WISP-2 in human gastric cancer and its potential metastatic suppressor role in gastric cancer cells mediated by JNK and PLC-γ pathways

Abstract

Background:It has recently been shown that WISP proteins (Wnt-inducted secreted proteins), a group of intra- and extra-cellular regulatory proteins, have been implicated in the initiation and progression of a variety of tumour types including colorectal and breast cancer. However, the role of WISP proteins in gastric cancer (GC) cells and their clinical implications have not yet been elucidated.Methods:The expression of WISP molecules in a cohort of GC patients was analysed using real-time quantitative PCR and immunohistochemistry. The expression of a panel of recognised epithelial–mesenchymal transition (EMT) markers was quantified using Q-PCR in paired tumour and normal tissues. WISP-2 knockdown (kd) sublines using ribozyme transgenes were created in the GC cell lines AGS and HGC27. Subsequently, several biological functions, including cell growth, adhesion, migration and invasion, were studied. Potential pathways for the interaction of EMT, extracellular matrix and MMP were evaluated.Results:Overexpression of WISP-2 was detected in GC and significantly correlated with early tumour node-metastasis staging, differentiation status and positively correlated with overall survival and disease-free survival of the patients. WISP-2 expression was inversely correlated with that of Twist and Slug in paired samples. Kd of WISP-2 expression promoted the proliferation, migration and invasion of GC cells. WISP-2 suppressed GC cell metastasis through reversing EMT and suppressing the expression and activity of MMP9 and MMP2 via JNK and ERK. Cell motility analysis indicated that WISP-2 kd contributed to GC cells' motility and can be attenuated by PLC-γ and JNK small inhibitors.Conclusions:Increased expression of WISP-2 in GC is positively correlated with favourable clinical features and the survival of patients with GC and is a negative regulator of growth, migration and invasion in GC cells. These findings suggest that WISP-2 is a potential tumour suppressor in GC.

miR-146a-5p mediates epithelial–mesenchymal transition of oesophageal squamous cell carcinoma via targeting Notch2

“…EMT progression triggers the dissociation of carcinoma cells from primary carcinomas, which subsequently migrate and disseminate to distant sites (Nieto et al , 2016). This progression can be triggered by many signaling pathways, including Notch (Chen et al , 2010), transforming growth factor- β (Chen et al , 2016), epidermal growth factor (Liu et al , 2015), fibroblast growth factor (Du et al , 2015) and PLC- γ (Ji et al , 2015) pathways.…”

Deficiency of CCN5/WISP-2-Driven Program in breast cancer Promotes Cancer Epithelial cells to mesenchymal stem cells and Breast Cancer growth

“…9). Thus, it is enticing to speculate that restoring of CCN5 or CCN5 protein treatment may exert therapeutic benefit in BC and possibly other cancers via regulating BC cell plasticity 28, 47–49 .

Figure 9Diagram illustrating CCN5 regulation of molecular markers associated with cell growth, EMT and stemness in TNBC cells. Blue indicates upregulated proteins and orange indicates downregulated proteins.

…”

CCN5 inhibits proliferation and promotes apoptosis of oral squamous cell carcinoma cells

“…In general, CCN proteins play important roles in various biological processes, such as cell proliferation, differentiation, invasion, migration, apoptosis, and EMT (Dhar et al, 2007; Chen and Lau, 2009). Over the last few years, studies have shown that CCN5 plays a crucial part in tumor malignancies (Cervello et al, 2004; Dhar et al, 2007; Banerjee et al, 2008; Davies et al, 2010; Frewer et al, 2013; Haque et al, 2015; Ji et al, 2015). Downregulation of CCN5 has been suggested in human HNSC (Oncomine database).…”

“…The literature of Haque et al (2015) showed that activation of CCN5 reduced cell proliferation, arrested cell growth, and decreased cyclin D1 expression in triple‐negative breast cancer cells. Silencing CCN5 expression promoted proliferation of gastric cancer cells (Ji et al, 2015). However, several reports indicated that CCN5 suppression, but not its overexpression, significantly inhibited the proliferation of MCF7 cells (Banerjee et al, 2003).…”

“…Furthermore, current studies also highlight that inhibition of CCN5 promotes epithelial–mesenchymal transition (EMT) and generates a stem‐like cell phenotype (Ferrand et al, 2014), as well as activates cytotoxic T‐lymphocyte (CTL)‐induced killing and immunosurveillance evasion in MCF7 breast cancer cells (Akalay et al, 2015). Additional reports suggest that CCN5 acts as an inhibitor in the tumorigenesis and metastasis of gastric cancer, colorectal cancer, and pancreatic cancer (Dhar et al, 2007; Frewer et al, 2013; Ji et al, 2015). Weak expression of CCN5 has been observed in salivary gland tumors (Kouzu et al, 2006).…”