p38gamma MAPK signaling promotes intestinal tumorigenesis

结直肠癌(CRC)是美国第二大与恶性肿瘤相关的死亡原因， 炎症是其发展、生长和进展的关键驱动力。P38，p38成员 丝裂原活化蛋白激酶(p38MAPK和)是一种致癌、促炎和 在临床结直肠癌中高表达，但上皮性p38在结直肠癌发生中的作用尚未被证实。- 连环蛋白是Wnt转录的关键辅助因子，在90%的结直肠癌中异常激活。然而，-catenin是 无法用药，因此迫切需要确定用于治疗的可用药-连环蛋白激活剂 干预。我们认为肠上皮细胞中的p38MAPK信号通路参与了结直肠癌的发生。 通过刺激致癌的-连环蛋白磷酸化而发生肿瘤。 这一假设是基于我们的初步研究表明：1)炎症协同刺激 P38和-连环蛋白在结直肠癌细胞中的磷酸化；2)p38在S605直接磷酸化-连环蛋白。 增加-连环蛋白的稳定性、-连环蛋白-TCF4的相互作用、Wnt转录和结直肠癌生长；3) 炎症激活小鼠肠道组织中的p38，但不激活p38，以及IEC特异性的p38敲除(KO) 减少促炎细胞因子的表达，减轻结肠炎的严重程度；4)IEC p38KO抑制结肠 偶氮甲烷/葡聚糖硫酸钠的肿瘤发生与p--连环蛋白/S605/Wnt信号转导 结肠炎相关癌小鼠模型；5)p38药物抑制剂吡非尼酮(Pfd) 抑制野生型(WT)小鼠-连环蛋白/细胞因子的表达和结肠癌的发生，但对p38KO无影响 并与-连环蛋白-TCF4相互作用拮抗剂LF3和化疗药物进一步合作 5FU抑制结直肠癌生长；6)p38在临床癌组织和大肠癌组织中表达上调。 Apcmin和IL-10基因敲除(IL-10-/-)小鼠。这些结果共同表明，需要iec p38 通过刺激致癌的-连环蛋白磷酸化来促进癌和散发性结直肠癌的肿瘤发生。 使用遗传学和药理学方法，我们将通过确定(1)p38- 诱导-连环蛋白/S605磷酸化刺激-连环蛋白核转位，-连环蛋白-TCF4 相互作用、Wnt转录和结直肠癌生长；(2)IEC特异性p38KO是否阻断IL-1细胞的致瘤作用 10-/-和Apcmin小鼠，如果p38是-连环蛋白/TCF4/Wnt信号通路所必需的，则促进肿瘤发生 结直肠癌发病机制的研究进展；以及(3)p38药理抑制剂吡非尼酮(Pfd) 阻断结直肠癌的发生并通过干扰增强LF3和5FU的生长抑制活性 P38/-连环蛋白/TCF4/Wnt通路。完成后，这些研究将证明上皮性p38 通过刺激致癌的-连环蛋白/S605磷酸化和Wnt转录促进结直肠癌的发生。 靶向研究PFD抑制Wnt信号转导和结直肠癌发生的有效性 肠上皮细胞p38将揭示药物p38在结肠癌靶向治疗中的巨大潜力。

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.