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    • br Materials and Methods br Results br

    2018-11-09


    Materials and Methods
    Results
    Conclusion Our meta-analysis suggested that DNMT1 rs16999593 and DNMT3A rs1550117 could contribute to GC and that DNMT3B rs1569686 might function as a protective factor against gastric carcinogenesis. By using these significant SNPs as biomarkers, it is feasible to estimate the risk of catching GC and thus formulate timely preventive strategy.
    Author Contributions
    Funding This work was supported by Natural Science Foundation of China (NSFC, NO: 81473624) and Key Specialty Foundation of The State Administration of Traditional Chinese Medicine (NO:ZJ0901ZL020). The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
    Conflicts of Interest
    Introduction Malignant features such as sustained proliferative signaling, refractoriness to growth suppressors, resistance to cell death or aberrant motility and metastasis, can be triggered by a variety of distinctive mutations and signaling adaptations (Hanahan and Weinberg, 2011). This complexity translates into phenotypic variability among tumors. A prototypic example is breast cancer, a heterogeneous disease encompassing different histopathological entities with distinct molecular signatures, genetic and genomic variations (Bertos and Park, 2011). Ductal carcinomas (circa 80% of all breast cancers) are grouped in several types based on the phalloidin receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 or ERBB2). The most common is the luminal type characterized by ER+ and (or) PR+ with a HER− (A subtype) or HER+ (B subtype) status. Along with the luminal B subtype, the HER2ERBB2-positive (ER and PR negative) and basal-like tumors lacking ER, PR and ERBB2 expression (triple negative) exhibit the worst prognosis (Bertos and Park, 2011; Hanahan and Weinberg, 2011). Enhanced activation of the RAS-mitogen activated protein kinase (MAPK) pathway triggered by amplification or up-regulation of growth factor receptors (ERBB2, IGF1R, EGFR), ER activation and alterations in the PI3K-AKT pathway are major contributors to the uncontrolled cellular proliferation and increased survival of breast tumor cells (Saini et al., 2013). In addition to these oncogenic drivers, signaling nodes can act as cancer-associated factors by cooperating with oncogene-governed pathways or participating in compensatory transduction networks to strengthen tumor properties. G-protein-coupled receptor kinase 2 (GRK2) is emerging as one of such key nodes. Besides its canonical role in the desensitization of G protein-coupled receptors (GPCR) (Penela et al., 2010a; Premont and Gainetdinov, 2007), GRK2 is a positive effector of certain GPCR and receptor-tyrosine kinases (RTK) transduction cascades. Excessive signaling from diverse GPCRs can lead to aberrant survival, cellular growth and invasive motility in a variety of cancer cells (Lappano and Maggiolini, 2011). GRK2 has been identified as a rate-limiting mediator of MAPK activation and growth signaling triggered by some tumor-related GPCRs (Lipfert et al., 2013; Penela et al., 2008; Philipp et al., 2008). GPCRs can also trans-activate the EFGR by means of the GRK-β-arrestin-axis (Rozengurt, 2007). These effects may be explained by the ability of GRK2 to phosphorylate or dynamically interact with important modulators engaged along the MAPK pathway (Deiss et al., 2012; Penela et al., 2010b, 2008). Moreover, other relevant GRK2-interacting proteins or substrates are key players in the cellular stress response and survival (Lafarga et al., 2012b; Robinson and Pitcher, 2013) and references therein). Despite such potential connectivity to signaling pathways related to cell transformation, and available data showing altered GRK2 levels in some tumoral contexts (reviewed in Evron et al. (2012), Penela et al. (2010a)) a comprehensive study of the role of GRK2 in tumor formation and progression has not been addressed. We report here that GRK2 levels are altered in breast luminal tumors and that increased GRK2 functionality in diverse breast cancer cell types represents a driving signaling event in the acquisition and maintenance of tumoral proliferation and survival, by mechanisms involving the potentiation of Histone Deacetylase 6 (HDAC6) function and the modulation of Pin1 (Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) acetylation status and functionality.