ADAMTS10 通过 JAK/STAT/c-MYC 通路抑制侵袭性，并重塑巨噬细胞以在胃癌中创造抗恶性微环境。
ADAMTS10 inhibits aggressiveness via JAK/STAT/c-MYC pathway and reprograms macrophage to create an anti-malignant microenvironment in gastric cancer.
机构信息
Department of Gastrointestinal Surgery Section 2, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
出版信息
Gastric Cancer. 2022 Nov;25(6):1002-1016. doi: 10.1007/s10120-022-01319-4. Epub 2022 Aug 4.
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.
背景
解整合素金属蛋白酶 10（ADAMTS10）在细胞外基质中发挥作用，与 Weill-Marchesani 综合征相关。然而，其在胃癌中的作用尚不清楚。因此，我们开展了这项研究，旨在揭示 ADAMTS10 在胃癌（GC）中的作用。
方法
通过免疫组织化学染色和定量 RT-PCR（qRT-PCR）分析 GC 中 ADAMTS10 的表达。通过体外和体内功能实验研究 ADAMTS10 抑制 GC 细胞进展的作用。流式细胞术用于发现 ADAMTS10 在 GC 细胞中对细胞周期、凋亡和 ROS 的变化。Western blot 用于鉴定 ADAMTS10 的靶点。Western blot、qRT-PCR 和流式细胞术用于发现 ADAMT10 对 THP1 的影响。
结果
ADAMTS10 在 GC 组织中表达下调，ADAMTS10 水平较低的患者总生存率较差。ADAMTS10 过表达改变细胞周期，促进体外和体内的凋亡，并抑制增殖、迁移和侵袭。ADAMTS10 通过 JAK/STAT/c-MYC 通路调节 TXNIP 和 ROS。降低 TXNIP 和 ROS 逆转了 ADAMTS10 对细胞迁移和侵袭的抑制作用。GC 细胞分泌的 ADAMTS10 被 THP1 吸收，并调节 THP1 中的 TXNIP 和 ROS。GC 细胞分泌的 ADAMTS10 抑制巨噬细胞 M2 极化。
结论
这些结果表明，ADAMTS10 通过 JAK/STAT/c-MYC 通路靶向 TXNIP 和 ROS，可能在 GC 进展和巨噬细胞极化中发挥重要作用，这表明 ADAMTS10 可以作为胃癌的潜在生存标志物。
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