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Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218.

ABSTRACT: Radiotherapy is a major therapeutic strategy for breast cancer, while cancer radioresistance remains an obstacle for the successful control of the tumor. Novel radiosensitizing targets are to be developed to overcome radioresistance. Recently, long non-coding RNAs (lncRNAs) were proved to play critical roles in cancer progression. Among all, lncRNA HOTAIR was found to participate in cancer metastasis and chemoresistance. In the present study, we aimed to investigate the radiosensitizing effects of targeting HOTAIR and the underlying mechanism. Our data showed that HOTAIR (HOX antisense intergenic RNA) was up-regulated in breast cancer cells and tissues, and the expression of HOTAIR increased following irradiation. Knockdown of HOTAIR inhibited cell survival and increased cell apoptosis in response to ionizing radiation. Moreover, compared with control group, radiation induced more DNA damage and cell cycle arrest in HOTAIR knockdown cells. Finally, we found that the radiosentizing effects of HOTAIR were related to the up-regulation of miR-218, a ceRNA of HOTAIR. In conclusion, our finding showed that HOTAIR inhibition sensitizes breast cancer cells to ionizing radiation, induced severe DNA damage and activated apoptosis pathways, suggesting a possible role of HOTAIR as a novel target for breast cancer radiosensitization.

SUBMITTER: Hu X

PROVIDER: S-EPMC6449517 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218.

Hu Xuguang X Ding Dan D Zhang Jiayi J Cui Jianguo J

Bioscience reports 20190405 4

Radiotherapy is a major therapeutic strategy for breast cancer, while cancer radioresistance remains an obstacle for the successful control of the tumor. Novel radiosensitizing targets are to be developed to overcome radioresistance. Recently, long non-coding RNAs (lncRNAs) were proved to play critical roles in cancer progression. Among all, lncRNA HOTAIR was found to participate in cancer metastasis and chemoresistance. In the present study, we aimed to investigate the radiosensitizing effects ...[more]

PMID: 30429228

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Project description:BackgroundBreast cancer (BRCA) is the leading cause of cancer-related death in women worldwide. Pre- and postoperative radiotherapy play a pivotal role in BRCA treatment but its efficacy remains limited and plagued by the emergence of radiation resistance, which aggravates patient prognosis. The long noncoding RNA (lncRNA)-implicated mechanisms underlying radiation resistance are rarely reported. The aim of this study was to determine whether lncRNA HOX transcript antisense RNA (HOTAIR) modulated the radiosensitivity of breast cancer through HSPA1A.MethodsA Gammacell 40 Exactor was used for irradiation treatment. Bioinformatic tools and luciferase reporter assay were adopted to explore gene expression profile and demonstrate the interactions between lncRNA, miRNA and target mRNA 3'-untranslated region (3'-UTR). The expression levels of certain genes were determined by real-time PCR and western-blot analyses. in vitro and in vivo functional assays were conducted by cell viability and tumorigenicity assays.ResultsThe levels of oncogenic lncRNA HOTAIR were positively correlated with the malignancy of BRCA but reversely correlated with the radiosensitivity of breast cancer cells. Moreover, the expression levels of HOTAIR were positively associated with those of heat shock protein family A (Hsp70) member 1A (HSPA1A) in clinical BRCA tissues and HOTAIR upregulated HSPA1A at the mRNA and protein levels in irradiated BRCA cells. Mechanistically, miR-449b-5p restrained HSPA1A expression through targeting the 3'-UTR of HSPA1A mRNA, whereas HOTAIR acted as a competing sponge to sequester miR-449b-5p and thereby relieved the miR-449b-5p-mediated HSPA1A repression. Functionally, HOTAIR conferred decreased radiosensitivity on BRCA cells, while miR-449b-5p overexpression or HSPA1A knockdown abrogated the HOTAIR-enhanced BRCA growth under the irradiation exposure both in vitro and in vivo.ConclusionsLncRNA HOTAIR facilitates the expression of HSPA1A by sequestering miR-449b-5p post-transcriptionally and thereby endows BRCA with radiation resistance.Key pointsTherapeutically, HOTAIR and HSPA1A may be employed as potential targets for BRCA radiotherapy. Our findings shed new light into the mechanism by which lncRNAs modulate the radiosensitivity of tumors.

Dataset Information

Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218.

Publications

Knockdown of lncRNA HOTAIR sensitizes breast cancer cells to ionizing radiation through activating miR-218.

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