OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma.
OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma.
复制标题
OVOL2通过微调鼻咽癌的上皮-间质转化将干细胞与转移联系起来
作者：
Qi XK;Han HQ;Zhang HJ;Xu M;Li L;Chen L;Xiang T;Feng QS;Kang T;Qian CN;Cai MY;Tao Q;Zeng YX;Feng L
基本原理：转移是鼻咽癌（NPC）患者疾病相关死亡的主要原因。越来越多的证据表明，上皮间质转化（EMT）是癌细胞获得转移能力的关键。在这项研究中，我们的目的是澄清EMT参与各种癌症性质的程度，并确定新的标志物用于预测NPC患者的预后。研究方法：两个细胞模型来源于相同的鼻咽癌细胞系，具有不同的转移能力，用于微阵列分析，以确定关键的转录因子，驱动转移。通过伤口愈合和Transwell分析来分析细胞迁移和侵袭。肺转移采用尾静脉注射法。使用集落形成和异种移植测定分析癌症干性。使用免疫印迹、RT-qPCR和EMT标记物的免疫荧光来评估EMT程度。通过免疫组化方法检测鼻咽癌活检组织中OVOL 2的表达情况，以确定其在判断预后中的价值。结果：OVOL 2是鼻咽癌细胞转移模型中表达下调最明显的EMT转录因子（EMT-TF）。低水平的OVOL 2与NPC患者的总体生存率相关，其表达减少部分是由于启动子甲基化和上皮去分化。上皮样NPC细胞中OVOL 2的敲除部分激活EMT程序并显著促进癌症的干性和转移表型。相反，OVOL 2在间充质样细胞中的异位表达导致向上皮表型的部分转变和恶性程度的降低。通过消耗OVOL 2的主要靶点ZEB 1来逆转EMT，并不能消除OVOL 2缺陷细胞的干细胞优势，但确实降低了它们的侵袭能力。EMT不同阶段的亚群比较显示，EMT的程度与转移和耐药呈正相关;然而，只有中间EMT状态与癌症的干性相关。结论：与其他典型的EMT-TF不同，OVOL 2对EMT仅表现出适度的影响，但对转移和肿瘤发生都具有强烈的影响。因此，OVOL 2可以作为癌症患者的预后指标。
Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.
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影响因子：
3.7
作者：
Roca H;Hernandez J;Weidner S;McEachin RC;Fuller D;Sud S;Schumann T;Wilkinson JE;Zaslavsky A;Li H;Maher CA;Daignault-Newton S;Healy PN;Pienta KJ
通讯作者：
Pienta KJ
影响因子：
3.7
作者：
Kumar A;Bhandari A;Sinha R;Sardar P;Sushma M;Goyal P;Goswami C;Grapputo A
通讯作者：
Grapputo A
Ovol2的表达与上皮特征相关，并在肝细胞癌中显示出良好的临床结果
影响因子：
4
作者：
Fu H;Qi L;Chen L;He Y;Zhang N;Guo H
通讯作者：
Guo H
影响因子：
11.8
作者：
Lee, Briana;Villarreal-Ponce, Alvaro;Fallahi, Magid;Ovadia, Jeremy;Sun, Peng;Yu, Qian-Chun;Ito, Seiji;Sinha, Satrajit;Nie, Qing;Dai, Xing
通讯作者：
Dai, Xing
影响因子：
8
作者：
Grooteclaes, ML;Frisch, SM
通讯作者：
Frisch, SM