Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, Jiangsu, 210009, PR China; Department of Scientific Research, Jiangsu Cancer Hospital & the Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, Jiangsu, 210009, PR China; The Fourth Clinical College of Nanjing Medical University, Nanjing, Jiangsu, 210009, PR China.
Department of Thoracic Surgery, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, Jiangsu, 210009, PR China; Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
Cancer Lett. 2023 Nov 28;577:216426. doi: 10.1016/j.canlet.2023.216426. Epub 2023 Oct 9.
The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter's ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21 production and stabilizing DDX3X, to promote SCLC metastasis.
长链非编码 RNA（lncRNAs）在小细胞肺癌（SCLC）转移中的作用机制尚不清楚。在这里，我们发现 lncRNA ITPR1-AS1 在 SCLC 和淋巴结转移组织中上调，并与 SCLC 恶性特征呈正相关。ITPR1-AS1 在 SCLC 中的过表达是 SCLC 患者总生存期的独立危险因素。我们的数据证实 ITPR1-AS1 可在体外和体内诱导 SCLC 细胞转移。在机制上，ITPR1-AS1 作为支架增强了有丝分裂 68 kDa SRC 相关蛋白 68 kDa 和异质核核糖核蛋白 A1 之间的相互作用，从而促进 H-Ras 原癌基因（HRAS）前体 mRNA（P21）的可变剪接。此外，我们观察到 ITPR1-AS1 可以与 DEAD 框多肽 3（DDX3X）形成复合物并维持其稳定性，从而抑制后者的泛素化和降解。我们的数据提供了证据表明，ITPR1-AS1 通过上调 P21 的产生和稳定 DDX3X 来激活 cRaf-MEK-ERK 级联反应，从而促进 SCLC 转移。
