Open Access

ARTICLE

LncRNA HOTAIR promotes DNA damage repair and radioresistance by targeting ATR in colorectal cancer

HAIQING HU^1,#,*, HAO YANG^2,#, SHUAISHUAI FAN³, XUE JIA³, YING ZHAO³, HONGRUI LI³

1 Department of Endoscopic Center, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Huhhot, 010020, China
2 Department of Radiation Oncology, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Key Laboratory of Radiation Physics and Biology of Inner Mongolia Medical University, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Huhhot, 010020, China
3 Graduate School, Inner Mongolia Medical University, Huhhot, 010020, China

* Corresponding Author: HAIQING HU. Email:

Oncology Research 2024, 32(8), 1335-1346. https://doi.org/10.32604/or.2024.044174

Received 23 July 2023; Accepted 06 December 2023; Issue published 17 July 2024

Abstract

Long non-coding RNAs (lncRNAs) have been implicated in cancer progression and drug resistance development. Moreover, there is evidence that lncRNA HOX transcript antisense intergenic RNA (HOTAIR) is involved in colorectal cancer (CRC) progression. The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells, as well as the underlying mechanism. The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues, as well as in radiosensitive and radioresistant samples. The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test. Functional assays such as cell proliferation, colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation. RNA pull-down assay and fluorescence in situ hybridization (FISH) were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated- and Rad3-related (ATR). HOTAIR was significantly upregulated in CRC tumor tissues, especially in radioresistant tumor samples. The elevated expression of HOTAIR was correlated with more advanced histological grades, distance metastasis and the poor prognosis in patients with CRC. Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells. HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model. Moreover, the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway. Silencing HOTAIR impaired the ATR-ATR interacting protein (ATRIP) complex and signaling in cell cycle progression. Collectively, the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.

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