MMP7 Induces T-DM1 Resistance and Leads to the Poor Prognosis of Gastric Adenocarcinoma via a DKK1-Dependent Manner

Background: Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients Methods: Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression.

Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis.

Results: MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1.

Conclusion: DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.

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