MiR-152/PKM2/SLC7A5 axis in breast cancer development, chemo- and radiation-treatment response

MiR-152/PKM2/SLC7A5 轴在乳腺癌发展、化疗和放疗反应中的作用

基本信息

批准号：
10593136
负责人：
Jun He
金额：
$ 63.19万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593136
关键词：
Affect Alternative Splicing Amino Acids Animal Model Biology Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cell Line Cell model Cells Chemotherapy and/or radiation DNA DNA Methylation Data Development Doxorubicin Endothelial Cells Estrogen receptor positive Family Future Goals HNRPA3 gene Heterogeneous-Nuclear Ribonucleoproteins Homologous Gene Human Hypermethylation IL8 gene Malignant Neoplasms Mediating Metabolic Methylation MicroRNAs Modeling Molecular Muscle Pathway interactions Play Polypyrimidine Tract-Binding Protein Promoter Regions Protein Isoforms Protein Kinase Proteins Pyruvate Kinase Radiation Radiation therapy Research Project Grants Resistance Role Signal Pathway Testing Therapeutic Therapeutic procedure Tissues Tumor Angiogenesis Tumor Tissue Up-Regulation Warburg Effect Woman angiogenesis cancer cell cancer survival cancer therapy chemotherapy cohort experimental study improved knock-down malignant breast neoplasm member mortality multidisciplinary new therapeutic target orthotopic breast cancer overexpression paracrine patient derived xenograft model receptor solute therapy resistant translational potential treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor metabolism

项目摘要

Breast cancer (BCa) is the leading cause of women cancer mortality worldwide, and triple negative breast cancer (TNBC) cells accounts for 15-20% BCa. However, higher therapeutic resistance and lower survival of TNBC patients remain the major hinder of BCa treatment. Doxorubicin (Dox) and radiation are commonly used for TNBC treatment. In our preliminary study, we found that TNBC showed much lower expression levels of miR-152. Higher expression levels of zeste homologue 2 (EZH2) and DNA hypermethylation were involved in miR-152 suppression in TNBC cells. To understand mechanism of miR-152 suppression, and role and mechanism of miR-152 in regulating cancer development and Dox- and radiation-induced resistance, we performed a lot of preliminary experiments to identify what molecules that were potential miR-152 direct targets as well as that were upregulated in Dox-resistant TNBC or PDX tumor tissues. We found that pyruvate kinase muscle 2 (PKM2), solute Carrier Family 7 Member 5 (SLC7A5), and polypyrimidine tract-binding protein (PTBP1) as direct targets of miR-152 with potential ability to converse Dox-mediated resistance. PKM2, SLC7A5 and PTBP1 levels were increased when miR-152 expression was suppressed in TNBC cells and PDX model. We found that miR-152 suppression played an important role in mediating TNBC metabolic reprogramming, Warburg effect switch, tumor growth and Dox resistance through PKM2/SLC7A5/PTBP1. We showed that overexpression of miR-152 or PKM2 knockdown rendered TNBC cells more sensitive to radiation treatment. These new findings create new opportunity to investigate mechanism of TNBC therapeutic resistance. We hypothesize that resistance to chemotherapy and radiation treatment, metabolic reprogramming, and TNBC development are induced by miR-152 suppression and upregulation of PKM2, SLC7A5, and PTBP1. To test this central hypothesis, we will perform experiments through three aims. In Aim 1, we will investigate role and mechanism of miR-152 suppression in TNBC cells in doxorubicin- and radiation-induced resistance; and role and mechanism of PKM2 switch and induction via alternative splicing by miR-152 suppression to induce Warburg effect, therapeutic resistance, and tumor growth. In Aim 2, we will determine role and mechanism of miR- 152/SLC7A5/PTBP1 pathway in regulating metabolic reprogramming and Warburg effect switch, and in mediating doxorubicin- and radiation-induced therapeutic resistance. In Aim 3, we will determine whether miR-152 suppression and PKM2 induction regulate tumor angiogenesis through CXCL8 expression using a humanized chimeric tumor model; and whether levels of miR-152, PKM2, HIF-1α, hnRNPA3, SLC7A5, and PTBP1 are correlated each other, and are correlated with therapeutic responses and with the cancer stages and survival. This R01 project will identify mechanisms of therapeutic resistance, and metabolic reprogramming; and provide information for developing new treatment option of TNBC in the future.

乳腺癌 (BCa) 是全球女性癌症死亡的主要原因，而三阴性乳腺癌癌症（TNBC）细胞占BCa的15-20%，但治疗耐药性较高，生存率较低。 TNBC 患者的数量仍然是 BCa 治疗的主要障碍，而放射治疗也是常见的。在我们的初步研究中，我们发现 TNBC 的表达量要低得多。 miR-152 水平较高，zeste 同源物 2 (EZH2) 和 DNA 高甲基化水平较高。参与 TNBC 细胞中的 miR-152 抑制了解 miR-152 抑制的机制，以及 miR-152在调节癌症发展以及Dox和辐射诱导的癌症发展中的作用和机制为了抗性，我们进行了大量的初步实验来确定哪些分子是潜在的 miR-152 是直接靶标，并且在 Dox 抗性 TNBC 或 PDX 肿瘤组织中上调。发现丙酮酸激酶肌肉 2 (PKM2)、溶质载体家族 7 成员 5 (SLC7A5) 和聚嘧啶束结合蛋白 (PTBP1) 作为 miR-152 的直接靶标，具有潜在的逆转能力当 miR-152 表达时，Dox 介导的耐药性增加。我们发现 miR-152 的抑制在 TNBC 细胞和 PDX 模型中发挥了重要作用。在介导 TNBC 代谢重编程、Warburg 效应开关、肿瘤生长和 Dox 耐药性中的作用通过 PKM2/SLC7A5/PTBP1，我们发现 miR-152 的过度表达或 PKM2 的敲低会导致。 TNBC 细胞对放射治疗更敏感。这些新发现为研究创造了新的机会。我们捕获了 TNBC 治疗耐药的机制，并且放射治疗、代谢重编程和 TNBC 发展是由 miR-152 诱导的 PKM2、SLC7A5 和 PTBP1 的抑制和上调为了检验这一中心假设，我们将通过三个目标进行实验。在目标1中，我们将研究miR-152的作用和机制。 TNBC 细胞对阿霉素和辐射诱导的耐药性的抑制及其作用和机制； PKM2 通过选择性剪接进行开关和诱导，通过抑制 miR-152 来诱导 Warburg 效应，在目标 2 中，我们将确定 miR- 的作用和机制。 152/SLC7A5/PTBP1 通路在调节代谢重编程和 Warburg 效应开关中的作用在目标 3 中，我们将确定是否介导阿霉素和放射诱导的治疗耐药性。 miR-152抑制和PKM2诱导通过CXCL8表达调节肿瘤血管生成人源化嵌合肿瘤模型；以及 miR-152、PKM2、HIF-1α、hnRNPA3、SLC7A5 和 PTBP1 彼此相关，并且与治疗反应和癌症阶段相关该 R01 项目将确定治疗耐药性和代谢机制。重新编程；并为未来开发新的 TNBC 治疗方案提供信息。