CRUK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, United Kingdom.
Cancer Res. 2012 Jul 1;72(13):3424-36. doi: 10.1158/0008-5472.CAN-12-0423. Epub 2012 May 7.
New therapeutic strategies are needed to improve treatment of 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 HNSCCs 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.
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。FRMD4A 是一种人类表皮干细胞标志物，先前被认为与上皮极性有关，在 SCC 细胞中上调。在这里，我们报告 FRMD4A 的上调发生在原发性人 HNSCC 中，高水平的表达与复发风险增加相关。FRMD4A 沉默减少了人 SCC 异种移植物在皮肤和舌中的生长和转移，降低了 SCC 的增殖和细胞间黏附，并刺激了 caspase-3 活性和终末分化标志物的表达。值得注意的是，FRMD4A 的衰减导致 YAP 的核积累，表明 FRMD4A 在 Hippo 信号通路中可能具有潜在作用。用 HSP90 抑制剂 17-DMAG 或透明质酸与 CD44 的连接处理会导致 FRMD4A 的核耗竭、YAP 的核积累以及 SCC 生长和转移的减少。总之，我们的研究结果表明 FRMD4A 是 HNSCC 的一个新的候选治疗靶点，因为我们已经确定了它在转移性生长中的关键作用。
