FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis.
FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis.
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DOI：
10.1158/0008-5472.can-12-0423
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发表时间：
2012-07-01
期刊：
影响因子：
11.2
通讯作者：
Watt FM
中科院分区：
文献类型：
--
作者：
Goldie SJ;Mulder KW;Tan DW;Lyons SK;Sims AH;Watt FM
需要新的治疗策略来改善头颈部鳞状细胞癌（HNSCC）的治疗，HNSCC是一种侵袭性肿瘤，生存率低。FRMD 4A是一种人表皮干细胞标志物，先前与SCC细胞中上调的上皮极性有关。在这里，我们报告FRMD 4A上调发生在原发性人类HNSCC中，其中高表达水平与复发风险增加相关。FRMD 4A沉默降低皮肤和舌中人SCC异种移植物的生长和转移，减少SCC增殖和细胞间粘附，并刺激caspase-3活性和终末分化标志物的表达。值得注意的是，FRMD 4A衰减引起雅普的核积累，表明FRMD 4A在Hippo信号传导中的潜在作用。用HSP 90抑制剂17-DMAG处理或用透明质酸连接CD 44引起FRMD 4A的核耗竭、雅普的核积累并减少SCC生长和转移。总之，我们的研究结果表明，FRMD 4A作为一种新的候选治疗靶点，在HNSCC的基础上，我们已经确定的转移性生长的关键作用。
New therapeutic strategies are needed to improve treatment for head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here we report that FRMD4A upregulation occurs in primary human HNSCC where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified.