Wang Hui, Huang Weikang, Fan Xirui, He Xiaoxue, Chen Sijin, Yu Su, Zhang Yan
Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
Department of Gastroenterology, The Affiliated YanAn Hospital of Kunming Medical University, Kunming, China.
J Oncol. 2022 Apr 29;2022:8777697. doi: 10.1155/2022/8777697. eCollection 2022.
Emerging studies have proved that tRNA-derived fragments (tRFs) play vital roles in tumor metastasis; however, the function of tRFs in gastric cancer (GC) remains largely unclear. We investigated the role of tRF-24-V29K9UV3IU in growth and metastasis of GC using a xenograft mouse model. Differential gene expression downstream of tRF-24-V29K9UV3IU was identified by transcriptome sequencing, and interaction was then verified by a dual luciferase reporter and RNA immunoprecipitation. MKN-45 cells were also used to explore the biological functions of tRF-24-V29K9UV3IU . Here, knockdown of tRF-24-V29K9UV3IU promoted tumor growth and metastasis of GC . The expression of tRF-24-V29K9UV3IU and E-cadherin (epithelial cell marker) was down-regulated in tumors of mice following tRF-24-V29K9UV3IU knockdown, whereas the mesenchymal cell markers N-cadherin and vimentin displayed an opposite trend. Transcriptome sequencing identified 87 differentially expressed genes (DEGs) down-regulated in the tRF-24-V29K9UV3IU-overexpressed groups compared with the control group. Among them, G-protein-coupled receptor 78 (GPR78), the most significantly down-regulated DEG, was also predicted to be a target of tRF-24-V29K9UV3IU. Moreover, tRF-24-V29K9UV3IU could function as a miRNA-like fragment and bind to AGO2 and directly silence GPR78 expression by complementing with the 3'-untranslated region of the GPR78 mRNA. Functionally, overexpression of tRF-24-V29K9UV3IU significantly suppressed proliferation, migration, and invasion and promoted apoptosis of MKN-45 cells, whereas GPR78 attenuated these effects. Therefore, our data suggest that tRF-24-V29K9UV3IU functions as a miRNA-like fragment to suppress GPR78 expression and thus inhibit GC progression. These observations suggest that the tRF-24-V29K9UV3IU/GPR78 axis serves as a potential therapeutic target in GC.
新兴研究已证明，转运RNA衍生片段（tRFs）在肿瘤转移中发挥着至关重要的作用；然而，tRFs在胃癌（GC）中的功能仍 largely不清楚。我们使用异种移植小鼠模型研究了tRF-24-V29K9UV3IU在GC生长和转移中的作用。通过转录组测序鉴定了tRF-24-V29K9UV3IU下游的差异基因表达，然后通过双荧光素酶报告基因和RNA免疫沉淀验证了相互作用。还使用MKN-45细胞来探索tRF-24-V29K9UV3IU的生物学功能。在此，敲低tRF-24-V29K9UV3IU促进了GC的肿瘤生长和转移。敲低tRF-24-V29K9UV3IU后，小鼠肿瘤中tRF-24-V29K9UV3IU和E-钙黏蛋白（上皮细胞标志物）的表达下调，而间充质细胞标志物N-钙黏蛋白和波形蛋白则呈现相反趋势。转录组测序鉴定出与对照组相比，在tRF-24-V29K9UV3IU过表达组中有87个差异表达基因（DEGs）下调。其中，下调最显著的DEG——G蛋白偶联受体78（GPR78），也被预测为tRF-24-V29K9UV3IU的一个靶点。此外，tRF-24-V29K9UV3IU可以作为一种类似miRNA的片段，与AGO2结合，并通过与GPR78 mRNA的3'非翻译区互补直接沉默GPR78表达。在功能上，tRF-24-V29K9UV3IU的过表达显著抑制了MKN-45细胞的增殖、迁移和侵袭，并促进了其凋亡，而GPR78减弱了这些作用。因此，我们的数据表明，tRF-24-V29K9UV3IU作为一种类似miRNA的片段发挥作用，抑制GPR78表达，从而抑制GC进展。这些观察结果表明，tRF-24-V29K9UV3IU/GPR78轴可能是GC的一个潜在治疗靶点。
