长非编码RNA CXorf28促进非小细胞肺癌转移的分子机制

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumor with the highest morbidity and mortality worldwide. Metastasis is the major cause of death from cancer, even with constant investigations, prevention and destruction of cancer metastasis is still a rough topic in basic and clinical cancer research. Previously, we found that a long non-coding RNA CXorf28 is up-regulated by PI3K/Akt pathway. And analysis of NSCLC clinical data indicate that expression of CXorf28 in NSCLC with metastasis is higher than NSCLC without metastasis, meanwhile, CXorf28 expression is correlates with poor prognosis of NSCLC patients, suggesting that CXorf28 was involved in NSCLC metastasis. Furthermore, we found that ectopic expression of CXorf28 induces epithelial-mesenchymal transition phenotype, promotes NSCLC invasion and metastasis in vitro and in vivo. Our research suggests the pivotal role of CXorf28 in NSCLC metastasis. By using RNA pull-down assay, immunoprecipitation and mass spectrometry methods, we identified that Vimentin is one of the binding partner of CXorf28, and CXorf28 preserves Vimentin stability by enhancing Vimentin phosphorylation. In the current project, we will investigate the mechanisms of CXorf28-induced NSCLC metastasis by recruiting in vitro, in vivo assays and pathological analysis. Our work may help to identify a novel diagnostic marker and a therapeutic target for metastatic NSCLC.

非小细胞肺癌是发病率最高，死亡病例数最多的肿瘤。肿瘤转移是病人死亡的主要原因，因此寻找促进肿瘤转移的关键分子对肿瘤的早期诊断和治疗具有重要意义。我们前期研究发现PI3K/Akt激活上调长非编码RNA CXorf28表达。临床标本分析显示，转移性肺癌中CXorf28表达较高，且与肺癌病人较差的预后相关，提示CXorf28可能促进肿瘤转移。进一步预实验结果显示：高表达CXorf28可以诱导肺癌细胞发生EMT，促进肿瘤侵袭和转移，这表明CXorf28在非小细胞肺癌的转移中具有重要生物学功能。结合RNA pull-down，免疫共沉淀等研究方法，我们发现CXorf28与EMT关键蛋白Vimentin结合，并促进Vimentin磷酸化维持其蛋白稳定。本研究将在此基础上深层次解析长非编码RNA CXorf28促进非小细胞肺癌转移的分子机制，并与临床结合为转移性非小细胞肺癌提供新的诊断标记物和治疗靶点。

肺癌是目前发病率最高、死亡病例数最多的恶性肿瘤，肿瘤转移是导致肿瘤患者死亡的主要原因，然而调控肺癌转移的关键分子及其分子机制仍不完全清楚。本项目研究发现：（1）AKT信号通过上调长非编码RNA VAL表达，降低Trim16介导的Vimentin多泛素化降解，导致Vimentin蛋白水平升高，促进肺癌细胞的侵袭、黏附、抗失巢凋亡和非EMT形式的系统转移，此外通过siRNA的小鼠体内注射我们证明VAL是一个有效的肺癌转移治疗靶点（Nat Commun. 2020 Oct 12;11(1):5127.）；（2）长非编码RNA DUXAP9-206与非小细胞肺癌恶性进展和较差预后紧密相关，其直接与E3泛素连接酶Cbl-b相互作用，减少EGFR的多泛素化降解，促进EGFR信号通路的持续激活，进而导致肺癌细胞的恶性增殖和转移（J Cell Mol Med. 2019 Mar;23(3):1852-1864.）。以上研究结果表明了长非编码RNA在肺癌转移等恶性表型中的重要调节作用，并可以作为预后判断的潜在标志物和肿瘤转移治疗靶点。