Department of General surgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.
Department of Clinical Chinese Medicine Integrative With Western Medicine, International Education College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China.
J Cell Physiol. 2019 Apr;234(4):3478-3489. doi: 10.1002/jcp.26828. Epub 2018 Oct 26.
Cervical cancer is one of the most common female malignancies around the world, and radiation resistance is a major obstacle to cancer therapy. Previously, overexpression of the long noncoding ribonucleic acid (RNA) (lncRNA) HOX transcript antisense RNA (HOTAIR) has been found to be associated with the invasion and metastasis capacities of several epithelial cancers, including cervical cancer. To gain insights into the molecular mechanisms of HOTAIR in cervical cancer resistance to radiotherapy, we investigated cellular autophagy and epithelial-to-mesenchymal transition (EMT) in radioresistant human cervical cancer HeLa cells when HOTAIR was suppressed. HOTAIR levels were quantified in cancerous and noncancerous cervical tissues obtained from 108 patients with cervical cancer. Next, we inhibited HOTAIR by RNA interference and activated the Wnt signaling pathway by LiCl in radioresistant HeLa cells to investigate the regulatory mechanisms for the HOTAIR mediating Wnt signaling pathway. We determined that the upregulated HOTAIR may contribute to cervical cancer progression. We found that the short interfering ribonucleic acid (siRNA)-mediated knockdown of HOTAIR disturbed the Wnt signaling pathway, reduced autophagy, inhibited EMT, decreased cell proliferation, and induced apoptosis in radioresistant HeLa cells. It is worthy to note that the combination treatment of siRNA-HOTAIR and LiCl demonstrated that the activation of the Wnt signaling pathway is responsible for the beneficial effect of HOTAIR knockdown in enhancing sensitivity to radiotherapy in radioresistant HeLa cells. Together, our results revealed an important role of HOTAIR in regulating cervical cancer resistance to radiotherapy. Functional suppression of HOTAIR could enhance sensitivity to radiotherapy by reduction of autophagy and reversal of EMT through the suppression of the Wnt signaling pathway.
宫颈癌是全球最常见的女性恶性肿瘤之一，而放射抵抗是癌症治疗的主要障碍。先前的研究发现，长链非编码 RNA（lncRNA）HOX 转录反义 RNA（HOTAIR）的过表达与包括宫颈癌在内的几种上皮癌的侵袭和转移能力有关。为了深入了解 HOTAIR 在宫颈癌放射抵抗中的分子机制，我们研究了抑制 HOTAIR 后耐辐射人宫颈癌 HeLa 细胞中的细胞自噬和上皮-间充质转化（EMT）。从 108 例宫颈癌患者的癌组织和非癌组织中定量检测了 HOTAIR 的水平。接下来，我们通过 RNA 干扰抑制 HOTAIR，并通过 LiCl 激活 Wnt 信号通路，研究 HOTAIR 调节 Wnt 信号通路的调控机制。我们发现上调的 HOTAIR 可能有助于宫颈癌的进展。我们发现，HOTAIR 的短发夹 RNA（siRNA）介导的敲低扰乱了 Wnt 信号通路，减少了自噬，抑制了 EMT，降低了细胞增殖，并诱导了耐辐射 HeLa 细胞的凋亡。值得注意的是，siRNA-HOTAIR 和 LiCl 的联合治疗表明，Wnt 信号通路的激活是 HOTAIR 敲低增强耐辐射 HeLa 细胞放射敏感性的有益作用的原因。总之，我们的研究结果揭示了 HOTAIR 在调节宫颈癌放射抵抗中的重要作用。通过抑制自噬和逆转 EMT 来抑制 Wnt 信号通路，功能性抑制 HOTAIR 可以提高放射敏感性。
