RESUMO
PIK3CA and PAK1 are critical genes in the PI3K/AKT/PAK pathway. Amplification and strong expression of PIK3CA and PAK1 were identified in around 50% and 88% oral carcinomas, respectively, while co-expression of PIK3CA and PAK1 together was found to be present in 80% of oral carcinomas. PIK3CA and PAK1 amplification was more obvious in recurrent tumors than their primary counterparts. Low grade amplification of PAK1 was prevalent in tumor risk individuals. Knockdown of expression of PIK3CA and PAK1 reduced the oncogenic potential of tumor cells. This study is the first to demonstrate the concordant PIK3CA and PAK1 alterations in oral carcinoma.
Assuntos
Carcinoma de Células Escamosas/genética , Amplificação de Genes , Neoplasias Bucais/genética , Recidiva Local de Neoplasia/genética , Fosfatidilinositol 3-Quinases/genética , Quinases Ativadas por p21/genética , Carcinoma de Células Escamosas/metabolismo , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Neoplasias Bucais/metabolismo , Recidiva Local de Neoplasia/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Quinases Ativadas por p21/metabolismoRESUMO
Areca (betel) chewing was tightly linked to oral tumorigenesis in Asians. Areca nut was a recently confirmed group I carcinogen and a popular addictive substance used by Asians. Meanwhile, the pathogenetic impact of areca on oral epithelial cells was still unclear. This study investigated the association between the induction of autophagy by areca nut extract (ANE) and the molecular regulation underlying this induction in oral cancer cells. Oral cancer cells were treated with ANE to incite the signaling changes underlying phenotypic alterations. The NFkappaB activation and reactive oxygen species (ROS) genesis were induced by ANE and the NFkappaB activation could be the basis of the ROS genesis. Furthermore, p38 activation and upregulation of MKP-1 phosphatase occurred following ANE treatment. These effects can be inhibited by ROS blockers. ANE treatment induced autophagy among oral cancer cells, which was characterized by LC3-II accumulation, genesis of autophagosomes and the appearance of EGFP-LC3 puncta. This induction was mediated through the activation of p38, MKP-1 and HIF-1alpha. Knockdown of ANE-modulated HIF-1alpha expression reduced autophagy. Blockage of ANE-induced autophagy increased the proportion of oral cancer cells undergoing apoptotic death. This study identified for the first time that ANE modulates a signaling cascade that induces HIF-1alpha expression in oral cancer cells. The eventual induction of autophagy was beneficial to cell survival from ANE-induced apoptosis.