Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal-Epithelial Transition in Head and Neck Cancer Cells
Connective Tissue Growth Factor Activates Pluripotency Genes and Mesenchymal-Epithelial Transition in Head and Neck Cancer Cells
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DOI：
10.1158/0008-5472.can-12-4085
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发表时间：
2013-07-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Muh-Hwa
中科院分区：
文献类型：
--
作者：
Chang, Cheng-Chi;Hsu, Wen-Hao;Yang, Muh-Hwa
上皮-间质转化（epithelial-mesenchymal transition， EMT）是胚胎发育和肿瘤转移的重要机制。EMT将干细胞样特性引入癌细胞。然而，在体细胞重编程过程中，间充质-上皮转化（mesenchymal-epithelial transition， MET），即EMT的反向过程，是多能性的关键一步。结缔组织生长因子（CTGF）是一种多功能分泌蛋白，在不同的癌症中作为癌蛋白或肿瘤抑制因子。本研究表明，在头颈部鳞状细胞癌（HNSCC）中，CTGF促进MET并降低侵袭性。此外，我们发现CTGF增强了HNSCC细胞的干细胞样特性，增加了多个多能性基因的表达。机制研究表明，CTGF通过α v β 3整合素诱导c-Jun表达，c-Jun直接激活多能基因NANOG、SOX2、POU5F1的转录。在异种移植肿瘤中，敲低TW2.6细胞中的CTGF可减少肿瘤的形成，减弱E-cadherin的表达。在HNSCC患者样本中，CTGF表达与CDH1、NANOG、SOX2、POU5F1水平呈正相关。发现CTGF与多能性基因的共表达与较差的预后相关。这些发现在阐明癌症进展过程中上皮可塑性和干细胞样特性之间的相互作用方面具有价值，并为开发新的HNSCC分类系统和治疗策略提供了有用的信息。(c) 2013年aacr。
The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through alpha v beta 3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. (C) 2013 AACR.