Hypoxia‐induced tRNA‐derived fragments, novel regulatory factor for doxorubicin resistance in triple‐negative breast cancer

Abstract

Triple‐negative breast cancer (TNBC) is an aggressive subtype of epithelial breast malignancy, and chemoresistance is the major obstacle for cancer therapy. TNBC is associated with a hypoxic phenotype, and hypoxia contributes to the chemoresistance in breast cancer. Transfer RNA‐derived fragments (tDRs) represent a new class of small noncoding RNAs that can be induced specifically by hypoxia. Here, we conducted a comparative analysis of the aberrant expression of tDRs in hypoxia‐treated TNBC cell lines through the use of high‐throughput sequencing technique. Quantitative real‐time polymerase chain reaction was used to validate the differently expressed tDRs between two samples. The results showed that tDR‐0009 [derived from transfer RNA (tRNA)Gly‐GCC‐1‐1] and tDR‐7336 (derived from tRNA Gly‐GCC‐1–2) were significantly upregulated when the SUM‐1315 cell lines were stimulated by hypoxia. Gene ontology (GO) and pathway analysis indicated that these two upregulated tDRs were mainly involved in maintenance of stem cell population and cellular response to interleukin (IL)‐6, which may be the underlying mechanism of hypoxia‐induced tDRs that facilitate the doxorubicin resistance in TNBC. The protein–protein interaction network for predicted target genes established by the STRING database manifested that tDR‐0009 (tDR‐7336) might be involved in the chemoresistance of TNBC via regulation of the activation of phosphorylation of STAT3. In summary, our study provided a comprehensive analysis of the deviant expression profiling of tDRs in hypoxia‐treated TNBC cell lines. Specific tDRs may be a new class of regulatory factors involved in the hypoxia‐induced chemoresistance in TNBC, and they could serve as potential biomarkers and intervention targets.

Serum tRNA‐derived fragments (tRFs) as potential candidates for diagnosis of nontriple negative breast cancer

“…SKBR‐3 cells were cultured in Roswell Park Memorial Institute 1640 medium (Multicell), whereas MCF‐7 and HBL‐100 cells were cultured in Dulbecco's modified Eagle's medium (Gibco, UK) supplemented with 10% fetal bovine serum (Gibco), 100 U/ml penicillin and 100 μg/ml streptomycin (Multicell; Sun et al, ). Cells were cultured in an atmosphere at 37°C, where it contains 5% CO 2 and a certain humidity, and the cell medium was renewed per 48 hr (Cui et al, ).…”

Relationship between tRNA‐derived fragments and human cancers

“…The analysis showed that tDRs were involved in the maintenance of the stem cell population and regulated the phosphorylation of STAT3 and the cellular response to interleukin-6 (IL-6), which resulted in the doxorubicin resistance of TNBC. 69 Corce M et al also found that ts-47s and ts-46s were upregulated by KRAS and PIK3CA mutations, respectively. Both mutations were considered to be related to the formation of breast cancer chemoresistance, such as the resistance to lapatinib.…”

Systematic characterization of non‐coding RNAs in triple‐negative breast cancer

“…In addition to serving as biomarkers, tDRs also participate in the process of TNBC. Cui et al 151 found that tDR‐0009 and tDR‐7336 were notably upregulated in the SUM‐1315 cell lines stimulated by hypoxia; further, bioinformatic analysis indicated that these two upregulated tDRs might be involved in the chemoresistance to doxorubicin in TNBC via mediating the activation of phosphorylation of STAT3. As for other ncRNAs, such as snoRNA and snRNA, their tumour‐associated functions have been observed in multiple cancers, 152‐154 but no exact roles have been defined in TNBC, which need to be further explored in the future.…”