Department of Endoscopic Center, Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University, Huhhot, 010020, China.
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.
Oncol Res. 2024 Jul 17;32(8):1335-1346. doi: 10.32604/or.2024.044174. eCollection 2024.
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 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.
长链非编码 RNA（lncRNA）已被牵涉到癌症的进展和耐药性的发展中。此外，有证据表明 lncRNA HOX 转录反义基因间 RNA（HOTAIR）参与结直肠癌（CRC）的进展。本研究旨在研究 lncRNA HOTAIR 在赋予 CRC 细胞放射抵抗中的功能作用以及潜在的机制。在 70 对 CRC 肿瘤和癌旁组织以及放射敏感和放射抵抗样本中检测 HOTAIR 的相对表达水平。使用卡方检验评估 HOTAIR 表达水平与 CRC 患者临床特征之间的相关性。进行细胞增殖、集落形成和凋亡测定等功能测定，以确定在接受不同剂量辐射后沉默 HOTAIR 的 CRC 细胞的放射敏感性。使用 RNA 下拉测定和荧光杂交（FISH）来确定 HOTAIR 与 DNA 损伤反应介质共济失调毛细血管扩张症突变和 Rad3 相关（ATR）之间的相互作用。HOTAIR 在 CRC 肿瘤组织中显著上调，尤其是在放射抵抗的肿瘤样本中。HOTAIR 的上调表达与更高级别的组织学分级、远处转移和 CRC 患者的不良预后相关。沉默 HOTAIR 抑制了 CRC 细胞的增殖，促进了细胞凋亡和放射敏感性。HOTAIR 敲低还抑制了 CRC 细胞的肿瘤发生并增强了在小鼠异种移植模型中对放射治疗的敏感性。此外，数据表明 HOTAIR 可以与 ATR 相互作用，调节 DNA 损伤修复信号通路。沉默 HOTAIR 破坏了 ATR-ATR 相互作用蛋白（ATRIP）复合物和细胞周期进展中的信号转导。总之，本研究结果表明，lncRNA HOTAIR 通过靶向 ATR 促进 CRC 细胞的 DNA 损伤反应途径并促进放射抵抗。
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