Cooperation of deregulated Notch signaling and Ras pathway in human hepatocarcinogenesis |
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Authors: | Renhua?Fan Email author" target="_blank">Pingsheng?ChenEmail author Di?Zhao Jing?long?Tong Jing?Li Feng?Liu |
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Institution: | (1) Department of Pathology, School of Medicine, Southeast University, Nanjing, 210009, China;(2) Department of Radiology and nuclear medicine, School of Medicine, Southeast Universtiy, Nanjing, 210009, China;(3) Department of Clinical Laboratory of Changsha Central Hospital, Changsha, 410004, China; |
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Abstract: | Aberrant Notch signaling and Ras pathway had been highlighted a potential role for in human cancers. Yet, relatively little
was known about the roles of wild type Notch signaling and Ras in human hepatocarcinogenesis. The aim of this study was to
investigate the roles of Ras-Notch signaling cooperation in hepatic cells transformation and proliferation. Hepatocellular
carcinoma specimens from 25 patients were analyzed for Notch-1, Ras and Late Simian Virus 40 Factor (LSF) expression using
immunohistochemistry. Results showed that Notch-1(76%, 19/25, P < 0.0001), Ras (40%, 10/25, P < 0.01) and LSF (84%, 21/25, P < 0.0001) were significantly up-regulated in hepatocellular carcinoma compared with non-cancer samples. The correlations
between the expression and the biological effects of Notch1 and Ras were analyzed by genetic and pharmacological methods.
Constitutively active Notch1 alone failed to transform immortalized L02 cells in vivo, it synergized with the Ras pathway
to promote hepatic cells transformation. However, their cooperation increased the levels of LSF mRNA and protein, which stimulates
L02 cells proliferation. These results exhibited highly aggressive progression, suggesting that Notch-Ras cooperation maybe
lead to poor prognosis. Thus, combining the inhibition of the two pathways provided an attractive avenue for therapeutic intervention
to overcome this advanced disease. |
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Keywords: | |
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