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SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure5).pdf

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https://ir.library.oregonstate.edu/concern/articles/h415pc344

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  • RAS and Rho small GTPases are key molecular switches that control cell dynamics, cell growth and tissue development through their distinct signaling pathways. While much has been learnt about their individual functions in both cell and animal models, the physiological and pathophysiological consequences of their signaling crosstalk in multi-cellular context in vivo remain largely unknown, especially in liver development and liver tumorigenesis. Furthermore, the roles of RhoA in RAS-mediated transformation and their crosstalk in vitro remain highly controversial. When challenged with carcinogens, zebrafish developed liver cancer that resembles the human liver cancer both molecularly and histopathologically. Capitalizing on the growing importance and relevance of zebrafish (Danio rerio) as an alternate cancer model, we have generated liver-specific, Tet-on inducible transgenic lines expressing oncogenic Kras[superscript G12V], RhoA, constitutively-active RhoA[superscript G14V] or dominant-negative RhoA[superscript T19N]. Double transgenic lines expressing Kras[superscript G12V] with one of the three RhoA genes were also generated. Based on quantitative bioimaging and molecular markers for genetic and signaling aberrations, we showed that the induced expression of oncogenic Kras during early development led to liver enlargement and hepatocyte proliferation, associated with elevated Erk phosphorylation, Akt2-p21Cip expression and activation. Such an increase in liver size and Akt2 expression was augmented by dominant-negative RhoA[superscript T19N], but was abrogated by the constitutive-active RhoA[superscript G14V]. Consequently, induced expression of the oncogenic Kras in adult transgenic fish led to the development of hepatocellular carcinomas. Survival studies further revealed that the co-expression of dominant-negative RhoA[superscript T19N] with oncogenic Kras increased the mortality rate compared to the other single or double transgenic lines. This study represents the first in vivo investigation of the previously unappreciated signaling crosstalk between Kras and RhoA in regulating liver overgrowth and liver tumorigenesis. Our results also implicate that activating Rho could be beneficial to suppress the Kras-induced liver malignancies.
  • Keywords: Ras, Zebrafish, Akt, RhoA, Hepatocellular carcinoma, Signaling crosstalk
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