一、研究新知
Targeting IL-17B–IL-17RB signaling with an anti–IL-17RB antibody blocks pancreatic cancer metastasis by silencing multiple chemokines
Heng-Hsiung Wu, Wendy W. Hwang-Verslues, Wen-Hsin Lee, Chun-Kai Huang, Pei-Chi Wei, Chia-Lin Chen, Jin-Yuh Shew, Eva Y.-H.P. Lee, Yung-Ming Jeng, Yu-Wen Tien, Che Ma, Wen-Hwa Lee (李文華院士) J. Exp. Med. 2015 (DOI: 10.1084/jem.20141702)
Pancreatic cancer has an extremely high mortality rate due to its aggressive metastatic nature. Resolving the underlying mechanisms will be crucial for treatment. Here, we found that overexpression of IL-17B receptor (IL-17RB) strongly correlated with postoperative metastasis and inversely correlated with progression-free survival in pancreatic cancer patients. Consistently, results from ex vivo experiments further validated that IL-17RB and its ligand, IL-17B, plays an essential role in pancreatic cancer metastasis and malignancy. Signals from IL-17B–IL-17RB activated CCL20/CXCL1/IL-8/TFF1 chemokine expressions via the ERK1/2 pathway to promote cancer cell invasion, macrophage and endothelial cell recruitment at primary sites, and cancer cell survival at distant organs. Treatment with a newly derived monoclonal antibody against IL-17RB blocked tumor metastasis and promoted survival in a mouse xenograft model. These findings not only illustrate a key mechanism underlying the highly aggressive characteristics of pancreatic cancer but also provide a practical approach to tackle this disease.
A gp130–Src–YAP module links inflammation to epithelial regeneration
Koji Taniguchi, Li-Wha Wu (吳梨華教授), Sergei I. Grivennikov, Petrus R. de Jong, Ian Lian, Fa-Xing Yu, Kepeng Wang, Samuel B. Ho, Brigid S. Boland, John T. Chang, William J. Sandborn, Gary Hardiman, Eyal Raz, Yoshihiko Maehara, Akihiko Yoshimura, Jessica Zucman-Rossi, Kun-Liang Guan, Michael Karin
Nature 519, 57-62 (doi:10.1038/nature14228)
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.