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

Chunxiao Sun; Fan Yang; Yanhong Zhang; Jiahui Chu; Jian Wang; Yifan Wang; Yanqiu Zhang; Jun Li; Yongfei Li; Ruihua Fan; Wei Li; Xiang Huang; Hao Wu; Ziyi Fu; Zefei Jiang; Yongmei Yin

doi:10.1159/000492977

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

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

Authors

Chunxiao Sun^{1

2}, Fan Yang^{1

2}, Yanhong Zhang^{1

2}, Jiahui Chu^{1

2}, Jian Wang^{1

2}, Yifan Wang^{1

2}, Yanqiu Zhang^{1

2}, Jun Li^{1

2}, Yongfei Li^{1

2}, Ruihua Fan^{1

3}, Wei Li¹, Xiang Huang¹, Hao Wu¹, Ziyi Fu^{1

4}, Zefei Jiang⁵, Yongmei Yin^{1

6}

Affiliations

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.

PMID: 30153663
DOI: 10.1159/000492977

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.

MeSH terms

Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use*
Area Under Curve
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Breast Neoplasms / drug therapy*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Survival / drug effects
Disease-Free Survival
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation, Neoplastic
Humans
Neoplasm Metastasis
Nucleic Acid Conformation
Prognosis
Proportional Hazards Models
RNA, Transfer / chemistry
RNA, Transfer / metabolism*
ROC Curve
Receptor, ErbB-2 / metabolism
Survival Rate
Trastuzumab / pharmacology
Trastuzumab / therapeutic use*

Substances

Antineoplastic Agents, Immunological
Biomarkers, Tumor
RNA, Transfer
ERBB2 protein, human
Receptor, ErbB-2
Trastuzumab