Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5'-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

中文翻译：

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CD73通过调节胃癌中的RICS / RhoA信号传导和EMT促进肿瘤转移。

肿瘤微环境在塑造癌症多样性中起着至关重要的作用，而CD73（ecto-5'-核苷酸酶； NT5E）是通过将免疫刺激性ATP转换成免疫抑制腺苷来调节癌症进展的新兴免疫检查点。然而，CD73如何被调节及其在癌症进展中的功能尚不清楚。在这里，我们表明CD73过表达并且与胃癌的不良预后相关。CD73在微环境转换中将腺苷能信号转导与转移过程中胃癌上皮-间充质转化表型的诱导相关。转录组数据的进一步途径和基因集富集分析揭示了CD73在RICS / RhoA信号传导中的调节作用是由于其在腺苷能途径中的细胞外功能引起的，随后抑制LIMK / cofilin的磷酸化并促进β-catenin活化。发现药理抑制CD73腺苷能信号转导诱导RICS功能障碍。扩散和血行转移模型表明，靶向CD73在胃癌中可以抑制实验性转移。总而言之，它证实了CD73作为治疗胃癌转移的靶标，并证实RICS是将CD73 /腺苷能信号转导至RhoA / LIMK / cofilin途径的细胞内功能分子。