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  • Nuclear factor B br Gastric cancer

    2020-08-30

    Nuclear factor-κB
    Gastric cancer (GC), one of the most common cancers of the digestive system, results in high morbidity and mortality, but the molecular mechanisms underlying GC remain largely unknown. Cadherin-17 (CDH17) is a nonclassical member of the cadherin (CDH) superfamily of calcium-dependent proteins. Despite recent advances in the understanding of CDH17 biology, the mechanism of CDH17 in GC proliferation, migration, and invasion has not been extensively studied. In the present study, we observed that CDH17 14003-96-4 was increased in GC tissues compared with para-carcinoma tissues and was correlated with lymph node metastasis and the AJCC stage. Additionally, a significant correlation was found between CDH17 protein expression and the number of blood and lymph vessels in GC tissues. Furthermore, in vitro suppression of CDH17 expression using short-interfering RNA (siRNA) decreased AGS cell proliferation, migration and invasion. Conversely, overexpression of CDH17 through plasmid transfection enhanced the malignant activity of AGS cells. Moreover, CDH17 increased the matrix metallopeptidase 2 (MMP-2) levels via the canonical nuclear factor-kappaB (NF-κB) pathway. Our findings offer new insights into the mechanism of the CDH17/NF-κB/MMP-2 axis, and the associated signalling pathways might represent novel targets for the treatment of GC.
    1. Introduction
    Gastric cancer (GC) is the fourth most common malignancy and the second leading cause of cancer-specific mortality worldwide, which makes GC a serious health problem (Cutsem et al., 2016; Chen et al., 2016). Although the prognosis for early GC after radical gastrectomy is good, the prognosis of patients with advanced GC remains poor, with a 5-year survival rate of < 25% (Okumura et al., 2014). This poor prognosis is partially linked to the aggressive biological behaviour of GC and a lack of efficient molecularly targeted therapies. Several mo-lecular targets for human GC have been proposed in recent years, and these include phosphoinositide-3kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), human epidermal growth factor receptor-2 (HER2), E-cadherin, and epidermal growth factor re-ceptor (EGFR) (Wadhwa et al., 2013; Lordick and Janjigian, 2016). However, the molecular mechanisms underlying GC remain largely
    unknown. Therefore, the development of novel molecular targets and derived therapeutic strategies has become increasingly urgent.
    The cadherin (CDH) superfamily consists of calcium-dependent proteins that serve as critical cell-cell adhesion molecules and play significant roles in embryonic development and the structural integrity of cells and tissues (Takeichi, 1995; Kemler, 1993). Disordered CDH expression is usually associated with disease pathologies, including tissue dysplasia or defects, autoimmune disorders, cancer invasion and cancer metastasis (Tu and You, 2014; Marie et al., 2014; Nieman et al., 1999).
    Cadherin-17 (CDH17) is a nonclassical member of the CDH super-family of calcium-dependent proteins that is found only in the em-bryonic gastrointestinal tract and foetal liver, whereas this gene is si-lenced in healthy adult liver and stomach tissues (Nollet et al., 2000; Hertel, 2012; Berndorff et al., 1994). However, recent studies have revealed abnormal CDH17 expression in major gastrointestinal
    Abbreviations: GC, gastric cancer; CDH17, cadherin-17; CDH, cadherin; siRNA, short-interfering RNA; MMP2, matrix metallopeptidase 2; NF-κB, nuclear factor-kappaB; HER2, human epidermal growth factor receptor-2; EGFR, epidermal growth factor receptor; PI3K/AKT/mTOR, phophoinositide-3-kinase/protein kinase B/ mammalian target of rapamycin
    Corresponding author.
    E-mail address: [email protected] (H.-j. Zhang). 1 These authors contributed equally to this manuscript.
    malignancies, including hepatocellular carcinoma, pancreatic cancer and colorectal cancer, and have indicated an association of CDH17 with invasive tumour phenotypes and poor survival (Luk et al., 2003; Su et al., 2008; Kwak et al., 2007). Furthermore, unlike the classical cad-herins (E-, N-, and P-cadherin), CDH17 is capable of mediating Ca2+-dependent homophilic cell-cell adhesion independent of cytoskeletal interactions (Kreft et al., 1997; Wendeler et al., 2007). This function indicates that CDH17 might play a crucial role in tumour development and progression, and this cadherin has therefore garnered increasing attention.
    In the present study, we showed that CDH17 expression was ele-vated in human GC tissues and that CDH17 expression was associated with clinical lymph node metastasis and the AJCC stage. Moreover, CDH17 was identified as a carcinogenic factor that promoted GC cell proliferation, migration and invasion in vitro, and we confirmed that these CDH17-induced activities occurred through the NF-κB/MMP-2 pathway.