Clinical Laboratory of Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Key Laboratory of Oncotarget Gene, Changsha, China.
Institute of Medical Technology, Peking University Health Science Center, Beijing, China.
Cell Death Dis. 2022 Apr 23;13(4):401. doi: 10.1038/s41419-022-04846-1.
Nasopharyngeal carcinoma (NPC) is a common malignant cancer in southern China that has highly invasive and metastatic features and causes high mortality, but the underlying mechanisms of this malignancy remain unclear. In this study, we utilized ChIP-Seq to identify metastasis-specific super enhancers (SEs) and found that the SE of LOC100506178 existed only in metastatic NPC cells and powerfully aggravated NPC metastasis. This metastatic SE transcribed into lncRNA LOC100506178, and it was verified as a seRNA through GRO-Seq. Furthermore, SE-derived seRNA LOC100506178 was found to be highly expressed in metastatic NPC cells and NPC lymph node metastatic tissues. Knockdown of seRNA LOC100506178 arrested the invasion and metastasis of NPC cells in vitro and in vivo, demonstrating that seRNA LOC100506178 accelerates the acquisition of NPC malignant phenotype. Mechanistic studies revealed that seRNA LOC100506178 specifically interacted with the transcription factor hnRNPK and modulated the expression of hnRNPK. Further, hnRNPK in combination with the promoter region of MICAL2 increased Mical2 transcription. Knockdown of seRNA LOC100506178 or hnRNPK markedly repressed MICAL2, Vimentin and Snail expression and upregulated E-cadherin expression. Overexpression of seRNA LOC100506178 or hnRNPK markedly increased MICAL2, Vimentin and Snail expression and decreased E-cadherin expression. Therefore, seRNA LOC100506178 may promote MICAL2 expression by upregulating hnRNPK, subsequently enhancing EMT process and accelerating the invasion and metastasis of NPC cells. seRNA LOC100506178 has the potential to serve as a novel prognostic biomarker and therapeutic target in NPC patients.
鼻咽癌（NPC）是中国南方常见的恶性肿瘤，具有高度侵袭性和转移性特征，死亡率高，但这种恶性肿瘤的潜在机制尚不清楚。在这项研究中，我们利用 ChIP-Seq 来识别转移特异性超级增强子（SE），发现 LOC100506178 的 SE 仅存在于转移性 NPC 细胞中，并强力加重 NPC 转移。这种转移性 SE 转录为 lncRNA LOC100506178，并通过 GRO-Seq 被验证为 seRNA。此外，发现 SE 衍生的 seRNA LOC100506178 在转移性 NPC 细胞和 NPC 淋巴结转移组织中高度表达。seRNA LOC100506178 的敲低在体外和体内均阻止 NPC 细胞的侵袭和转移，表明 seRNA LOC100506178 加速了 NPC 恶性表型的获得。机制研究表明，seRNA LOC100506178 特异性地与转录因子 hnRNPK 相互作用，并调节 hnRNPK 的表达。进一步地，hnRNPK 与 MICAL2 的启动子区域结合，增加了 Mical2 的转录。seRNA LOC100506178 或 hnRNPK 的敲低显著抑制了 MICAL2、Vimentin 和 Snail 的表达，并上调了 E-cadherin 的表达。seRNA LOC100506178 或 hnRNPK 的过表达显著增加了 MICAL2、Vimentin 和 Snail 的表达，并降低了 E-cadherin 的表达。因此，seRNA LOC100506178 可能通过上调 hnRNPK 促进 MICAL2 的表达，进而增强 EMT 过程并加速 NPC 细胞的侵袭和转移。seRNA LOC100506178 可能成为 NPC 患者新的预后标志物和治疗靶点。
