精氨酸琥珀酸合成酶（ASS1）作为新型乳腺癌分子分型标记物及乳腺癌个体化治疗新靶点的研究
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摘要
乳腺癌的发病率和死亡率在女性患者中均高居首位。乳腺癌本身的异质性很强,如何甄别不同的乳腺癌亚型,并给予相应的个体化治疗是目前乳腺癌治疗的研究热点。临床上常根据ER/PR、HER-2、Ki-67免疫组化结果将乳腺癌分成Luminal A、Luminal B、三阴性及HER-2阳性4种亚型来指导治疗,但这4种亚型分类对于高异质性的乳腺癌不够完善。大量研究资料证实肿瘤细胞进行代谢重编程,使其自身在能量代谢、氨基酸代谢等方面具备一些独有的特点,因此通过剥夺特定氨基酸来杀伤肿瘤细胞正成为肿瘤代谢治疗的新研究领域。精氨酸是一种半必需氨基酸,精氨酸琥珀酸合成酶(Argininosaccinate Synthase1, ASS1)是其合成的关键限速酶。研究表明一些肿瘤组织中不表达ASS1,意味着这些肿瘤细胞自身不能合成精氨酸而必须依赖血清中的精氨酸,这称为精氨酸营养缺陷。目前研究人员常利用聚乙二醇化精氨酸脱亚胺酶(Pegylated Arginine Deiminase, ADI-PEG20)将精氨酸转换为瓜氨酸以实现精氨酸剥夺,并有研究资料证实ADI-PEG20可杀伤肝细胞癌、恶性黑色素瘤等多种肿瘤,但在乳腺癌中尚未见系统研究。
本论文中,我们利用组织芯片检测149名临床乳腺癌患者,证实63.8%(95/149)患者的乳腺癌组织为ASS1低表达；进一步结合患者临床随访资料,利用Kaplan-Meier分析显示,ASS1低表达与乳腺癌的总生存率低、无病生存率低相关。此外,采用COX多因素分析以排除混杂因素干扰,分析结果提示ASS1是乳腺癌总生存率、无病生存率的独立预后因素,且ASS1的预后指示作用与常用的分子分型标记无关,提示可作为乳腺癌分子分型的候选新标记。
在此基础上,我们探索了精氨酸治疗在乳腺癌个体化治疗中的潜在作用和意义。首先,我们检测了不同ASS1表达水平的乳腺癌细胞对ADI-PEG20的敏感性,体内外结果提示ADI-PEG20可杀伤ASS1低表达乳腺癌细胞；其次,进一步利用基因干扰技术证实ASS1可以作为精氨酸剥夺疗效的预测标记,并发现ASS1是乳腺癌潜在的肿瘤抑制基因。此外,我们对精氨酸剥夺治疗杀伤乳腺癌细胞的机制进行了研究,实验结表明：精氨酸剥夺对细胞凋亡影响较小,但精氨酸剥夺能显著抑制细胞ATP的产生及线粒体氧化磷酸化,诱导细胞内尤其是线粒体内ROS增多,进而降低线粒体膜电位,使线粒体功能受损害。为维持线粒体稳态,细胞在精氨酸剥夺时启动细胞自噬机制,选择性清除功能受损的线粒体,最终可出现致死性的导致线粒体自噬。
本课题首次发现ASS1是乳腺癌独立预后标记,其预后预测作用独立于常用的分子分型标记,可作为一个新的候选分子分型标记；进一步创新性地将精氨酸剥夺引入乳腺癌的个体化治疗,体内外实验研究表明精氨酸剥夺可用于ASS1低表达乳腺癌亚型的个体化治疗,并发现精氨酸剥夺可引起致死性的线粒体自噬。本论文的研究成果为揭示ASS1在乳腺癌预后及个体化治疗中的作用与意义、明确精氨酸剥夺杀伤乳腺癌的内在机制提供了重要的理论和实验依据。
Breast cancer is the most common malignant tumor and the leading cause of death in female. In clinics, breast cancer is classified into four subtypes including Luminal A, Luminal B, Triple negative and Her-2positive according to the expression status of ER, PR, Ki-67and Her-2protein in tumor tissues. This classification is useful for making treatment plans for patients, but it is obviously defective due to the high heterogeneity of breast cancer. Abundant evidence has shown that tumor tissues have unique metabolic features different from normal tissues, which has provided potential tumor-specific therapeutic targets for the treatment of cancer. For instance, arginine is a non-essential amino acid and Argininosaccinate Synthase1(ASS1) is the key rate-limiting enzyme in arginine synthesis. While normal tissues commonly express high level of ASS1, some tumors such as hepatic carcinoma and melanoma have arginine auxotrophy due to deficiency of ASS1. As a result, arginine deprivation through pegylated arginine deiminase (ADI-PEG20) which converting arginine to itrulline has been proven to be effective for the treatment of tumors with arginine auxotrophy. However, no related reports are available for breast cancer.
