ADAMTS10 inhibits aggressiveness via JAK/STAT/c-MYC pathway and reprograms macrophage to create an anti-malignant microenvironment in gastric cancer

Background:A disintegrin and metalloproteinase with thrombospondin motifs 10 (ADAMTS10) plays a role in extracellular matrix and correlates with Weill-Marchesani syndrome. However, its role in gastric cancer remains unknown. Thus, we started this research to unveil the role of ADAMTS10 in gastric cancer (GC).

Methods:The expression of ADAMTS10 in GC was analyzed by immunohistochemical staining and quantitative RT-PCR (qRT-PCR). The effects of ADAMTS10 inhibiting GC cell progression were conducted by functional experiments in vitro and in vivo. Flow cytometry was used to discover changing of cell cycle, apoptosis and ROS by ADAMTS10 in GC cell. Western blot was applied to identify targets of ADAMTS10. Western blot, qRT-PCR and flow cytometry were applied to discover the effect of ADAMT10 on THP1.

Results:ADAMTS10 expression was downregulated in GC tissue and patients with low ADAMTS10 levels had poorer overall survival. ADAMTS10 overexpression altered cell cycle, promoted apoptosis, and inhibited proliferation, migration, and invasion in vitro and in vivo. ADAMTS10 regulated TXNIP and ROS through the JAK/STAT/c-MYC pathway. Decreasing TXNIP and ROS reversed the inhibitory effect of ADAMTS10 on cell migration and invasion in vitro. ADAMTS10 secreted by GC cells was absorbed by THP1 and regulated TXNIP and ROS in THP1. ADAMTS10 secreted by GC cells inhibited macrophage M2 polarization.

Conclusions:These results suggest that ADAMTS10 targets TXNIP and ROS via the JAK/STAT/c-MYC pathway and that may play important roles in GC progression and macrophage polarization which indicates that ADAMTS10 can be a potential survival marker for gastric cancer.

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