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  • br Acknowledgment S A was

    2022-05-23


    Acknowledgment S.A was supported by V Plan Propio US-Acceso USE-14793-G.
    Introduction The Hippo signaling pathway is an evolutionarily conserved pathway that controls organ size and cell differentiation across diverse organisms through the regulation of cell proliferation and apoptosis (Di Cara et al., 2015, Pan, 2010, Yu and Guan, 2013, Zhao et al., 2007). The core of the Hippo pathway is a kinase cascade consisting of STE20-like protein kinase 1 (STK3, also known as MST2, and STK4, also known as MST1), the large tumor suppressors (LATS1 and LATS2), and adaptor proteins Salvador homolog 1 (SAV1) and MOB kinase activators (MOB1A/MOB1B) (Tapon et al., 2002). These kinases directly phosphorylate the major Hippo pathway downstream effectors, the yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ), and thus inhibit the transcription of their downstream target V5 Epitope sale (Cho et al., 2006, Hansen et al., 2015, Johnson and Halder, 2014, Oka et al., 2008). In recent years, the critical role of the Hippo pathway in cancer development has been increasingly recognized (Bonilla et al., 2016, Bueno et al., 2016, Gao et al., 2014, Yu et al., 2015, Zanconato et al., 2016). Dysregulated signaling by the Hippo pathway has been reported in several cancer types such as breast, liver, lung, prostate, gastric, and colorectal tumors (Cordenonsi et al., 2011, Harvey et al., 2013, Jiao et al., 2014, Lau et al., 2014, Nguyen et al., 2015, Yimlamai et al., 2014, Zhang et al., 2017, Zhou et al., 2009). Extensive studies have experimentally established its tumor suppressor function. For example, STK3/STK4 loss in a mouse liver leads to uncontrolled cell proliferation and differentiation (Zhou et al., 2009), and YAP/TAZ overexpression leads to tissue overgrowth and cancer (Camargo et al., 2007, Dong et al., 2007).
    Results
    Discussion Using the latest TCGA multi-dimensional molecular profiling data, we performed a comprehensive molecular characterization of the Hippo pathway across >9,000 samples of 33 cancer types. In addition to computational analyses, we have experimentally assessed the effects of YAP1/TAZ somatic mutations using cellular assays. In total, we identified 11 non-silent mutations that affect cell viability and proliferation, filling a critical knowledge gap about YAP1/TAZ somatic mutations. We inferred miRNA regulation by considering both sequence information and expression pattern, and validated two TAZ-negative regulators, miR-200a and miR-590. This combined computational and experimental approach represents the direction for characterizing key cancer pathways in the post-genome era. Our analysis reveals that diverse mechanisms drive pathway dysregulation in tumor contexts. We not only confirm the mutation-driven mechanisms in MESO as previously reported, but also highlight the critical role of Hippo pathway signaling in squamous cell cancers. Through our integrated analyses of BLCA, CESC, ESCA, LUSC, and HNSC, we reveal frequent YAP1/TAZ amplifications, high expression heterogeneity, and significant prognostic correlations. Given the strong selective pressure to alter the Hippo pathway and activate YAP/TAZ in these cancers, Hippo pathway signaling appears to play a major role in shaping tumor progression and may represent a promising target for future development of novel therapies. Another cancer of particular interest is LGG, for which Hippo pathway activity shows the strongest correlation with patient survival times and the most extensive associations with known drivers such as IDH1 mutations. However, this disease shows low-frequency aberrations among Hippo pathway genes in terms of both mutations and SCNAs, suggesting a role of unknown epigenetic mechanisms controlling Hippo pathway signaling. We systematically constructed cancer-type-specific Hippo regulatory networks by integrating various types of molecular data. The associations between somatic driver events with Hippo pathway signaling may coordinate the cross-talk between the Hippo pathway and other signaling pathways. In the modeling results, we identified the miR-200 family as master regulators for YAP/TAZ activity. The miR-200 family is best known for its regulatory role in the EMT pathway. Although it has been demonstrated that miR-200 targets YAP1 in breast cancer (Yu et al., 2013), its functional impact on the Hippo pathway remains largely unexplored and is worth further exploration in the future. Taken together, our focused and systematic analyses of this important molecular pathway will serve as a valuable resource for understanding its dysregulation in cancers and how to maximize its clinical utility.