作为曲妥珠单抗耐药乳腺癌新型预测生物标志物的tRNA衍生片段
tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer.
作者信息
Sun Chunxiao, Yang Fan, Zhang Yanhong, Chu Jiahui, Wang Jian, Wang Yifan, Zhang Yanqiu, Li Jun, Li Yongfei, Fan Ruihua, Li Wei, Huang Xiang, Wu Hao, Fu Ziyi, Jiang Zefei, Yin Yongmei
机构信息
Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
The First Clinical College of Nanjing Medical University, Nanjing, China.
出版信息
Cell Physiol Biochem. 2018;49(2):419-431. doi: 10.1159/000492977. Epub 2018 Aug 28.
BACKGROUND/AIMS: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs, a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tRNA-derived fragments and trastuzumab resistance is still unknown.
METHODS
We detected the levels of tRNA-derived fragments expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed fragments in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tRNA-derived fragments. Progression-free survival (PFS) was analyzed using Cox-regression.
RESULTS
Our sequence results showed that tRNA-derived fragments were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression were associated with significantly shorter PFS in patients with metastatic HER-2 positive breast cancer.
CONCLUSION
Our results suggest that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN play important roles in trastuzumab resistance. Patients with high levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these molecules. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.
背景/目的：对曲妥珠单抗耐药仍是HER-2阳性乳腺癌面临的常见挑战。到目前为止，曲妥珠单抗耐药的潜在机制仍不清楚。tRNA衍生的小非编码RNA是一类新的小非编码RNA（sncRNAs），已观察到其在癌症进展中起重要作用。然而，tRNA衍生片段与曲妥珠单抗耐药之间的关系仍不清楚。
方法
我们使用高通量测序检测了正常乳腺上皮细胞系、曲妥珠单抗敏感和耐药乳腺癌细胞系中tRNA衍生片段的表达水平。进行qRT-PCR以验证曲妥珠单抗敏感和耐药患者血清中差异表达的片段。进行受试者工作特征（ROC）曲线分析以评估特定tRNA衍生片段的效能。使用Cox回归分析无进展生存期（PFS）。
结果
我们的序列结果显示，tRNA衍生片段在HBL-100、SKBR3和JIMT-1细胞系中差异表达。与敏感个体相比，在曲妥珠单抗耐药患者中发现tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN显著上调，并且ROC分析表明tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN与曲妥珠单抗耐药相关。在多变量分析中，较高水平的tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN表达与转移性HER-2阳性乳腺癌患者的PFS显著缩短相关。
结论
我们的结果表明，tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN在曲妥珠单抗耐药中起重要作用。与表达较低水平这些分子的患者相比，tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN表达水平高的患者从基于曲妥珠单抗的治疗中获益较少。tRF-30-JZOYJE22RR33和tRF-27-ZDXPHO53KSN可能是曲妥珠单抗耐药乳腺癌临床治疗中的潜在生物标志物和干预靶点。
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