转移 RNA (tRNA) 影响各种癌症的发生和进展，但在三阴性乳腺癌 (TNBC) 进展过程中个体 tRNA 的调节方式仍知之甚少。在这里，我们发现 XPOT (Exportin-T) 是 tRNA 的核输出蛋白受体，与乳腺癌的不良预后相关，并直接协调一部分 tRNA 的核输出，随后促进人 TNBC 细胞的蛋白质合成和增殖。 XPOT敲低在体外抑制TNBC细胞增殖，RNA-seq表明XPOT参与TNBC细胞胞质分裂的完成。 tRNA 高通量测序表明，XPOT 特异性影响参与核质运输的 tRNA 同解码器子集，包括 tRNA-Ala-AGC-10-1。通过密码子优先分析和蛋白质质谱分析，我们发现XPOT优先将核tRNA-Ala-AGC-10-1转运至细胞质，驱动TPR重复蛋白19（TTC19）的翻译。 TTC19对于TNBC细胞的胞质分裂和增殖也是不可或缺的。总而言之，这些发现为通过 XPOT 优先 tRNA 同解码器核质运输提供了一种新的调节翻译机制，它协调特定 tRNA 的空间位置和 mRNA 的翻译，以促进 TNBC 的增殖和进展。靶向 XPOT 可能是治疗 TNBC 的一种新颖的治疗策略。© 作者。

Transfer RNAs (tRNAs) impact the development and progression of various cancers, but how individual tRNAs are modulated during triple-negative breast cancer (TNBC) progression remains poorly understood. Here, we found that XPOT (Exportin-T), a nuclear export protein receptor of tRNAs, is associated with poor prognosis in breast cancer and directly orchestrates the nuclear export of a subset of tRNAs, subsequently promoting protein synthesis and proliferation of human TNBC cells. XPOT knockdown inhibited TNBC cell proliferation in vitro, and RNA-seq indicated that XPOT is involved in the completion of cytokinesis in TNBC cells. High-throughput sequencing of tRNA revealed that XPOT specifically influenced a subset of tRNA isodecoders involved in nucleocytoplasmic trafficking, including tRNA-Ala-AGC-10-1. Through codon preferential analysis and protein mass spectrometry, we found that XPOT preferentially transported nuclear tRNA-Ala-AGC-10-1 to the cytoplasm, driving the translation of TPR Repeat Protein 19 (TTC19). TTC19 is also indispensable for cytokinesis and proliferation of TNBC cells. Altogether, these findings provide a novel regulatory translation mechanism for preferential tRNA isodecoder nucleocytoplasmic transport through XPOT, which coordinates the spatial location of specific tRNA and the translation of mRNA to facilitate TNBC proliferation and progression. Targeting XPOT may be a novel therapeutic strategy for treating TNBC.© The author(s).