Raf-1 Addiction in Ras-Induced Skin Carcinogenesis

Ehrenreiter K., Kern F., Velamoor V., Meissl K., Galabova-Kovacs G., Sibilia M.,and Baccarini M.

Cancer Cell 16, 149–160, 2009

Speaker：Yu-Chan Yang (楊于嬋)                                       Time：13:00~14:00, Jun. 09 2010

Commentator：Dr. Pei- Jung Frank Lu (呂佩融 教授)      Place：Room 601

Abstract：

Ras oncogene promotes the initiation of tumorgenesis and maintains tumor growth. Raf kinase, the first Ras effector identified, has been widely implicated in Ras-driven tumorigenesis¹. Ras and Raf function may support cell proliferation capacity and oppose differentiation in adult epidermis that are two important factors of central carcinogenesis. Human Squamous Cell Carcinoma (SCC) is the common cancer around the world and it displays increase levels of active Ras without mutations in Ras genes². The authors used two Raf-1 ablation mouse models to explore the function of Raf in Ras-driven SCC: (1) the DMBA/TPA chemical carcinogenesis model in which H-Ras was activated by a codon 61 mutation, and (2) K5-SOS-F transgenic mice, in which constitutive activation of the endogenous Ras pathway under the control of the full-length cytokeratin 5 (K5) promoter. The later one mimics SCCs more closely because Ras is mutated in only a small percentage of SCC. They found that Raf-1 ablation in keratinocytes prevents chemically induced skin carcinogenesis and tumor formation and tumor progression in K5-SOS-F+ Mice. Moreover, tumor regression following Raf-1 ablation is coincident with an increase in differentiated cells. Therefore, the authors define the mechanisms by which Raf-1 interferes with keratinocyte differentiation and Rok-α inhibition, which is through the activation of cofilin/STAT3/Myc pathway and the increased differentiation of Ras-induced tumors in vivo. Furthermore, by demonstrating the complete differentiation induced by Raf-1 ablation, the authors propose that different therapies may be applied to treat solid tumors and provide a unique opportunity for therapeutic targeting for at least in the treatment of skin epidermis tumors containing active Ras.

References：

1. Grabocka E. and Bar-Sagi D. Raf-1 and Squamous cell carcinoma: Rok-ing the Boat Cancer cell 2009, 16: 85-86.

2. Ridky T. W. and Khavari P. A. Pathways sufficient to induce epidermal carcinogenesis. Cell cycle 2004, 3: 621-624.