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Title: The role of Wnt-induced secreted proteins (WISPs) in gastric cancer
Author: Ji, Jiafu
ISNI:       0000 0004 5359 8819
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Introduction: It has been recently shown that the WISP proteins (Wnt-inducted secreted proteins), a group of intra- and extra-cellular regulatory proteins, have been implicated in the initiation and progression of variety types of tumours including colorectal and breast cancer. However, the role of WISP proteins in gastric cancer (GC) cells and clinical implication in gastric cancer has not yet been fully elucidated. Materials and methods: The expression of the WISP transcript and proteins in a cohort of GC patients was analysed using real-time quantitative PCR and immunohistochemistry, respectively. The expression of a panel of recognised EMT (epithelial-mesenchymal transition) markers were quantified (Q-PCR) in paired tumour and normal gastric tissues. WISP-2 knockdown sublines using anti-WISP-2 ribozyme transgenes were created in GC cell lines AGS and HGC27. Using the cell models and proteins extracted from gastric tissue samples, protein microarray was used to search for potential protein partners and signalling pathways involved with WISP-2. Subsequently, the biological functions, namely, cell growth, adhesion, migration and invasion, were studied. Potential mechanisms related with EMT, extracellular matrix and MMP (Matrix metalloproteinases) and signalling pathways were investigated. Results: Expression of WISP-2 was frequently detected in GC tissues. Levels of WISP-2, not WISP-1 and WISP-3, was significantly correlated with early TNM staging and differentiation status. High levels of WISP-2 were associated with a favourable clinical outcome and survival of the patients. We also found that WISP-2 expression inversely correlated with Twist and Slug in the paired gastric samples. Knockdown of WISP-2 expression increased the rate of proliferation, migration and invasion of GC cells and influenced expression of EMT biomarkers including Twist, Slug and Ecadherin. Using an antibody based protein microarray, ERK, JNK as well as AKT proteins were found to be co-precipiated with WISP-2 protein from human gastric tissue proteins. Furthermore, WISP-2 knockdown gastric cell lines also demonstrated a change in the ERK and JNK phophorylation. Mechanistically, WISP-2 suppressed GC cell metastasis through reversing epithelial-mesenchymal transition and suppressing the expression and activity of MMP-9 and MMP-2 via JNK and ERK. Cell motility analysis indicated that WISP-2 knockdown contributed to GC cells’ motility, an effect attenuated by PLC-γ and JNK small inhibitors. Conclusions: WISP-2 transcript and protein expressions are inversely linked to disease progression and linked to the survival of patients with gastric cancer. WISP-2 has a profound influence on the migration and adhesion of gastric cancer cells and is a powerful factor to reverse the EMT process in these cells. These effects of WISP-2 are via its involvement in the ERK and JNK pathways, which in turn modulate the MMP activities. Together, WISP-2 is an important regulator of the cellular function and an important factor in the progression of gastric cancer. It acts as a potential tumour suppressor in gastric cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)