The Extracellular Small Leucine-Rich Proteoglycan Biglycan Is a Key Player in Gastric Cancer Aggressiveness

SIMPLE SUMMARY: Approximately 80% of gastric cancer patients are diagnosed at advanced stages with an average five-year survival rate of less than 30%. Alterations of the extracellular matrix proteins have been largely demonstrated in all steps of the disease. Thus, studies for the identification of novel prognostic biomarkers and efficient therapeutic strategies are urgently needed. In this study, we report the oncogenic role of biglycan, an extracellular proteoglycan, in gastric carcinogenesis. Biglycan was able to modulate gastric cancer aggressive features as cell survival, migration, and angiogenesis. Additionally, high levels of biglycan expression correlates with tumorigenic gene signatures and they are associated with poor patient prognosis in advanced stages of the disease. These results point biglycan as a key player in gastric cancer aggressiveness and further studies should be done to investigate the therapeutic potential of biglycan to tackle gastric cancer progression. ABSTRACT: Biglycan (BGN gene), an extracellular proteoglycan, has been described to be associated with cancer aggressiveness. The purpose of this study was to clarify the clinical value of biglycan as a biomarker in multiple independent GC cohorts and determine the in vitro and in vivo role of biglycan in GC malignant features. We found that BGN is commonly over-expressed in all analyzed cohorts, being associated with disease relapse and poor prognosis in patients with advanced stages of disease. In vitro and in vivo experiments demonstrated that biglycan knock-out GC cells display major phenotypic changes with a lower cell survival, migration, and angiogenic potential when compared with biglycan expressing cells. Biglycan KO GC cells present increased levels of PARP1 and caspase-3 cleavage and a decreased expression of mesenchymal markers. Importantly, biglycan deficient GC cells that were supplemented with exogenous biglycan were able to restore biological features, such as survival, clonogenic and migratory capacities. Our in vitro and in vivo findings were validated in human GC samples, where BGN expression was associated with several oncogenic gene signatures that were associated with apoptosis, cell migration, invasion, and angiogenesis. This study provided new insights on biglycan role in GC that should be taken in consideration as a key cellular regulator with major impact in tumor progression and patients’ clinical outcome.