Klf4 reduces stemness phenotype, triggers mesenchymal-epithelial transition (MET)-like molecular changes, and prevents tumor progression in nasopharygeal carcinoma.
Klf4 reduces stemness phenotype, triggers mesenchymal-epithelial transition (MET)-like molecular changes, and prevents tumor progression in nasopharygeal carcinoma.
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Klf4 降低干性表型，触发间充质上皮转化 (MET) 样分子变化，并防止鼻咽癌的肿瘤进展
DOI：
10.18632/oncotarget.21370
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发表时间：
2017-11-07
期刊：
影响因子：
--
通讯作者：
Jia J
中科院分区：
文献类型：
--
作者：
Li X;Zhao Z;Zhang X;Yang S;Lin X;Yang X;Lin X;Shi J;Wang S;Zhao W;Li J;Gao F;Liu M;Ma N;Luo W;Yao K;Sun Y;Xiao S;Xiao D;Jia J
重编程因子Krüppel-like factor4(KLF4)是山中重编程因子之一，在将体细胞重编程为诱导多能干细胞(IPSCs)的过程中起着至关重要的作用。KLF4在多种恶性肿瘤中表达异常，功能各异，但其在鼻咽癌中的生物学作用尚不清楚。本研究揭示了一组人鼻咽癌活检组织中KLF4的下调与鼻咽癌的侵袭和转移表型显著相关。我们的结果表明，外源性KLF4的表达显著抑制了鼻咽癌细胞的增殖，降低了细胞的干性，触发了间充质-上皮转化(MET)样的分子变化，并抑制了鼻咽癌细胞的迁移和侵袭，而内源性KLF4的缺失则逆转了上述生物学行为和特征。KLF4沉默显著增强鼻咽癌细胞体内转移能力。此外，芯片实验证实E-钙粘蛋白是KLF4在鼻咽癌细胞中的转录靶点。进一步的研究表明，KLF4诱导的MET样细胞标志物的改变，以及鼻咽癌细胞运动性和侵袭性的降低是由E-钙粘蛋白介导的。本研究揭示了鼻咽癌组织中KLF4的表达与上皮-间充质转化(EMT)生物标记物(包括其靶基因E-钙粘素)的临床相关性。综上所述，我们的研究结果首次表明，KLF4在鼻咽癌中作为肿瘤抑制因子发挥作用，减少干性表型，抑制EMT，防止肿瘤进展，提示恢复KLF4功能可能为鼻咽癌提供治疗益处。
The reprogramming factor Krüppel-like factor 4 (Klf4), one of the Yamanaka's reprogramming factors, plays an essential role in reprogramming somatic cells into induced pluripotent stem cells (iPSCs). Klf4 is dysregulated and displays divergent functions in multiple malignancies, but the biological roles of Klf4 in nasopharyngeal carcinoma (NPC) remain unknown. The present study revealed that Klf4 downregulation in a cohort of human NPC biopsies is significantly associated with invasive and metastatic phenotypes of NPC. Our results showed exogenous expression of Klf4 significantly inhibited cell proliferation, decreased stemness, triggered mesenchymal-epithelial transition (MET)-like molecular changes, and suppressed migration and invasion of NPC cells, whereas depletion of endogeneous Klf4 by RNAi reversed the aforementioned biological behaviors and characheristics. Klf4 silencing significantly enhanced the metastatic ability of NPC cells in vivo. In addition, CHIP assay confirmed that E-cadherin is a transcriptional target of Klf4 in NPC cells. Additional studies demonstrated that Klf4-induced MET-like cellular marker alterations, and reduced motility and invasion of NPC cells were mediated by E-cadherin. This study revealed the clinical correlation between Klf4 expression and epithelial-mesenchymal transition (EMT) biomarkers (including its target gene E-cadherin) in a cohort of NPC biopsies. Taken together, our findings suggest, for what we believe is the first time, that Klf4 functions as a tumor suppressor in NPC to decrease stemness phenotype, inhibit EMT and prevent tumor progression, suggesting that restoring Klf4 function may provide therapeutic benefits in NPC.
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