Abstract
Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFβ in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFβ pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFβ, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFβ. Possible activation of the canonical TGFβ pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFβ with ASPN in GC and DCN with TGFβ in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFβ interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.
Highlights
According to GLOBOCAN 2018, about 782,685 people have died from gastric cancer (GC) and almost a million new cases have been added since [1]
One of the most interesting candidates that emerged from the pathway analysis was asporin (ASPN), a small leucine-rich proteoglycan (SLRP), which is a component of extracellular matrix organization protein [8,9,10]
In order to identify prognostic markers of stomach adenocarcinoma we have identified transcriptomic signatures that are consistently modulated according to the stages of tumor progression
Summary
According to GLOBOCAN 2018, about 782,685 people have died from gastric cancer (GC) and almost a million new cases have been added since [1]. Previous studies focused its roles in orthopedic diseases [11,12,13,14]; recent findings have reported it to have an oncogenic role in several cancers—pancreatic, colorectal, gastric, prostate cancers, and in invasive ducal breast carcinoma [15,16,17,18,19,20,21]. In triple-negative breast cancer, it is reported to function as a tumor suppressor gene [22]. Targeting the specific molecular signaling pathway of ASPN may unravel its role in precision medicine. Another SLRP which warranted concomitant attention was decorin (DCN), a putative tumor suppressor gene [23,24,25]
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