In this thesis, using breast cancer multiple tissue array assay, we found that63.75%(95/149) of breast tumors enrolled in this study were ASS1low-expressing. Subsequent Kaplan-Meier analysis demonstrated that low expression level of ASS1was associated with poor overall survival and poor disease-free survival. Further COX multivariate analysis indicated that ASS1was an independant indicator for overall survival and disease-free survival, and the predictive role of ASS1was independent of other known biomarkers such as ER, PR, Ki-67and Her-2, suggesting that ASS1may serve as a new biomarker for breast cancer molecular classification.
Moreover, we investigated whether arginine deprivation was efficacious for the treatment of breast cancer. The obtained data demonstrated that ADI-PEG20significantly inhibited the growth of ASS1low-expressing bresat cancer cells in vitro and in vivo, while had little impact on ASS1high-expressing breast cancer cells, indicating that ASS1might be a useful therapeutic target for breast cancer personalized medicine. Further molecular studies demonstrated that arginine deprivatin had little influence on the induction of apoptosis, but dramatically inhibited ATP production and mitochondrial oxidative phosphorylation (OXPHOS). Subsequently, ROS (especially mitochondria ROS) production was significantly increased and the mitochondria membrane potential (MMP) was lowered. Due to these massive mitochondria dysfunctions, arginine deprivation ultimately caused lethal mitophagy in order to selectively remove damaged mitochondria and maintain mitochondrial homeostasis.
In summary, for the first time, this study demonstrated that ASS1holds the promise to become an independent factor for prognosis prediction and a candidate novel biomarker for classification in breast cancer. Arginine deprivation may be adopted for personerlized medicine of breast cancer, e.g. for the treatment of ASS1low-expression breast tumors. We also demonstrated that arginine deprivation could induce lethal mitophagy, which may play critical role in arginine deprivation-mediated breast cancer cell death.
