Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo, 315020, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China.
Oncogene. 2024 Jul;43(28):2160-2171. doi: 10.1038/s41388-024-03062-9. Epub 2024 May 23.
It has been demonstrated that tRNA-derived small RNAs (tsRNAs) perform essential functions in the pathophysiology of cancer. In this study, we focused on the possible mechanisms of tRF-33-P4R8YP9LON4VDP (tRF-33) underlying the development of gastric malignancy. In total, 454 tissue samples with different gastric mucosal lesions were collected. The tRF-33 expression level in different cohorts was determined, and its value for diagnostic efficiency and prognosis evaluation were assessed. Cell proliferation assays, Transwell assay, flow cytometry, and xenotransplantation model were used to evaluate its effect on gastric cancer cells. The molecular mechanism was verified by fluorescence in situ hybridization, dual luciferase assay, Western blot, and RNA binding protein immunoprecipitation. The results showed that the expression of tRF-33 exhibited a gradual modification from normal control samples to gastritis tissues, early and latent stage of gastric cancer tissues. Consequently, tRF-33 holds significant potential as a predictive and diagnostic biomarker for gastric malignancy. Over-expression of tRF-33 inhibited gastric cancer cell progression and metastatic viability, and induced cell apoptosis. Tumorigenicity in nude mice showed the suppressive characteristics of tRF-33. Mechanistic investigation revealed that tRF-33 exerted silencing on STAT3 mRNA via binding to AGO2. In conclusion, tRF-33 exhibited values in diagnosing gastric cancer and evaluating its prognosis, and suppressed tumor cell viability by inhibiting STAT3 signaling pathway. The schematic mechanisms underlying tRF-33 regulating gastric cancer occurrence. tRF-33 binds to AGO2 proteins and then negatively regulates STAT3 expression through targeting its 3'UTR. The downregulated expression of STAT3 results in the decrease of STAT3 and p-STAT3 and further blocks the transcription of the downstream genes and finally inhibits the gastric cancer occurrence. MMP-9, matrix metalloproteinase-9; Bcl-2, B-cell lymphoma-2; STAT3, signal transducer and activator of transcription 3; UTR, untranslated region.
已经证明 tRNA 衍生的小 RNA（tsRNAs）在癌症的病理生理学中发挥着重要作用。在这项研究中，我们专注于 tRF-33-P4R8YP9LON4VDP（tRF-33）在胃癌发生发展中的潜在机制。共收集了 454 份具有不同胃黏膜病变的组织样本。测定不同队列中 tRF-33 的表达水平，并评估其对诊断效率和预后评估的价值。细胞增殖实验、Transwell 实验、流式细胞术和异种移植模型用于评估其对胃癌细胞的影响。通过荧光原位杂交、双荧光素酶报告基因检测、Western blot 和 RNA 结合蛋白免疫沉淀验证其分子机制。结果表明，tRF-33 的表达从正常对照样本到胃炎组织、胃癌早期和潜伏期组织逐渐改变。因此，tRF-33 作为胃癌的预测和诊断生物标志物具有重要意义。tRF-33 的过表达抑制了胃癌细胞的进展和转移活力，并诱导细胞凋亡。裸鼠肿瘤生成显示了 tRF-33 的抑制作用。机制研究表明，tRF-33 通过与 AGO2 结合对 STAT3 mRNA 发挥沉默作用。总之，tRF-33 在诊断胃癌和评估其预后方面具有价值，并通过抑制 STAT3 信号通路抑制肿瘤细胞活力。tRF-33 调节胃癌发生的机制示意图。tRF-33 与 AGO2 蛋白结合，然后通过靶向其 3'UTR 负调控 STAT3 表达。STAT3 表达下调导致 STAT3 和 p-STAT3 减少，进一步阻断下游基因的转录，最终抑制胃癌的发生。MMP-9，基质金属蛋白酶-9；Bcl-2，B 细胞淋巴瘤-2；STAT3，信号转导和转录激活因子 3；UTR，非翻译区。
