丙二酰辅酶A脱羧酶调控卵巢癌铂类耐药的机制及其临床应用价值

doi:10.3969/j.issn.1004-616x.2025.03.008

癌变·畸变·突变 ›› 2025, Vol. 37 ›› Issue (3): 221-227,247.doi: 10.3969/j.issn.1004-616x.2025.03.008

• 论著 • 上一篇

丙二酰辅酶A脱羧酶调控卵巢癌铂类耐药的机制及其临床应用价值

郑瑞淇¹, 胡洵¹, 崔潆², 郭会芹², 肖汀¹

1. 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院, 分子肿瘤学全国重点实验室, 病因及癌变研究室, 北京 100021;
2. 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院, 病理科, 北京 100021

收稿日期:2025-03-29 修回日期:2025-04-17 发布日期:2025-06-13
通讯作者: 肖汀
作者简介:郑瑞淇，E-mail：zrq3171401118@163.com。
基金资助:
国家重点研发计划(2022YFE0103600)；中国医学科学院临床与转化医学研究基金(2022-I2M-C&T-B-082)

Mechanism of malonyl-CoA decarboxylase regulating platinum resistance in ovarian cancer and its clinical application

ZHENG Ruiqi¹, HU Xun¹, CUI Ying², GUO Huiqin², XIAO Ting¹

1. Department of Etiology and Carcinogenesis, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021;
2. Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

Received:2025-03-29 Revised:2025-04-17 Published:2025-06-13

摘要/Abstract

摘要： 目的：探讨丙二酰辅酶A脱羧酶(MLYCD)在调控卵巢癌铂类耐药的机制及其临床应用价值。方法：采用卵巢癌组织芯片进行免疫组织化学染色验证不同铂敏感性患者的 MLYCD 表达水平。利用临床蛋白质组肿瘤分析联盟(CPTAC)和癌症基因组图谱(TCGA)数据库，探讨在不同铂敏感性卵巢癌患者中MLYCD蛋白和mRNA的表达水平及其与临床特征的关系，使用pRRophetic算法评估样本对顺铂的敏感性。选取与 MLYCD 表达显著相关的蛋白构建蛋白相互作用网络，用 GEPIA2 数据库检索转录水平上与MLYCD相关的基因，并使用京都基因与基因组百科全书和基因本体方法富集相关的信号通路。采用免疫浸润分析Estimate算法、肿瘤免疫功能障碍和排斥(TIDE)以及免疫表型评分(IPS)评估患者肿瘤组织的免疫浸润状况。使用Western blot验证铂类敏感/耐药卵巢癌细胞株中MLYCD蛋白的表达情况。结果：组织芯片免疫组织化学染色结果及CPTAC数据显示，铂类耐药患者中MLYCD表达水平较铂敏感者升高，并且随肿瘤分期亚阶段(P=0.046)的进展呈上升趋势。CPTAC和TCGA数据库分析结果均表明，MLYCD表达与顺铂耐药性呈正相关(r>0.3，P<0.05)。此外，MLYCD及其相互作用蛋白主要参与促进脂质分解代谢的代谢重编程。Estimate、TIDE和IPS评分显示，相较于低表达组，MLYCD高表达组的卵巢癌组织中，功能障碍性免疫细胞的浸润程度更高，抗肿瘤活性更低。Western blot实验结果显示铂耐药卵巢癌细胞株中MLYCD表达的显著升高(P<0.05)。结论：MLYCD在卵巢癌耐药组织中高表达，且其参与了脂质分解代谢重编程为卵巢癌细胞提供能量。MLYCD可作为卵巢癌铂类耐药标志物和潜在治疗靶点。

关键词: 卵巢癌, 铂类耐药, 丙二酰辅酶A脱羧酶, 免疫微环境

Abstract: OBJECTIVE： To investigate the mechanisms by which malonyl-CoA decarboxylase (MLYCD) regulates platinum resistance in ovarian cancer and its clinical application value. METHODS： Immunohistochemical staining (IHC) was performed on ovarian cancer tissue microarrays to validate MLYCD expression levels in patients with varying platinum sensitivities. Using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and The Cancer Genome Atlas (TCGA) databases， protein and mRNA expression levels of MLYCD among these patients were evaluated and their association with clinical characteristics was examined. The pRRophetic algorithm was used to evaluate sensitivity of the samples to cisplatin. Proteins significantly correlated with MLYCD expression were selected to construct a protein-protein interaction (PPI) network，and the GEPIA2 database was used to retrieve MLYCD-related genes at the transcriptome level. Related signaling pathways were enriched using the KEGG and GO methods. The immune infiltration status of patients' tumor tissues was evaluated using the Estimate algorithm，tumor immune dysfunction and exclusion (TIDE) score，and Immunophenoscore (IPS). Western blot (WB) was used to validate the expression of MLYCD protein in cisplatin-sensitive/resistant ovarian cancer cell lines. RESULTS： The tissue microarray IHC results， together with CPTAC data， showed that MLYCD expression was higher in platinum-resistant patients than in platinum-sensitive patients and exhibited an increasing trend with tumor substage progression (P=0.046). Both CPTAC and TCGA data indicated that MLYCD expression was positively correlated with cisplatin resistance (r> 0.3， P<0.05). Furthermore， MLYCD and its interacting proteins were mainly involved in metabolic reprogramming that promoted lipid catabolism. The Estimate，TIDE，and IPS scores indicated that，compared to the low-expression group， ovarian tumors with high MLYCD expression harbored greater infiltration of dysfunctional immune cells and exhibited reduced antitumor activity. Western blot experiments further confirmed a significant increase in MLYCD expression in platinum-resistant ovarian cancer cell lines (P<0.05). CONCLUSION： MLYCD was highly expressed in platinum-resistant ovarian cancer tissues and participated in metabolic reprogramming toward lipid catabolism to supply energy for ovarian cancer cells. Thus，MLYCD may serve as a biomarker for platinum resistance and a potential therapeutic target in ovarian cancer.

Key words: ovary neoplasms, platinum resistance, malonyl-CoA decarboxylase, immune microenvironment

中图分类号:

R737.31

郑瑞淇, 胡洵, 崔潆, 郭会芹, 肖汀. 丙二酰辅酶A脱羧酶调控卵巢癌铂类耐药的机制及其临床应用价值[J]. 癌变·畸变·突变, 2025, 37(3): 221-227,247.

ZHENG Ruiqi, HU Xun, CUI Ying, GUO Huiqin, XIAO Ting. Mechanism of malonyl-CoA decarboxylase regulating platinum resistance in ovarian cancer and its clinical application[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2025, 37(3): 221-227,247.

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丙二酰辅酶A脱羧酶调控卵巢癌铂类耐药的机制及其临床应用价值

Mechanism of malonyl-CoA decarboxylase regulating platinum resistance in ovarian cancer and its clinical application

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