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Abstract
Upregulation of long non-coding RNA LINC00963 has been observed in several cancer types. In this study, we analyzed the clinical and biological significance of LINC00963 in breast cancer. The key microRNA (miR) mediating the action of LINC00963 was identified. We show that LINC00963 upregulation is correlated with aggressive parameters of breast cancer. Silencing of LINC00963 suppresses the proliferation and tumorigenesis of breast cancer cells, whereas LINC00963 overexpression exerts an opposite effect. Knockdown of LINC00963 enhances DNA damage and oxidative stress and sensitizes breast cancer cells to radiation. Mechanistically, LINC00963 antagonizes the repressive activity of miR-324-3p on ACK1 expression. Clinically, there is a negative correlation between miR-324-3p and LINC00963 expression in breast cancer tissues. Overexpression of LINC00963 or ACK1 rescues the inhibitory effects of miR-324-3p on breast cancer cell proliferation and radiosensitivity. In addition, knockdown of ACK1 attenuates LINC00963-dependent breast cancer growth and tumorigenesis. Taken together, LINC00963 promotes tumorigenesis and radioresistance in breast cancer through interplay with miR-324-3p and derepression of ACK1. LINC00963 may represent a potential target for the treatment of breast cancer.
Highlights
Breast cancer is the most common and lethal malignancy in women.[1]
LncRNA AGAP2-AS1 is upregulated in breast cancer and contributes to cancer cell growth and trastuzumab resistance.[9] long ncRNAs (lncRNAs) MIR31HG exerts tumor-suppressive activity in hepatocellular carcinoma through the interplay with miR-575.10 Several studies have indicated the implication of lncRNAs in radioresistance of cancer cells.[11,12]
The results demonstrated a significant upregulation of LINC00963 in breast cancer specimens in comparison with adjacent noncancerous tissues (p < 0.0001; Figure 1A)
Summary
Breast cancer is the most common and lethal malignancy in women.[1] Adjuvant radiotherapy shows benefits in reducing breast cancer recurrence and mortality.[2,3] the therapeutic efficacy is often hampered by the development of radioresistance in cancer cells.[4] Understanding the mechanism contributing to radioresistance is pivotal to exploring strategies to improve radiotherapy against breast cancer. Non-coding RNAs (ncRNAs), which can be classified into small (< 200 nt) and long (> 200 nt) ncRNAs, account for the majority of transcriptomes of a cell.[5] One class of small ncRNAs, microRNAs (miRNAs) have been found to be involved in a wide range of biological and pathological processes, including development and cancer.[6] miRNAs bind to the 30 UTR of target mRNA, leading to repression of mRNA translation or induction of mRNA degradation. Zou et al.[12] reported that lncRNA OIP5-AS1 is involved in radioresistance of colorectal cancer cells
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