Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy.
Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy.
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DOI：
10.1016/j.ebiom.2021.103560
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发表时间：
2021-09
期刊：
影响因子：
11.1
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Sha R;Xu Y;Yuan C;Sheng X;Wu Z;Peng J;Wang Y;Lin Y;Zhou L;Xu S;Zhang J;Yin W;Lu J
最近的证据表明，诱导铁凋亡可能会提高肿瘤治疗的疗效。然而，在乳腺癌患者中，特别是在新辅助治疗中，铁蛋白沉积相关基因的研究很少。ACSL 4和GPX 4已分别被确定为铁凋亡的正调节剂和负调节剂。本研究旨在探讨ACSL 4和GPX 4对乳腺癌患者接受新辅助化疗的预测价值。本研究纳入了接受基于紫杉醇-顺铂的新辅助化疗的患者。对空芯针活检标本进行ACSL 4和GPX 4免疫组化染色。进行Logistic回归以探索病理完全缓解（pCR）的预测生物标志物。生存分析采用对数秩检验和考克斯比例风险回归。共纳入199例患者进行分析。ACSL 4表达和ACSL 4/GPX 4联合状态可作为pCR的独立预测因素。ACSL 4与肿瘤临床分期之间存在pCR的相互作用。此外，ACSL 4表达、GPX 4表达及其联合状态是无病生存的独立预后因素。Kaplan-Meier Plotter数据库的分析表明，ACSL 4表达越高，总生存率越高，GPX 4表达越高，无远处转移生存率越高。通路分析显示，ACSL 4和GPX 4可能在细胞凋亡、自噬、细胞粘附、脂质代谢等关键通路中发挥作用。本研究揭示了ACSL 4和GPX 4作为新辅助化疗乳腺癌患者新的预测和预后生物标志物的临界值。这可能是一个新的策略，诱导铁凋亡，以提高化疗敏感性。需要进一步的研究来阐明潜在的机制。本工作得到了上海市自然科学基金[批准号19 ZR 1431100]、上海市医院发展中心临床研究计划[批准号SHDC 2020 CR 3003 A、16 CR 3065 B、12016231]、上海市“医学人才新星”青年医学人才培养计划-专科项目[批准号2018-15]的资助，上海市“医学人才新星”杰出青年医学人才培养计划[批准号2018-16]、上海市转化医学协同创新中心[批准号TM 201908]、上海交通大学多学科交叉研究基金[批准号YG 2017 QN 49、ZH 2018 QNA 42、YG 2019 QNA 28]、仁济医院培育基金[资助号PYMDT-002、PY 2018-IIC-01、PY 2018-III-15、PYIII 20 -09]、上海市科委[资助号20 DZ 2201600、15 JC 1402700]、上海市临床重点专科。
Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy. This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression. A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc. This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms. This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shanghai Municipal Key Clinical Specialty.
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影响因子：
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