Liang Xinxin, Li Xueping, Wang Ping, Chen Zhongmin, Yan Ziyan, Ao Xingkun, Liu Yuhao, Zhu Jiaojiao, Xi Tingting, Zhou Shenghui, Li Zhongqiu, Li Chao, Zhu Maoxiang, Zhou Ping-Kun, Gu Yongqing
Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, AMMS, Beijing 100850, China.
Toxicol Res (Camb). 2022 Apr 1;11(2):348-360. doi: 10.1093/toxres/tfac008. eCollection 2022 Apr.
Radioresistance is one of the key obstacles that may lead to the failure of cancer treatment. The underlying mechanisms of radioresistance remain largely unknown; however, increasing evidence has shown that long noncoding RNAs (lncRNAs) are involved in radiotherapy resistance of several cancers. In the present study, we demonstrated that radiation-elevated transcript (RET), a newly identified lnRNA, was highly expressed in cancer cells. Knockdown of RET significantly inhibited the proliferation and colony formation of cancer cells and markedly inhibited apoptosis. Furthermore, downregulation of RET in cancer cells significantly inhibited cell growth, decreased colony survival fractions, and promoted apoptosis in response to radiation treatment, indicating a role in radiation resistance. Moreover, RET knockdown significantly increased the expression of γ-H2AX, an indicator of DNA double strand damage, and reversed radiation-induced EMT, both of which contributed to its radiation resistance. In addition, a negative correlation was found between the expression of RET and PTEN. Rescue assays confirmed RET knockdown enhanced radiosensitivity of cancer cells by upregulating the expression of PTEN. Mechanistically, RET positively regulated Slug, a repressor of PTEN transcription, by acting as a molecular sponge of miR-3179. Our present study showed that RET conferred radioresistance by regulating miR-3179/Slug/PTEN axis, indicating that RET may be a potential target for the clinical application in cancer patients with radioresistance.
放射抗性是可能导致癌症治疗失败的关键障碍之一。放射抗性的潜在机制在很大程度上仍然未知；然而，越来越多的证据表明长链非编码RNA（lncRNAs）参与了几种癌症的放射治疗抗性。在本研究中，我们证明了辐射升高转录本（RET），一种新鉴定的lnRNA，在癌细胞中高表达。敲低RET显著抑制癌细胞的增殖和集落形成，并明显抑制细胞凋亡。此外，癌细胞中RET的下调显著抑制细胞生长，降低集落存活分数，并促进辐射治疗后的细胞凋亡，表明其在放射抗性中起作用。此外，敲低RET显著增加了DNA双链损伤指标γ-H2AX的表达，并逆转了辐射诱导的上皮-间质转化（EMT），这两者都导致了其放射抗性。此外，发现RET的表达与PTEN之间存在负相关。挽救实验证实敲低RET通过上调PTEN的表达增强了癌细胞的放射敏感性。机制上，RET通过作为miR-3179的分子海绵正向调节PTEN转录抑制因子Slug。我们目前的研究表明，RET通过调节miR-3179/Slug/PTEN轴赋予放射抗性，表明RET可能是放射抗性癌症患者临床应用的潜在靶点。
