LncRNA HOTAIR enhances breast cancer radioresistance through facilitating HSPA1A expression via sequestering miR‐449b‐5p

Abstract

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.

Functional Interaction among lncRNA HOTAIR and MicroRNAs in Cancer and Other Human Diseases

“…HOTAIR facilitates expression of the HSPA1A by sequestering miR-449b-5P, its direct suppressor. The HOTAIR/miR-449b-5p/HSPA1A axis represents a new mechanism associated in vitro and in vivo with BC radioresistance [ 147 ].…”

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

“…In many studies, the intracellular HSP70 level in cancer cells was found to be correlated with their radioresistance [ 195 , 196 , 197 , 198 , 199 , 200 ]. The radioprotective function of inducible HSP70 was also revealed in cancer cells treated with HSP90 activity inhibitors [ 166 , 174 ].…”

Long and short non-coding RNA and radiation response: a review

“…In breast cancer models, the lncRNA HOTAIR has been shown to increase radioresistance through targeting of miR-218 and miR-449b-5p. 42,43 Hu et al showed that HOTAIR is upregulated in breast cancer cell lines over normal tissue and increases in expression after 8 Gy irradiation. Furthermore, they reported that knockdown of HOTAIR prevents sponging of miR-218, which sensitizes cells.…”

“…42 Zhang et al reported that HOTAIR sponges miR-449b-5p, which facilitates downstream chaperone protein HSPA1A expression and thereby enhances radioresistance. 43 This provides a potential therapeutic target for the treatment of breast cancer.…”

“…120 Currently, we are also examining ncRNA profiles in mouse hearts and in liver-on-a-chip and lung-on-a-chip models to determine organ-specific changes after irradiation. HOTAIR has been shown to sponge miR-218 42 and miR-449b-5p 43 to increase radioresistance.…”