本论文中,我们利用组织芯片检测149名临床乳腺癌患者,证实63.8%(95/149)患者的乳腺癌组织为ASS1低表达；进一步结合患者临床随访资料,利用Kaplan-Meier分析显示,ASS1低表达与乳腺癌的总生存率低、无病生存率低相关。此外,采用COX多因素分析以排除混杂因素干扰,分析结果提示ASS1是乳腺癌总生存率、无病生存率的独立预后因素,且ASS1的预后指示作用与常用的分子分型标记无关,提示可作为乳腺癌分子分型的候选新标记。
在此基础上,我们探索了精氨酸治疗在乳腺癌个体化治疗中的潜在作用和意义。首先,我们检测了不同ASS1表达水平的乳腺癌细胞对ADI-PEG20的敏感性,体内外结果提示ADI-PEG20可杀伤ASS1低表达乳腺癌细胞；其次,进一步利用基因干扰技术证实ASS1可以作为精氨酸剥夺疗效的预测标记,并发现ASS1是乳腺癌潜在的肿瘤抑制基因。此外,我们对精氨酸剥夺治疗杀伤乳腺癌细胞的机制进行了研究,实验结表明：精氨酸剥夺对细胞凋亡影响较小,但精氨酸剥夺能显著抑制细胞ATP的产生及线粒体氧化磷酸化,诱导细胞内尤其是线粒体内ROS增多,进而降低线粒体膜电位,使线粒体功能受损害。为维持线粒体稳态,细胞在精氨酸剥夺时启动细胞自噬机制,选择性清除功能受损的线粒体,最终可出现致死性的导致线粒体自噬。
本课题首次发现ASS1是乳腺癌独立预后标记,其预后预测作用独立于常用的分子分型标记,可作为一个新的候选分子分型标记；进一步创新性地将精氨酸剥夺引入乳腺癌的个体化治疗,体内外实验研究表明精氨酸剥夺可用于ASS1低表达乳腺癌亚型的个体化治疗,并发现精氨酸剥夺可引起致死性的线粒体自噬。本论文的研究成果为揭示ASS1在乳腺癌预后及个体化治疗中的作用与意义、明确精氨酸剥夺杀伤乳腺癌的内在机制提供了重要的理论和实验依据。
Breast cancer is the most common malignant tumor and the leading cause of death in female. In clinics, breast cancer is classified into four subtypes including Luminal A, Luminal B, Triple negative and Her-2positive according to the expression status of ER, PR, Ki-67and Her-2protein in tumor tissues. This classification is useful for making treatment plans for patients, but it is obviously defective due to the high heterogeneity of breast cancer. Abundant evidence has shown that tumor tissues have unique metabolic features different from normal tissues, which has provided potential tumor-specific therapeutic targets for the treatment of cancer. For instance, arginine is a non-essential amino acid and Argininosaccinate Synthase1(ASS1) is the key rate-limiting enzyme in arginine synthesis. While normal tissues commonly express high level of ASS1, some tumors such as hepatic carcinoma and melanoma have arginine auxotrophy due to deficiency of ASS1. As a result, arginine deprivation through pegylated arginine deiminase (ADI-PEG20) which converting arginine to itrulline has been proven to be effective for the treatment of tumors with arginine auxotrophy. However, no related reports are available for breast cancer.
In this thesis, using breast cancer multiple tissue array assay, we found that63.75%(95/149) of breast tumors enrolled in this study were ASS1low-expressing. Subsequent Kaplan-Meier analysis demonstrated that low expression level of ASS1was associated with poor overall survival and poor disease-free survival. Further COX multivariate analysis indicated that ASS1was an independant indicator for overall survival and disease-free survival, and the predictive role of ASS1was independent of other known biomarkers such as ER, PR, Ki-67and Her-2, suggesting that ASS1may serve as a new biomarker for breast cancer molecular classification.
Moreover, we investigated whether arginine deprivation was efficacious for the treatment of breast cancer. The obtained data demonstrated that ADI-PEG20significantly inhibited the growth of ASS1low-expressing bresat cancer cells in vitro and in vivo, while had little impact on ASS1high-expressing breast cancer cells, indicating that ASS1might be a useful therapeutic target for breast cancer personalized medicine. Further molecular studies demonstrated that arginine deprivatin had little influence on the induction of apoptosis, but dramatically inhibited ATP production and mitochondrial oxidative phosphorylation (OXPHOS). Subsequently, ROS (especially mitochondria ROS) production was significantly increased and the mitochondria membrane potential (MMP) was lowered. Due to these massive mitochondria dysfunctions, arginine deprivation ultimately caused lethal mitophagy in order to selectively remove damaged mitochondria and maintain mitochondrial homeostasis.
In summary, for the first time, this study demonstrated that ASS1holds the promise to become an independent factor for prognosis prediction and a candidate novel biomarker for classification in breast cancer. Arginine deprivation may be adopted for personerlized medicine of breast cancer, e.g. for the treatment of ASS1low-expression breast tumors. We also demonstrated that arginine deprivation could induce lethal mitophagy, which may play critical role in arginine deprivation-mediated breast cancer cell death.
引文
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