| Objective This study was aimed to investigate the expression of tRNA-derived small non-coding RNAs(tDRs)in HER-2 positive breast cancer and discuss their application values of biomarkers related with trastuzumab resistance.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.Finally,progression-free survival(PFS)was analyzed using Cox-regression to reveal the relationship between expression of tDRs and prognosis of HER-2 positive breast cancer.Results 1.Our sequence results showed that tDRs were differentially expressed in theHBL-100,SKBR3,and JIMT-1 cell lines.The percentage of each subtype of differentially expressed tDRs indicated that more than 80% of the tDRs were tRFs in all three cell lines.The scatter plot indicated that the expression level in the two groups(up-and down-regulated tDRs)in all three cell lines correlated well.2.tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals.3.The ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance.4.In a multivariate analysis,higher levels of tDR-1960 and tDR-1969 expression were associated with significantly shorter PFS in patients with metastatic HER-2 positive breast cancer.Conclusion Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance.Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs.tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer. |
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