Cooperation of deregulated Notch signaling and Ras pathway in human hepatocarcinogenesis

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.

The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma

“…Other studies examined the interaction of NOTCH1 receptor with LSF factor (late SV40 factor) in HCC cells with mutated RAS. This interaction inhibits apoptosis and promotes cell division (Fan et al., ,b). An increase in NOTCH1 receptor expression in HCC cells leads to enhanced cell proliferation.…”

Activation of signal transduction pathways during hepatic oncogenesis

“…Furthermore, Wnt/β-catenin and Notch signaling may cooperate functionally to regulate hepatocyte proliferation and biliary differentiation [46]. IN/IGF and Notch signaling may behave synergistically to induce hepatocyte transformation [47]. …”

OncomiRdbB: a comprehensive database of microRNAs and their targets in breast cancer

“…McCubrey et al ., [28] have shown that there is interaction among Ras/Raf/MEK/ERK/PI3K/PTEN and Akt pathways during carcinogenesis. Likewise, cooperative interaction of Notch and Ras/MAPK pathway in human breast carcinogenesis and hepatocarcinogenesis was demonstrated by Fan et al ., [29]. Therefore, the percentage cooperative analysis was carried out to address the role of miRNAs in deregulating multiple oncogenic pathway genes in breast cancer development along with the percentage of target hits by the miRNAs among the total number of targets present in each pathway.…”