025-00925-5","DOIUrl":null,"url":null,"abstract":"<p><p>The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.</p>","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy.\",\"authors\":\"Zhuoxin Wang, Xinyang Huang, Tingting Bai, Yixun Jin, Tingting Gong, Wei Wu, Berik Kouken, Qi Wang, Lifu Wang\",\"doi\":\"10.1038/s41417-025-00925-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.</p>\",\"PeriodicalId\":9577,\"journal\":{\"name\":\"Cancer gene therapy\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer gene therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41417-025-00925-5\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer gene therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41417-025-00925-5","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
对于野生型BRCA1/2或PALB2的大多数胰腺癌患者，由于耐药，联合顺铂化疗的临床应用并不理想。在没有BRCA1/2或PALB2突变的患者中，与顺铂耐药相关的基因应该被追踪。通过生物信息学分析，我们发现肌营养因子（MTPN）的表达与参与顺铂敏感性调节的核因子κB （NF-κB）的表达相关。免疫组化显示MTPN在人胰腺癌组织中的表达高于正常组织。MTPN促进胰腺癌细胞的恶性生物学行为，激活上皮-间质转化过程。此外，MTPN在PC细胞中诱导顺铂耐药，上调BRCA1/2，同时促进DNA修复。MTPN对顺铂耐药和BRCA1/2上调的增强作用被i - κ b α磷酸化抑制剂所消除。这些研究提示MTPN可能通过激活IκBα调控BRCA1/2表达而增加顺铂耐药。总之，靶向MTPN可能是一种潜在的治疗策略，因为MTPN敲除增加了野生型BRCA1/2胰腺癌患者对顺铂化疗的敏感性。
Targeting MTPN sensitizes pancreatic cancer of wild-type BRCA1/2 to Cisplatin-based chemotherapy.
The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.
期刊介绍：
Cancer Gene Therapy is the essential gene and cellular therapy resource for cancer researchers and clinicians, keeping readers up to date with the latest developments in gene and cellular therapies for cancer. The journal publishes original laboratory and clinical research papers, case reports and review articles. Publication topics include RNAi approaches, drug resistance, hematopoietic progenitor cell gene transfer, cancer stem cells, cellular therapies, homologous recombination, ribozyme technology, antisense technology, tumor immunotherapy and tumor suppressors, translational research, cancer therapy, gene delivery systems (viral and non-viral), anti-gene therapy (antisense, siRNA & ribozymes), apoptosis; mechanisms and therapies, vaccine development, immunology and immunotherapy, DNA synthesis and repair.
Cancer Gene Therapy publishes the results of laboratory investigations, preclinical studies, and clinical trials in the field of gene transfer/gene therapy and cellular therapies as applied to cancer research. Types of articles published include original research articles; case reports; brief communications; review articles in the main fields of drug resistance/sensitivity, gene therapy, cellular therapy, tumor suppressor and anti-oncogene therapy, cytokine/tumor immunotherapy, etc.; industry perspectives; and letters to the editor.
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