Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver

Abstract

How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1 , mst1 , and mst2 , orthologs of Drosophila Salvador and hippo , respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5–6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1 , a second core Hippo signaling component that facilitates activation of mst1 and mst2 . Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Overexpression of TAZ has also been noted in human breast cancer samples and non-small cell lung cancer cell lines (Chan et al, 2008;Zhou et al, 2011b). Similar to YAP overexpression, ablation of the Hippo pathway components Mer and Sav and double knockout of Mst1/2 in mice result in liver enlargement and tumor formation characteristic of HCC and cholangiocarcinoma (CC) (Zhou et al, 2009;Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010;. Aberrant Mst1/2 and Lats1/2 expression is observed in human cancers (Hisaoka et al, 2002;Jimé-nez-Velasco et al, 2005;Takahashi et al, 2005;Jiang et al, 2006;Minoo et al, 2007;Seidel et al, 2007;Cho et al, 2009;Zhou et al, 2009).…”

“…It was first observed that intestinal-specific overexpression of YAP or knockout of Mst1/2 in mice caused marked expansion of the stem cell compartment (Camargo et al, 2007;Zhou et al, 2011a). Knockout of Hippo pathway components Mst1/2, Sav1, and Mer in liver also leads to accumulation of liver stem cells (Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010). The regulation of liver and intestinal stem cells by the Hippo pathway and its role in regeneration were discussed in great detail elsewhere (Chen et al, 2012).…”

hSav1 interacts with HAX1 and attenuates its anti-apoptotic effects in MCF-7 breast cancer cells

“…We also found that HAX1 is up-regulated in breast cancer samples compared to normal breast tissues by searching the Oncomine database, and therefore it may also play an important role in breast cancer progression. Recently the Hippo signaling pathway was reported to be a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation (36). The mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors (37).…”

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

“…Of course, Drosophila offers an ideal model system for such studies: The wide range of genetic and genomic approaches available for use in flies has helped in elucidation of the mechanisms underlying determination of leg size and leg or wing disc regeneration (Bergantiñ os et al, 2010;Sun and Irvine, 2010). Recent evidence encouragingly suggests that the Wts-Hpo signaling pathway and Yki may act through the regulation of cell fate to control organ size in vertebrate systems (Dong et al, 2007;Lu et al, 2010;Pan, 2010;Zhao et al, 2010). Further work is needed, however, to identify the upstream signals and downstream master regulatory genes of the Ds-Ft signaling pathway in limb development and regeneration.…”