A genetic variant in PNPLA3 (PNPLA3 I148M ), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3 WT ) or mutant PNPLA3 (PNPLA3 I148M ) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3 I148M , but not PNPLA3 WT , in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3 I148M transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3 I148M in NAFLD.
The Hippo signaling pathway and its two downstream effectors, the YAP and TAZ transcriptional coactivators, are drivers of tumor growth in experimental models. Studying mouse models, we show that YAP and TAZ can also exert a tumor-suppressive function. We found that normal hepatocytes surrounding liver tumors displayed activation of YAP and TAZ and that deletion of Yap and Taz in these peritumoral hepatocytes accelerated tumor growth. Conversely, experimental hyperactivation of YAP in peritumoral hepatocytes triggered regression of primary liver tumors and melanoma-derived liver metastases. Furthermore, whereas tumor cells growing in wild-type livers required YAP and TAZ for their survival, those surrounded by Yap- and Taz-deficient hepatocytes were not dependent on YAP and TAZ. Tumor cell survival thus depends on the relative activity of YAP and TAZ in tumor cells and their surrounding tissue, suggesting that YAP and TAZ act through a mechanism of cell competition to eliminate tumor cells.
The Hippo signal transduction pathway is an important regulator of organ growth and cell differentiation, and its deregulation contributes to the development of cancer. The activity of the Hippo pathway is strongly dependent on cell junctions, cellular architecture, and the mechanical properties of the microenvironment. In this review, we discuss recent advances in our understanding of how cell junctions transduce signals from the microenvironment and control the activity of the Hippo pathway. We also discuss how these mechanisms may control organ growth during development and regeneration, and how defects in them deregulate Hippo signaling in cancer cells.
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19−), combined hepatocellular–cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19− HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19− HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
IntroductionHematopoietic stem cells (HSCs) give rise to all lineages of mature blood cells and maintain hematopoiesis in vivo through a balance of self-renewal and differentiation. To maintain this balance, HSCs are supported within a complex milieu known as the hematopoietic microenvironment (HM) or HSC niche. 1,2 This HM includes cellular components (osteoblastic cells, 3,4 perivascular cells, 5 and sympathetic neurons 6 ), bone mineral matrix, 7 and ionic gradients. 8 Trabecular bone appears to be particularly important in HSC biology 3,9,10 ; however, there is ongoing controversy regarding the existence or identity of one predominant cell type that is necessary and sufficient for HSC survival in vivo. Apparently conflicting results have identified osteoblastic cells, 3,11-13 perivascular cells, 5 and a nestin-positive common precursor cell type with the ability to differentiate into either lineage as key cells within the HSC niche. Irrespective of this controversy, it has been firmly established that key ligand/receptor signaling interactions are responsible for HSC engraftment and mobilization from the HM. These include the interactions between CXCL12 (also known as SDF1) and CXCR4,14,15 between the cKit receptor and SCF, 16 and between fibronectin and 1-integrins. 17,18 The Rac family of Rho GTPases (encompassing Rac1, Rac2, and Rac3) integrates a critical downstream common pathway of the aforementioned signaling pathways. Through this, Rac proteins regulate the homing, engraftment, mobilization, and survival of HSCs in vivo (for a recent, comprehensive review, see Cancelas and Williams 19 ). Deletion of Rac1 in HSCs causes failed HSC engraftment and reduced HSC proliferation in vivo. 20 Deletion of Rac2 alone has modest but significant effects on HSC mobilization and engraftment 21 and leads to reduced HSC survival through impaired growth factor signaling and increased apoptosis. 20 Combined deletion of Rac1 and Rac2 causes a massive egress of HSCs from the HM and profoundly impaired engraftment. 20,22 Vav1, a hematopoietic-specific guanine exchange factor for Rac, differentially regulates endosteal/osteoblast and perivascular retention and subsequent engraftment. 23 Moreover, Rac1 and Rac2 were shown to be important for the survival of leukemia stem cells in a murine model of chronic myeloid leukemia. 24 These findings were reinforced by the development and preclinical testing of NSC23766, a small-molecule inhibitor of Rac signaling that has substantial in vivo effects including HSC mobilization 22 and antileukemic efficacy. 24 Whereas Rac3 is widely expressed with high levels of expression in the CNS 25 and Rac3-deficient mice show no obvious hematopoietic phenotype, we have previously shown functional redundancy of Rac3 in leukemic cells expressing p210-BCR-ABL. 24 Interestingly, despite the breadth of knowledge regarding the cell-intrinsic requirements for Rac signaling in HSC function, little is known about the function of Rac within HM components and therefore about cell-extrinsic Rac signaling...
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