5月31日，瑞典卡罗林斯卡医学院宣布发现了胰腺癌细胞变化的新机理，这将有助于胰腺癌的早期诊断。

根据现有研究成果，胰腺癌与以下两种特殊的细胞结构变化有关：RAS致癌基因发生突变；大量分子信号是按照一种“刺猬”式信号传递的。

瑞典卡罗林斯卡医学院的研究人员在对老鼠实验后，发现了RAS基因和“刺猬”式信号传递相互作用的机理。当RAS基因被激活时，肿瘤细胞就会分泌SHH，这种物质会引发“刺猬”式信号传递活动，同时阻止肿瘤细胞对这种信号做出反应。整个过程分为两个阶段：第一阶段在“刺猬”式信号刺激下，肿瘤细胞周围的细胞会迅速生长，而肿瘤细胞在SHH保护下处于安全状态；第二阶段当SHH的作用消失时，肿瘤细胞在“刺猬”式信号的刺激下加速生长，肿瘤开始逐渐恶化，直至形成癌症。

这一成果发表在新一期《自然·结构与分子生物学》杂志上。

原文出处：

Nature Structural & Molecular Biology  doi:10.1038/nsmb.1833

DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS
Matthias Lauth1,4, ?sa Bergstr?m1, Takashi Shimokawa1, Ulrica Tostar1, Qianren Jin1, Volker Fendrich2, Carmen Guerra3, Mariano Barbacid3 & Rune Toftg?rd1

Synergism between the RAS and Hedgehog (HH) pathways has been suggested for carcinogenesis in the pancreas, lung and colon. We investigated the molecular cross-talk between RAS and HH signaling and found that, although mutant RAS induces or enhances SHH expression and favors paracrine HH signaling, it antagonizes autocrine HH signal transduction. Activated RAS can be found in primary cilia, the central organelle of HH signal transduction, but functions in a cilium-independent manner and interferes with Gli2 function and Gli3 processing. In addition, the cell-autonomous negative regulation of HH signal transduction involves the RAS effector molecule dual specificity tyrosine phosphorylated and regulated kinase 1B (DYRK1B). In line with a redirection of autocrine toward paracrine HH signaling by a KRAS-DYRK1B network, we find high levels of GLI1 expression restricted to the stromal compartment and not to SHH-expressing tumor cells in human pancreatic adenocarcinoma.