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p38gamma MAPK signaling promotes intestinal tumorigenesis

p38gamma MAPK 信号促进肠道肿瘤发生

基本信息

批准号：
10620848
负责人：
GUAN CHEN
金额：
$ 34.97万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620848
关键词：
APC gene Anti-Inflammatory Agents Attenuated Azoxymethane Carcinoma Cessation of life Clinical Colitis Collaborations Colon Carcinoma Colorectal Cancer Complex DNA Development Effectiveness Epithelial Cells Epithelium Fluorouracil Genetic Genetic Transcription Growth Growth and Development function Human In Vitro Inflammation Inflammatory Interleukin-10 Intestines Knock-out Knockout Mice Leucocytic infiltrate Life MAP Kinase Gene MAPK12 gene Malignant - descriptor Mission Mus Mutant Strains Mice Nuclear Translocation Oncogenic Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Pirfenidone Play Public Health Research Role Severities Signal Transduction Sodium Dextran Sulfate Specimen Spontaneous colitis Suppressor Mutations TCF7L2 gene Testing Therapeutic Therapeutic Intervention Tissues United States National Institutes of Health WNT Signaling Pathway Wild Type Mouse Xenograft procedure antagonist burden of illness c-myc Genes cancer cell chemotherapy cofactor colitis associated cancer colon tumorigenesis cytokine dextran sulfate sodium induced colitis driving force druggable target in vivo inhibitor intestinal epithelium intestinal tumorigenesis member mouse model multicatalytic endopeptidase complex murine colitis novel novel strategies overexpression p38 Mitogen Activated Protein Kinase pharmacologic promoter response targeted cancer therapy targeted treatment tumorigenesis

项目摘要

Colorectal cancer (CRC) is the second leading cause of malignant-associated death in the USA with inflammation as a key driving force for its development, growth, and progression. p38, a member of p38 mitogen-activated protein kinases (p38 MAPK  , and ), is oncogenic, pro-inflammatory, and overexpressed in clinical CRC but the role of epithelial p38 in CRC tumorigenesis has not been tested. - catenin, a critical cofactor of Wnt transcription, is aberrantly activated in 90% of CRC. And yet, -catenin is undruggable and there is thus an urgent need to identify druggable -catenin activators for therapeutic intervention. Here we propose that p38 MAPK in intestinal epithelial cells (IEC) drives CRC tumorigenesis by stimulating oncogenic -catenin phosphorylation. This hypothesis is based on our preliminary studies showing that: 1) inflammation coordinately stimulates p38 and -catenin phosphorylation in CRC cells; 2) p38 directly phosphorylates -catenin at S605, which increases -catenin stability, the -catenin-TCF4 interaction, Wnt transcription and CRC growth; 3) inflammation activates p38, but not p38, in intestinal tissues of mice, and IEC-specific p38 knockout (KO) reduces pro-inflammatory cytokine expression and attenuates colitis severity; 4) IEC p38 KO inhibits colon tumorigenesis and p--catenin/S605/Wnt signaling in the azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model of colitis-associated cancer (CAC); 5) the p38 pharmacological inhibitor pirfenidone (PFD) suppresses -catenin/cytokine expression and colon tumorigenesis in wild-type (WT) mice, but not in p38 KO mice, and further collaborates with the -catenin-TCF4 interaction antagonist LF3 and chemotherapeutic drug 5FU to inhibit CRC growth, and 6) p38 is upregulated in clinical CAC specimens and in intestinal tissues of Apcmin and interleukin-10 knockout (IL-10-/-) mice. These results together indicate that IEC p38 is required for tumorigenesis of both CAC and sporadic CRC by stimulating oncogenic -catenin phosphorylation. Using genetic and pharmacological approaches, we will test this hypothesis by determining (1) if p38- induced -catenin/S605 phosphorylation stimulates -catenin nuclear translocation, -catenin-TCF4 interaction, Wnt transcription and CRC growth; (2) if IEC-specific p38 KO blocks tumorigenesis in IL- 10-/- and Apcmin mice and if p38 is essential for the -catenin/TCF4/Wnt signaling to promote malignant progression in CRC pathogenesis; and (3) if the p38 pharmacological inhibitor pirfenidone (PFD) blocks CRC tumorigenesis and increases the growth-inhibitory activity of LF3 and 5FU by disrupting the p38/-catenin/TCF4/Wnt pathway. Upon completion, these studies will demonstrate if epithelial p38 promotes CRC tumorigenesis by stimulating oncogenic -catenin/S605 phosphorylation and Wnt transcription. Demonstrating the effectiveness of PFD in inhibiting Wnt signaling and CRC tumorigenesis by targeting intestinal epithelial p38 will reveal that drugging p38 has a great potential for colon cancer targeted therapy.

