{"title":"RAN通过调节Wnt/PCP通路促进多发性骨髓瘤患者硼替佐米耐药。","authors":"Linmeng Li, Lu Xu","doi":"10.4149/neo_2025_250207N65","DOIUrl":null,"url":null,"abstract":"<p><p>Previous studies have shown that Ras-Related Nuclear Protein (RAN), a member of the RAS superfamily, is a small GTPase and an important oncogene in several cancers. However, its role in multiple myeloma (MM) and its potential contribution to drug resistance remain undetermined. Bioinformatics was employed to analyze differentially expressed genes in MM samples. RT-qPCR and western blotting were utilized for protein transcription and expression analysis. The CCK-8 assay was adopted to evaluate cell proliferation, and in vivo animal experiments were conducted to validate the results. The findings reveal that RAN represents one of the most significantly aberrant genes in MM, with its expression significantly elevated in both MM tissues and cells. Genetic manipulation experiments demonstrated that RAN promotes MM cell proliferation by activating the Wnt/PCP pathway. Concurrently, RAN governs the response of MM cells to the anti-cancer drug bortezomib (BTZ). Knockdown of RAN leads to increased sensitivity to BTZ. Mechanistic studies indicate that RAN influences drug response by regulating the activation of the JNK/c-Jun axis, thereby affecting the therapeutic response of MM cells. In summary, the upregulated expression of RAN in MM leads to BTZ resistance via activation of the Wnt/PCP pathway, potentially serving as a novel therapeutic target for MM.</p>","PeriodicalId":19266,"journal":{"name":"Neoplasma","volume":"72 3","pages":"153-163"},"PeriodicalIF":2.2000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RAN contributes to bortezomib resistance in multiple myeloma via regulating the Wnt/PCP pathway.\",\"authors\":\"Linmeng Li, Lu Xu\",\"doi\":\"10.4149/neo_2025_250207N65\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Previous studies have shown that Ras-Related Nuclear Protein (RAN), a member of the RAS superfamily, is a small GTPase and an important oncogene in several cancers. However, its role in multiple myeloma (MM) and its potential contribution to drug resistance remain undetermined. Bioinformatics was employed to analyze differentially expressed genes in MM samples. RT-qPCR and western blotting were utilized for protein transcription and expression analysis. The CCK-8 assay was adopted to evaluate cell proliferation, and in vivo animal experiments were conducted to validate the results. The findings reveal that RAN represents one of the most significantly aberrant genes in MM, with its expression significantly elevated in both MM tissues and cells. Genetic manipulation experiments demonstrated that RAN promotes MM cell proliferation by activating the Wnt/PCP pathway. Concurrently, RAN governs the response of MM cells to the anti-cancer drug bortezomib (BTZ). Knockdown of RAN leads to increased sensitivity to BTZ. Mechanistic studies indicate that RAN influences drug response by regulating the activation of the JNK/c-Jun axis, thereby affecting the therapeutic response of MM cells. In summary, the upregulated expression of RAN in MM leads to BTZ resistance via activation of the Wnt/PCP pathway, potentially serving as a novel therapeutic target for MM.</p>\",\"PeriodicalId\":19266,\"journal\":{\"name\":\"Neoplasma\",\"volume\":\"72 3\",\"pages\":\"153-163\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neoplasma\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.4149/neo_2025_250207N65\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neoplasma","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4149/neo_2025_250207N65","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
先前的研究表明RAS相关核蛋白(RAS - related Nuclear Protein, RAN)是RAS超家族成员,是一种小的GTPase,是多种癌症的重要致癌基因。然而,其在多发性骨髓瘤(MM)中的作用及其对耐药性的潜在贡献仍未确定。采用生物信息学方法分析MM样品中的差异表达基因。利用RT-qPCR和western blotting对蛋白进行转录和表达分析。采用CCK-8法评价细胞增殖,并进行动物体内实验验证结果。结果表明,RAN是MM中最显著的异常基因之一,其在MM组织和细胞中的表达均显著升高。基因操作实验表明,RAN通过激活Wnt/PCP通路促进MM细胞增殖。同时,RAN控制MM细胞对抗癌药物硼替佐米(BTZ)的反应。RAN的敲除导致对BTZ的敏感性增加。机制研究表明,RAN通过调节JNK/c-Jun轴的激活来影响药物反应,从而影响MM细胞的治疗反应。综上所述,RAN在MM中的表达上调通过激活Wnt/PCP通路导致BTZ耐药,可能成为MM的新治疗靶点。
RAN contributes to bortezomib resistance in multiple myeloma via regulating the Wnt/PCP pathway.
Previous studies have shown that Ras-Related Nuclear Protein (RAN), a member of the RAS superfamily, is a small GTPase and an important oncogene in several cancers. However, its role in multiple myeloma (MM) and its potential contribution to drug resistance remain undetermined. Bioinformatics was employed to analyze differentially expressed genes in MM samples. RT-qPCR and western blotting were utilized for protein transcription and expression analysis. The CCK-8 assay was adopted to evaluate cell proliferation, and in vivo animal experiments were conducted to validate the results. The findings reveal that RAN represents one of the most significantly aberrant genes in MM, with its expression significantly elevated in both MM tissues and cells. Genetic manipulation experiments demonstrated that RAN promotes MM cell proliferation by activating the Wnt/PCP pathway. Concurrently, RAN governs the response of MM cells to the anti-cancer drug bortezomib (BTZ). Knockdown of RAN leads to increased sensitivity to BTZ. Mechanistic studies indicate that RAN influences drug response by regulating the activation of the JNK/c-Jun axis, thereby affecting the therapeutic response of MM cells. In summary, the upregulated expression of RAN in MM leads to BTZ resistance via activation of the Wnt/PCP pathway, potentially serving as a novel therapeutic target for MM.