MAP3K10激活Hedgehog旁路途径对胰腺癌干细胞生物学特性的影响及机制研究

Pancreatic cancer stem cells(PCSCs) are malignant core cells of pancreatic cancer and contribute to the initiation, progression and prognosis of pancreatic cancer.Hedgehog (Hh) signaling is one of the most crucial pathways of PCSCs that aberrantly activated.Although the classic blocker of Hh signaling could reduce the proportion of PCSCs in pancreatic cancer,it could not kill the PCSCs completely.Through our previous research we find that MAP3K10 are activated abnormally in PCSCs,which may activate the downstream of Hh signaling bypass via DYRK2/GIL, by which PCSCs escape chemotherapy.The objective of our research is to confirm the expression levels of MAP3K10/DYRK2 in pancreatic cancer cells and PCSCs and its relationship with clinicopathologic degree,to verify the activation of Hh signaling by MAP3K10/DYRK2 through IP and BiFC,to detect the effects of MAP3K10/DYRK2 on the malignant biological behaviors of pancreatic cancer and the maintenance of PCSCs, to exploit new blockers targeting MAP3K10/DYRK2 proteins and confirm their pharmacological effect on PCSCs.Our project may gain a clear idea of the molecular mechanisms of PCSCs escaping chemotherapy and may be crucial for the development of new targetd agents.It may lay a foundation for the improvement on treatment effect of pancreatic cancer.

胰腺癌干细胞是胰腺癌恶性核心细胞，决定了胰腺癌的发生、发展和转归。Hedgehog信号通路是胰腺癌干细胞中最重要的异常激活通路，其阻滞剂能有效的降低胰腺癌干细胞比例，但并不能彻底的杀灭胰腺癌干细胞。我们前期研究发现MAP3K10在胰腺癌干细胞中异常激活，其通过DYRK2/GIL激活Hedgehog旁路途径而导致胰腺癌干细胞逃逸治疗。本研究拟在前期研究基础上：明确MAP3K10/DYRK2在胰腺癌及胰腺癌干细胞中的表达及临床病理联系；运用IP和BiFC技术证实MAP3K10/DYRK2对Hedgehog信号通路的激活；检测MAP3K10/DYRK2对胰腺癌恶性生物学行为和胰腺癌干细胞"干性"维持的影响；开发MAP3K10/DYRK2蛋白阻滞性药物，检测其对胰腺癌干细胞的杀灭作用。本项目有望进一步揭示胰腺癌干细胞逃逸当前治疗的分子机制，为提高胰腺癌治疗效果设计合理靶向药物奠定实验基础。

1胰腺癌干细胞是胰腺癌恶性核心细胞，决定了胰腺癌的发生、发展和转归。Hedgehog 信号通路是胰腺癌干细胞中最重要的异常激活通路，其阻滞剂能有效的降低胰腺癌干细胞比例，但并不能彻底的杀灭胰腺癌干细胞。我们前期研究发现MAP3K10 在胰腺癌干细胞中异常激活，其通过DYRK2/GIL 激活Hedgehog 旁路途径而导致胰腺癌干细胞逃逸治疗。本研究拟在前期研究基础上：明确MAP3K10/DYRK2 在胰腺癌及胰腺癌干细胞中的表达及临床病理联系；运用IP 和BiFC 技术证实MAP3K10/DYRK2 对Hedgehog 信号通路的激活；检测MAP3K10/DYRK2 对胰腺癌恶性生物学行为和胰腺癌干细胞“干性”维持的影响；开发MAP3K10/DYRK2 蛋白阻滞性药物，检测其对胰腺癌干细胞的杀灭作用。本项目有望进一步揭示胰腺癌干细胞逃逸当前治疗的分子机制，为提高胰腺癌治疗效果设计合理靶向药物奠定实验基础。