结直肠癌（CRC）是美国恶性相关死亡的第二大原因，炎症是其发展、生长和进展的关键驱动力。p38 p38的成员丝裂原活化蛋白激酶（p38 MAPK激酶和p38 MAPK激酶）是致癌的、促炎的，在临床CRC中过度表达，但上皮p38 β在CRC肿瘤发生中的作用尚未得到证实。- 连环蛋白是Wnt转录的关键辅因子，在90%的CRC中被异常激活。然而，β-连环蛋白是因此迫切需要鉴定可药用的β-连环蛋白激活剂用于治疗干预在这里，我们提出肠上皮细胞（IEC）中的p38 MAPK驱动CRC 通过刺激致癌的β-连环蛋白磷酸化来促进肿瘤发生。这一假设是基于我们的初步研究表明：1）炎症协调刺激 p38 β和β-连环蛋白在CRC细胞中的磷酸化; 2）p38 β在S605处直接磷酸化β-连环蛋白，增加β-连环蛋白稳定性、β-连环蛋白-TCF 4相互作用、Wnt转录和CRC生长; 3）炎症激活小鼠肠组织中的p38 β，但不激活p38 β，IEC特异性p38 β敲除（KO）降低促炎细胞因子表达并减轻结肠炎严重程度; 4）IEC p38 K50抑制结肠炎氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）中的肿瘤发生和β-catenin/S605/Wnt信号转导结肠炎相关癌症（CAC）小鼠模型; 5）p38 β药理学抑制剂吡非尼酮（PFD）在野生型（WT）小鼠中抑制β-连环蛋白/细胞因子表达和结肠肿瘤发生，但在p38 β KO中不抑制小鼠，并进一步与β-连环蛋白-TCF 4相互作用拮抗剂LF 3和化疗药物合作 5 FU抑制CRC生长，以及6）p38 β在临床CAC样本和大肠癌患者的肠组织中上调。 Apcmin和白细胞介素-10敲除（IL-10-/-）小鼠。这些结果共同表明，IEC p38要求通过刺激致癌β-连环蛋白磷酸化导致CAC和散发性CRC的肿瘤发生。使用遗传学和药理学方法，我们将通过确定（1）如果p38突变，诱导的β-catenin/S605磷酸化刺激β-catenin核转位，β-catenin-TCF 4 相互作用、Wnt转录和CRC生长;（2）如果IEC特异性p38 PKO阻断IL-10中的肿瘤发生， 10-/-和Apcmin小鼠，并且如果p38 β对于β-连环蛋白/TCF 4/Wnt信号传导是必需的，则促进恶性肿瘤的发生。 CRC发病机制的进展;和（3）如果p38 β药理学抑制剂吡非尼酮（PFD）阻断CRC肿瘤发生，并通过破坏 p38 β/β-连环蛋白/TCF 4/Wnt途径。完成后，这些研究将证明上皮p38是否能抑制通过刺激致癌β-连环蛋白/S605磷酸化和Wnt转录促进CRC肿瘤发生。证明PFD通过靶向抑制Wnt信号传导和CRC肿瘤发生的有效性肠上皮p38基因的表达将揭示p38基因药物化在结肠癌靶向治疗中具有巨大的潜力。