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Cell Physiol Biochem. 2018;49(2):419-431. doi: 10.1159/000492977. Epub 2018 Aug 28.

tRNA-Derived Fragments as Novel Predictive Biomarkers for Trastuzumab-Resistant Breast Cancer.

Sun C1,2, Yang F1,2, Zhang Y1,2, Chu J1,2, Wang J1,2, Wang Y1,2, Zhang Y1,2, Li J1,2, Li Y1,2, Fan R1,3, Li W1, Huang X1, Wu H1, Fu Z1,4, Jiang Z5, Yin Y1,6.

Author information

1
Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
2
The First Clinical College of Nanjing Medical University, Nanjing, China.
3
Department of Medical Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huaian, China.
4
Nanjing Maternal and Child Health Medical Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China.
5
Department of Breast Cancer, The 307 Hospital of Chinese People's Liberation Army, Beijing, China.
6
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.

Abstract

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.

KEYWORDS:

Breast cancer; Trastuzumab resistance; tRNA-derived fragments

PMID:
30153663
DOI:
10.1159/000492977
[Indexed for MEDLINE]
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