Targeted inhibition of Ninjurin2 promotes chemosensitivity in chemoresistant gastric cancer by suppressing cancer-initiating cells.

IF 9.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomarker Research Pub Date : 2025-06-15 DOI:10.1186/s40364-025-00792-0

Hyo Shik Shin, Jae-Il Choi, Hye Won Chung, Hee Jung Park, Hak Park, John Hoon Rim, Jong-Baeck Lim

{"title":"Targeted inhibition of Ninjurin2 promotes chemosensitivity in chemoresistant gastric cancer by suppressing cancer-initiating cells.","authors":"Hyo Shik Shin, Jae-Il Choi, Hye Won Chung, Hee Jung Park, Hak Park, John Hoon Rim, Jong-Baeck Lim","doi":"10.1186/s40364-025-00792-0","DOIUrl":null,"url":null,"abstract":"Background: The combination of epirubicin, cisplatin, and 5-fluorouracil (ECF) is widely used for gastric cancer treatment. However, cancer cells can acquire chemoresistance over multiple treatment cycles, leading to recurrence. This study aimed to investigate a novel biomarker for predicting ECF resistance and its biological roles in gastric cancer.Methods: ECF-resistant (ECF-R) gastric cancer cell lines were established through stepwise ECF treatment. Transcriptome analysis was performed to identify resistance-related genes, which were validated in tumor organoids and in vivo models. Additionally, gastric cancer patient tumor tissues were analyzed for clinical relevance.Results: Transcriptome analysis revealed that NINJURIN2 and CD44 were highly expressed in ECF-R cells but rarely expressed in normal gastric tissues. NINJURIN2 inhibition significantly increased chemosensitivity to ECF in vitro and in vivo. Liquid chromatography-tandem mass spectrometry identified periostin as a binding partner of NINJURIN2, mediating chemoresistance. Furthermore, VAV2 phosphorylation was markedly upregulated in ECF-R cells but was inhibited by NINJURIN2 knockdown. Clinical analysis showed that high NINJURIN2 expression correlated with poor survival outcomes in gastric cancer patients.Conclusion: Our findings suggest that NINJURIN2 can be used as a novel biomarker for chemoresistant gastric cancer patients and that inhibiting NINJURIN2 along with standard chemotherapy could prevent chemoresistance-associated relapse in gastric cancer.","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"13 1","pages":"84"},"PeriodicalIF":9.5000,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12168268/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomarker Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40364-025-00792-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: The combination of epirubicin, cisplatin, and 5-fluorouracil (ECF) is widely used for gastric cancer treatment. However, cancer cells can acquire chemoresistance over multiple treatment cycles, leading to recurrence. This study aimed to investigate a novel biomarker for predicting ECF resistance and its biological roles in gastric cancer.

Methods: ECF-resistant (ECF-R) gastric cancer cell lines were established through stepwise ECF treatment. Transcriptome analysis was performed to identify resistance-related genes, which were validated in tumor organoids and in vivo models. Additionally, gastric cancer patient tumor tissues were analyzed for clinical relevance.

Results: Transcriptome analysis revealed that NINJURIN2 and CD44 were highly expressed in ECF-R cells but rarely expressed in normal gastric tissues. NINJURIN2 inhibition significantly increased chemosensitivity to ECF in vitro and in vivo. Liquid chromatography-tandem mass spectrometry identified periostin as a binding partner of NINJURIN2, mediating chemoresistance. Furthermore, VAV2 phosphorylation was markedly upregulated in ECF-R cells but was inhibited by NINJURIN2 knockdown. Clinical analysis showed that high NINJURIN2 expression correlated with poor survival outcomes in gastric cancer patients.

Conclusion: Our findings suggest that NINJURIN2 can be used as a novel biomarker for chemoresistant gastric cancer patients and that inhibiting NINJURIN2 along with standard chemotherapy could prevent chemoresistance-associated relapse in gastric cancer.

查看原文本刊更多论文

靶向抑制ninurin2通过抑制癌起始细胞促进化疗耐药胃癌的化疗敏感性。

背景：表柔比星、顺铂、5-氟尿嘧啶（ECF）联合应用于胃癌的治疗已被广泛应用。然而，癌细胞可以在多个治疗周期中获得化疗耐药，从而导致复发。本研究旨在探讨一种新的预测ECF耐药的生物标志物及其在胃癌中的生物学作用。方法：通过逐步培养ECF耐药胃癌细胞系。转录组分析鉴定了耐药性相关基因，并在肿瘤类器官和体内模型中得到了验证。此外，对胃癌患者肿瘤组织进行临床相关性分析。结果：转录组分析显示，NINJURIN2和CD44在ECF-R细胞中高表达，而在正常胃组织中很少表达。抑制ninurin2显著增加体外和体内对ECF的化学敏感性。液相色谱-串联质谱分析发现，periostin是ninurin2的结合伙伴，介导耐药。此外，VAV2磷酸化在ECF-R细胞中显著上调，但被NINJURIN2敲除抑制。临床分析显示，ninurin2高表达与胃癌患者生存预后差相关。结论：我们的研究结果表明，NINJURIN2可以作为胃癌化疗耐药患者的一种新的生物标志物，在标准化疗的同时抑制NINJURIN2可以预防胃癌化疗耐药相关复发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

15.80

自引率

1.80%

发文量

审稿时长

10 weeks

期刊介绍： Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.