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:
    10445658
  • 负责人:
  • 金额:
    $ 64.48万
  • 依托单位:
  • 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

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)是全世界妇女癌症死亡的主要原因,三阴性乳腺癌

项目成果

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Jun He的其他文献

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{{ truncateString('Jun He', 18)}}的其他基金

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
  • 批准号:
    10593136
  • 财政年份:
    2022
  • 资助金额:
    $ 64.48万
  • 项目类别:
New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer
非小细胞肺癌EGFR-TKIs获得性耐药的新机制
  • 批准号:
    10098004
  • 财政年份:
    2020
  • 资助金额:
    $ 64.48万
  • 项目类别:
New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer
非小细胞肺癌EGFR-TKIs获得性耐药的新机制
  • 批准号:
    10085027
  • 财政年份:
    2020
  • 资助金额:
    $ 64.48万
  • 项目类别:
New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer
非小细胞肺癌EGFR-TKIs获得性耐药的新机制
  • 批准号:
    10328910
  • 财政年份:
    2020
  • 资助金额:
    $ 64.48万
  • 项目类别:
Chromium in carcinogenesis and angiogenesis
铬在致癌和血管生成中的作用
  • 批准号:
    10447777
  • 财政年份:
    2018
  • 资助金额:
    $ 64.48万
  • 项目类别:
Chromium in carcinogenesis and angiogenesis
铬在致癌和血管生成中的作用
  • 批准号:
    10208885
  • 财政年份:
    2018
  • 资助金额:
    $ 64.48万
  • 项目类别:
NOX4 Mediates Oxidative Stress in Ovarian Tumor growth and treatment Response
NOX4 介导卵巢肿瘤生长和治疗反应中的氧化应激
  • 批准号:
    10304003
  • 财政年份:
    2015
  • 资助金额:
    $ 64.48万
  • 项目类别:

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