Xiang Cheng, Zhang Mao-Lin, Zhao Qun-Zi, Xie Qiu-Ping, Yan Hai-Chao, Yu Xing, Wang Ping, Wang Yong
Department of Thyroid Surgery, Second Affiliated Hospital of Medical College, Zhejiang University, Hangzhou, Zhejiang Province, China.
Oncotarget. 2017 Apr 4;8(14):22954-22967. doi: 10.18632/oncotarget.14578.
Recent studies have indicated that long non-coding RNAs play crucial roles in numerous cancers, including thyroid cancer, while their function in the mechanism of thyroid cancer 131I resistance has not been elucidated to date. The present study identified a functional long non-coding RNA, SLC6A9-5:2, which was involved in the radioactive therapy resistance of thyroid cancer. We demonstrated that SLC6A9-5:2 was remarkably downregulated in 131I-resistant thyroid cancer cell lines and 131I-insensitive patients and was positively correlated with Poly (ADP-ribose) polymerase 1 (PARP-1) expression and its activation. After downregulating SLC6A9 or blocking PARP-1 artificially, the sensitive thyroid cancer cells mostly displayed a tolerant phenotype under 131I exposure. Furthermore, SLC6A9-5:2 overexpression was positively correlated with PARP-1 mRNA and protein levels, which restored the sensitivity of resistant thyroid cancer cells. The present study further revealed that cancer cell death was primarily caused by ATP exhaustion in excessive DNA repair with high PARP-1 activity. In patients with thyroid cancer, a positive correlation between SLC6A9-5:2 and PARP-1 was identified, and low SLC6A9-5:2 expression was associated with a worse prognosis of papillary thyroid carcinoma. Hence, our data provide a new lncRNA-mediated regulatory mechanism implying that SLC6A9-5:2 can be used as a novel therapeutic target for 131I-resistant thyroid cancer.
近期研究表明，长链非编码RNA在包括甲状腺癌在内的多种癌症中发挥着关键作用，然而其在甲状腺癌131I抵抗机制中的功能迄今尚未阐明。本研究鉴定出一种功能性长链非编码RNA，即SLC6A9-5:2，其参与了甲状腺癌的放射治疗抵抗。我们证明，SLC6A9-5:2在131I抵抗的甲状腺癌细胞系和对131I不敏感的患者中显著下调，且与聚（ADP-核糖）聚合酶1（PARP-1）的表达及其激活呈正相关。人工下调SLC6A9或阻断PARP-1后，敏感的甲状腺癌细胞在131I暴露下大多表现出耐受表型。此外，SLC6A9-5:2的过表达与PARP-1的mRNA和蛋白水平呈正相关，这恢复了耐药甲状腺癌细胞的敏感性。本研究进一步揭示，癌细胞死亡主要是由PARP-1活性高导致的过度DNA修复中的ATP耗竭引起的。在甲状腺癌患者中，发现SLC6A9-5:2与PARP-1之间呈正相关，且SLC6A9-5:2低表达与甲状腺乳头状癌的预后较差有关。因此，我们的数据提供了一种新的lncRNA介导的调节机制，表明SLC6A9-5:2可作为131I抵抗性甲状腺癌的新型治疗靶点。
