Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer.
Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer.
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外泌体传递的tRF-16-K8 J7 K1 B通过减少乳腺癌中药物诱导的细胞凋亡促进他莫昔芬耐药性
作者：
虽然激素受体阳性(HR+)乳腺癌的预后已得到显著改善，但他莫昔芬耐药仍是HR+乳腺癌治疗中的一个挑战。本研究证实TRF-16-K8J7K1B是一种源于tRNAAla-TGC 3‘端的新的小ncRNA，与亲本细胞相比，TRF-16-K8J7K1B在三苯氧胺耐药细胞中高表达。此外，细胞外TRF-16-K8J7K1B通过掺入外切体产生对他莫昔芬的耐药性，进而降低细胞凋亡相关蛋白的表达，从而降低药物诱导的细胞凋亡比例。因此，我们认为外体TRF-16-K8J7K1B可能成为克服他莫昔芬耐药性的潜在预测生物标志物和治疗靶点。激素受体阳性(HR+)乳腺癌患者对他莫昔芬的耐药性仍然是一个挑战。最近的证据表明，转移核糖核酸(TRNA)衍生的片段在各种肿瘤的发生和发展中起着关键作用。然而，tRNA衍生片段与他莫昔芬耐药性之间的关系尚不清楚。在本研究中，我们发现与他莫昔芬敏感细胞相比，TRF-16-K8J7K1B在他莫昔芬耐药细胞中的表达上调。在HR+乳腺癌中，TRF-16-K8J7K1B水平较高与较短的无病生存期相关。TRF-16-K8J7K1B的过表达促进了他莫昔芬的耐药性。此外，胞外TRF-16-K8J7K1B可以被包装成外切体，并将他莫昔芬耐药性传播给受体细胞。机制上，外体TRF-16-K8J7K1B通过靶向受体细胞中肿瘤坏死因子相关的凋亡诱导配体，下调caspase 3和聚ADP-核糖聚合酶等凋亡相关蛋白的表达，从而减少药物诱导的细胞凋亡。在治疗方面，抑制外体TRF-16-K8J7K1B增加了乳腺癌细胞对三苯氧胺的体内敏感性。这些数据表明，外体TRF-16-K8J7K1B可能是克服HR+乳腺癌他莫昔芬耐药的一个新的治疗靶点。
While the prognosis of hormone receptor-positive (HR+) breast cancer has been significantly improved, tamoxifen resistance remains a challenge in the treatment of HR+ breast cancer. This study identified that tRF-16-K8J7K1B, a novel small ncRNA derived from the 3′-end of tRNAAla-TGC, was highly expressed in tamoxifen-resistant cells compared to parental cells. Moreover, extracellular tRF-16-K8J7K1B confers tamoxifen resistance via incorporation into exosomes and then degrades the expression of apoptosis-related proteins, reducing the proportion of drug-induced cell apoptosis. Therefore, we propose that exosomal tRF-16-K8J7K1B could be a potential predictive biomarker and therapeutic target for overcoming tamoxifen resistance. Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
18.4
作者：
Deng D;Shah K
通讯作者：
Shah K
影响因子：
64.5
作者：
Goodarzi H;Liu X;Nguyen HC;Zhang S;Fish L;Tavazoie SF
通讯作者：
Tavazoie SF
长非编码RNA H19通过自噬促进乳腺癌他莫昔芬耐药
影响因子：
28.5
作者：
Wang, Ji;Xie, Shuduo;Zhou, Jichun
通讯作者：
Zhou, Jichun
外泌体传输的 lncARSR 通过充当竞争性内源性 RNA 促进肾癌舒尼替尼耐药
影响因子：
50.3
作者：
Qu, Le;Ding, Jin;Wang, Lin-Hui
通讯作者：
Wang, Lin-Hui