Overexpression of HOTAIR leads to radioresistance of human cervical cancer via promoting HIF-1\u03b1 expression

Ning Li,Yan Zhang,Yue Xu,Xiao-Jing Tie,Pei-Jie Liu,Ling Gao,Zhi-Qiao Xu,Dan-Dan Meng,Yong-Wei Tian,Zhen-Ying Yi

doi:10.1186/s13014-018-1153-4

Abstract

BackgroundHOTAIR was known to enhance radioresistance in several cancers. However, the function of HOTAIR on radioresistance involving the regulation of HIF-1α in cervical cancer has not been reported.MethodsBALB/c nude mice were injected subcutaneously with HeLa cells and irradiated by X-ray. The tumor volume was measured and the expression of HOTAIR in tumors was detected by quantitative real-time PCR. Western blot was performed to detect the protein level of HIF-1α. MTT (3-(4,5-Dimethylthiazol-2-yl) 22,5-diphenyltetrazolium bromide) assay and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to examine the cell viability and cell apoptosis of HeLa cells and C33A cells exposed to radiation.ResultsRadiotherapy inhibited the tumor growth in mice bearing HeLa cells. Radiotherapy reduced the expression of HOTAIR and HIF-1α in tumor tissues and HeLa cells or C33A cells. HOTAIR overexpression abrogated the effect of radiation on the cell viability and cell apoptosis of HeLa and C33A cells. HOTAIR also upregulated the expression of HIF-1α in HeLa and C33A cell exposed to radiation. HIF-1α knockdown reversed increasing cell viability and reducing apoptosis of HeLa and C33A cell induced by HOTAIR overexpression. HOTAIR overexpression promoted tumor growth in mice bearing HeLa and exposed to radiation.ConclusionRadiotherapy might inhibit cervical cancer cell growth through HOTAIR/HIF-1α pathway.

Highlights

HOX transcript antisense intergenic RNA (HOTAIR) was known to enhance radioresistance in several cancers
Radiotherapy inhibited the tumor growth in mice bearing HeLa and reduced the expression of HOTAIR and Hypoxia inducible factor-1α (HIF-1α) Compared with normal tissue, HOTAIR expression level increased 2.2 fold (p = 0.0045) in cervical cancer tissue, Fig. 1 Effect of radiotherapy on the tumor growth in mice bearing HeLa cells and on the expression of HOTAIR and HIF-1α
As HIF-1α was reported to upregulate the expression of HOTAIR at transcriptional level in hypoxic cancer cells, we examined the effect of HIF-1α overexpression on the level of HOTAIR in HeLa and C33A cells

Summary

Introduction

The function of HOTAIR on radioresistance involving the regulation of HIF-1α in cervical cancer has not been reported. Reports have demonstrated that hypoxia is an important factor impacting the effectiveness of radiotherapy and causing the tumor cells obtaining radioresistance [2]. It is urgently required to elucidate the mechanisms underlying radioresistance of cervical cancer cells and improve the hypoxic condition in cells. The expression of several genes in hypoxic-tumor cells were altered, such as hypoxia-inducible factor 1 (HIF-1), causing the increase in cellular radioresistance [3]. HIF-1α is a key regulatory factor of cellular response to hypoxia, mediating the gene expression for cell survival and resistance to oxidative stress. It has been shown that HIF-1α regulated the expression of genes involving angiogenesis, tumor invasion, metastasis, proliferation and apoptosis [4].

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