Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2024-01-02 DOI:10.1186/s13058-023-01758-6
Jinqiu Tao, Cailin Xue, Meng Cao, Jiahui Ye, Yulu Sun, Hao Chen, Yinan Guan, Wenjie Zhang, Weijie Zhang, Yongzhong Yao
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Abstract

Despite radiotherapy ability to significantly improve treatment outcomes and survival in triple-negative breast cancer (TNBC) patients, acquired resistance to radiotherapy poses a serious clinical challenge. Protein disulfide isomerase exists in endoplasmic reticulum and plays an important role in promoting protein folding and post-translational modification. However, little is known about the role of protein disulfide isomerase family member 4 (PDIA4) in TNBC, especially in the context of radiotherapy resistance. We detected the presence of PDIA4 in TNBC tissues and paracancerous tissues, then examined the proliferation and apoptosis of TNBC cells with/without radiotherapy. As part of the validation process, xenograft tumor mouse model was used. Mass spectrometry and western blot analysis were used to identify PDIA4-mediated molecular signaling pathway. Based on paired clinical specimens of TNBC patients, we found that PDIA4 expression was significantly higher in tumor tissues compared to adjacent normal tissues. In vitro, PDIA4 knockdown not only increased apoptosis of tumor cells with/without radiotherapy, but also decreased the ability of proliferation. In contrast, overexpression of PDIA4 induced the opposite effects on apoptosis and proliferation. According to Co-IP/MS results, PDIA4 prevented Tax1 binding protein 1 (TAX1BP1) degradation by binding to TAX1BP1, which inhibited c-Jun N-terminal kinase (JNK) activation. Moreover, PDIA4 knockdown suppressed tumor growth xenograft model in vivo, which was accompanied by an increase in apoptosis and promoted tumor growth inhibition after radiotherapy. The results of this study indicate that PDIA4 is an oncoprotein that promotes TNBC progression, and targeted therapy may represent a new and effective anti-tumor strategy, especially for patients with radiotherapy resistance.
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蛋白二硫异构酶家族成员 4 通过 JNK 通路促进三阴性乳腺癌的肿瘤发生和放疗耐受性
尽管放疗能够明显改善三阴性乳腺癌(TNBC)患者的治疗效果和生存率,但获得性放疗耐药性却构成了严峻的临床挑战。蛋白质二硫异构酶存在于内质网中,在促进蛋白质折叠和翻译后修饰方面发挥着重要作用。然而,人们对蛋白二硫异构酶家族成员4(PDIA4)在TNBC中的作用知之甚少,尤其是在放疗耐药性方面。我们检测了 TNBC 组织和癌旁组织中 PDIA4 的存在,然后研究了接受/不接受放疗的 TNBC 细胞的增殖和凋亡情况。在验证过程中,使用了异种移植肿瘤小鼠模型。质谱分析和免疫印迹分析用于鉴定 PDIA4 介导的分子信号通路。基于TNBC患者的配对临床标本,我们发现肿瘤组织中PDIA4的表达明显高于邻近的正常组织。在体外,PDIA4基因敲除不仅能增加肿瘤细胞在放疗或非放疗情况下的凋亡,还能降低肿瘤细胞的增殖能力。相反,过表达 PDIA4 对凋亡和增殖的影响正好相反。根据Co-IP/MS结果,PDIA4通过与TAX1BP1结合阻止了TAX1结合蛋白1(TAX1BP1)的降解,从而抑制了c-Jun N-末端激酶(JNK)的激活。此外,PDIA4敲除抑制了体内肿瘤异种移植模型的生长,同时伴随着凋亡的增加,促进了放疗后肿瘤生长的抑制。该研究结果表明,PDIA4是一种促进TNBC进展的肿瘤蛋白,靶向治疗可能是一种新的有效抗肿瘤策略,尤其是对于放疗耐药的患者。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
0.00%
发文量
76
期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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