Abstract
Colorectal cancer (CRC) is a global healthcare problem. Radioresistance is a huge setback for CRC radiotherapy. In this text, the roles and molecular mechanisms of long non-coding RNA HOTAIR in CRC tumorigenesis and radioresistance were further investigated. ATG12 mRNA, HOTAIR, and microRNA-93 (miR-93) levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) assay. Protein levels of LC3 I, LC3 II, p62, ATG12, cleaved caspase 3, Bax, and Bcl-2 were detected by western blotting assay in cells and were examined by immunohistochemistry (IHC) assay in tissues. Cell survival fractions, viability, and apoptotic rates were determined by clonogenic survival assay, CCK-8 assay, and flow cytometry analysis, respectively. The relationships of HOTAIR, miR-93, and ATG12 were tested by bioinformatics analysis and luciferase reporter assay. Mouse xenograft tumor models were established to investigate the influence of HOTAIR knockdown on CRC radioresistance in vivo. We found that HOTAIR expression was markedly upregulated in plasma from CRC patients after radiotherapy and CRC cells after irradiation. HOTAIR knockdown, miR-93 overexpression, or ATG12 silencing weakened cell viability, induced cell apoptosis, inhibited cell autophagy, and enhanced cell radiosensitivity in CRC. HOTAIR exerted its functions by downregulating miR-93. Moreover, HOTAIR functioned as a molecular sponge of miR-93 to regulate ATG12 expression. ATG12 protein expression was markedly upregulated and associated with miR-93 and HOTAIR expression in CRC tissues. Furthermore, HOTAIR knockdown enhanced radiosensitivity of CRC xenograft tumors by regulating miR-93/ATG12 axis. In conclusion, HOTAIR knockdown potentiated radiosensitivity through regulating miR-93/ATG12 axis in CRC, further elucidating the roles and molecular basis of HOTAIR in CRC radioresistance.
Highlights
Colorectal cancer (CRC) is a serious healthcare problem in the world, accounting for ~10% of all cancer cases and deaths[1]
Homeobox transcript antisense intergenic RNA (HOTAIR) was highly expressed in CRC tissues and cells, and HOTAIR expression was markedly upregulated in plasma samples from CRC patients after radiotherapy and CRC cells after IR treatment
We demonstrated that HOTAIR was highly expressed in CRC tissues and cells, which was in line with previous studies[18,19]
Summary
Colorectal cancer (CRC) is a serious healthcare problem in the world, accounting for ~10% of all cancer cases and deaths[1]. It was estimated that more than 1.8 million new cases and 881,000 deaths from CRC occurred in 2018 globally, with a higher incidence rate in Europe[1]. The 5-year relative survival rate ranges from higher than 90%. RNAs including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been found to be key regulators or potential biomarkers in tumor initiation, progression, and radioresistance of CRC5–7. LncRNAs longer than 200 nucleotides (nt) in length and miRNAs with the size of about 21 nt are two major families of transcripts that lack protein-coding potential[8]. LncRNAs and miRNAs have been extensively studied for Official journal of the Cell Death Differentiation Association. Some evidences disclose that lncRNAs can function as competing endogenous RNAs (ceRNAs) of miRNAs, resulting in the reduction of miRNA levels and increase of miRNA target levels[12,13]
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