ALOX15 regulation of colon cancer invasiveness via PI3P-linoleic acid metabolism

ALOX15 通过 PI3P-亚油酸代谢调节结肠癌侵袭性

基本信息

  • 批准号:
    10545078
  • 负责人:
  • 金额:
    $ 63.89万
  • 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:
    2022-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Colorectal cancer is the third leading cause of cancer deaths in the United States. The long-term goal of our research is to develop novel interventions to prevent colorectal carcinogenesis (CRC). CRC invasiveness, a critical adverse step during CRC progression, requires a combination of certain genetic mutations (e.g. APC, KRAS and Trp53 mutations), which are the key events to drive CRC. However, CRC progression also requires additional factors which increase aberrant Beta-catenin (B-catenin) activation above levels induced by APC/B- catenin mutations. Linoleic acid (LA), the most commonly consumed omega-6 polyunsaturated fatty acids in humans, increases both chemically (AOM)– and APC mutation– induced CRC tumorigenesis in mice. Nonetheless, human studies have been inconclusive regarding the impact of dietary LA on CRC. Determination of LA's role in CRC is important because American diets are enriched with LA while expression of the main metabolizing enzyme for LA,15-lipoxygenase-1 (ALOX15), is lost in human CRC. Recently, we found that 1) high dietary levels of LA promoted CRC by increasing phosphatidylinositol 3-phosphate (PI3P) containing LA (PI3P_LA), which increases LRP5 membranous recycling and subsequently B-catenin activation; 2) ALOX15- induced conversion of PI3P_LA to PI3P_13-HODE suppresses; LRP5 membranous recycling, B-catenin activation, CRC stemness and LA promotion of CRC, especially formation of large tumors, associated with CRC invasiveness; 3) ALOX15 loss of function (LOF) promotes large CRC tumor formation by azoxymethane in 12/15LOX-KO-12LOX (ALOX15-LOF) mice. Whether loss of ALOX15 expression promotes CRC invasiveness remains unknown. Our preliminary data show that ALOX15-LOF mice increased CRC invasiveness and targeted APC mutation into Lgr5+ colorectal stem cells induced CRC in the mice, which was blocked by transgenic ALOX15 expression. We therefore hypothesize that ALOX15 loss of function promotes CRC invasiveness by increasing PI3P_LA levels, which enhances LRP5 membranous recycling, thus potentiating Wnt/B-catenin signaling and subsequently stemness. Aim 1 will determine the effects of ALOX15 gain of function and ALOX15 LOF on LRP5, B-catenin activation, CRC stemness and invasiveness using CRC mouse models in which CRC invasiveness is promoted by either a combination of APC, KRASG12D and Trp53R172H mutations or Trp53R172H mutation with AOM induced B-catenin and KRAS mutations. Aim 2 will determine the effects of ALOX15 LOF on PI3P-LA, LRP5, B-catenin activation, stemness and invasiveness in human CRCs and examine the effects of ALOX15 re-expression via lentivirus Tet-on inducible system in human CRC-derived organoids on invasiveness in-vitro and in-vivo studies. The proposed studies are expected to provide important mechanistic insights into whether colonic ALOX15 expression as a host factor affects CRC invasiveness risk especially with high dietary LA intake. This gained knowledge could inform subjects with colorectal ALOX15 LOF to avoid high LA intake and spur development of interventions to target ALOX15 for re-expression to prevent invasive CRC.
结直肠癌是美国癌症死亡的第三大原因。我们的长期目标

项目成果

期刊论文数量(0)
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Imad Shureiqi其他文献

Imad Shureiqi的其他文献

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{{ truncateString('Imad Shureiqi', 18)}}的其他基金

ALOX15 regulation of colon cancer invasiveness via PI3P-linoleic acid metabolism
ALOX15 通过 PI3P-亚油酸代谢调节结肠癌侵袭力
  • 批准号:
    10339182
  • 财政年份:
    2022
  • 资助金额:
    $ 63.89万
  • 项目类别:
15-LOX-1 Modulation of Colon Cancer Promotion by Linoleic Acid
亚油酸对 15-LOX-1 促进结肠癌的调节
  • 批准号:
    10330050
  • 财政年份:
    2021
  • 资助金额:
    $ 63.89万
  • 项目类别:
15-LOX-1 regulation of resolving generation to modulate colon cancer
15-LOX-1 调节分解生成以调节结肠癌
  • 批准号:
    10301423
  • 财政年份:
    2016
  • 资助金额:
    $ 63.89万
  • 项目类别:
15-LOX-1 Modulation of Colon Cancer Promotion by Linoleic Acid
亚油酸对 15-LOX-1 促进结肠癌的调节
  • 批准号:
    9886073
  • 财政年份:
    2016
  • 资助金额:
    $ 63.89万
  • 项目类别:
15-LOX-1 Regulation of Resolving Generation to Modulate Colon Cancer
15-LOX-1 调节分解生成以调节结肠癌
  • 批准号:
    9980183
  • 财政年份:
    2016
  • 资助金额:
    $ 63.89万
  • 项目类别:
15-LOX-1 Regulation of Resolving Generation to Modulate Colon Cancer
15-LOX-1 调节分解生成以调节结肠癌
  • 批准号:
    9187612
  • 财政年份:
    2016
  • 资助金额:
    $ 63.89万
  • 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
  • 批准号:
    7987654
  • 财政年份:
    2010
  • 资助金额:
    $ 63.89万
  • 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
  • 批准号:
    8259197
  • 财政年份:
    2010
  • 资助金额:
    $ 63.89万
  • 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
  • 批准号:
    8091356
  • 财政年份:
    2010
  • 资助金额:
    $ 63.89万
  • 项目类别:
Molecular targeting of PPAR-delta in colon cancer
结肠癌中 PPAR-δ 的分子靶向
  • 批准号:
    8657861
  • 财政年份:
    2010
  • 资助金额:
    $ 63.89万
  • 项目类别:

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APC 突变与乳腺癌:姜黄素预防
  • 批准号:
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  • 财政年份:
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APC 突变与乳腺癌:姜黄素预防
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APC突变与结直肠癌的发生
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  • 资助金额:
    $ 63.89万
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    NHMRC Project Grants
Development of novel screening method by detection of APC mutation from colorectal cancer cells in stool
开发粪便中结直肠癌细胞APC突变检测新筛查方法
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    17591404
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DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER
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