FRMD4A Upregulation in Human Squamous Cell Carcinoma Promotes Tumor Growth and Metastasis and Is Associated with Poor Prognosis

Abstract

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. Cancer Res; 72(13); 3424-36. Ó2012 AACR.

Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study

“…The gene product of FRMD4A is an epidermal stem cell marker (32); genetic polymorphisms at this locus have been associated with nicotine dependence in East Asian populations (33), and a smoking cessation genotype success score (34) in European populations. The product of the PARVA gene is a focal adhesion protein (35); relative hypermethylation at this locus has been reported in the small airway epithelium of smokers (21).…”

- Children Are Not Little Adults (Excerpt From Children’s Health and the Environment: A Global Perspective)

“…Beyond nicotine dependence, altered DNA methylation of FRMD4A may have the potential to affect other downstream health outcomes, since the gene has recently been implicated as a risk factor for both Alzheimer's disease and squamous cell carcinoma. [27,28] Very little is currently known about the other replicated locus within C11orf52. C11orf52 describes an uncharacterized protein that is expressed in the lung and which has been associated with increased phosphorylation in non-small cell lung cancer tumor n/a n/a n/a n/a…”

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

“…Níveis elevados da proteína S6 fosforilada nas serinas 240/244 também foram relacionados a um pior prognóstico de pacientes com carcinoma de esôfago em estagio inicial (139) . 80 Os níveis da proteína fosforilada S6 em serinas 235/236, serinas 240/244, bem como níveis totais da proteína ribossômica S6 foram então relacionados à resposta das linhagens celulares SCC9, SCC25 e DOK frente à LLLT. Sabe-se que o aumento da proliferação celular é acompanhado por uma atividade aumentada da sinalização mTOR, medida pelos níveis de pS6 (321) e, de fato a marcação com pS6…”

“…O inibidor de Hsp90 17-DMAG levou à diminuição do crescimento e formação de metástases de tumores xenógenos provenientes de carcinomas epidermoides de cabeça e pescoço (80) . Estes efeitos foram constatados uma vez que o inibidor de Hsp90 causou acúmulo nuclear de YAP e depleção nuclear de FRMD4A, um marcador de células-tronco epidermais superexpresso em carcinomas epidermoides (80) .…”

“…Estes efeitos foram constatados uma vez que o inibidor de Hsp90 causou acúmulo nuclear de YAP e depleção nuclear de FRMD4A, um marcador de células-tronco epidermais superexpresso em carcinomas epidermoides (80) . Assim, a inativação de Hsp90 é inquestionavelmente vantajosa para o tratamento de tumores caracterizados por múltiplos eventos mutacionais, como os de cabeça e pescoço (81) .…”