Similar retinitis pigmentosa (RP) phenotypes can result from mutations affecting different rhodopsin regions, and distinct amino acid substitutions can cause different RP severity and progression rates. Specifically, both the R135L and R135W mutations (cytoplasmic end of H3) result in diffuse, severe disease (class A), but R135W causes more severe and more rapidly progressive RP than R135L. The P180A and G188R mutations (second intradiscal loop) exhibit a mild phenotype with regional variability (class B1) and diffuse disease of moderate severity (class B2), respectively. Computational and in vitro studies of these mutants provide molecular insights into this phenotypic variability.

Purpose Signal Transducer and Activator of Transcription 5 (STAT5) is activated in squamous cell carcinoma of the head and neck (SCCHN), where targeting STAT5 inhibits tumor growth in vitro and in vivo. The role of STAT5 activation in carcinogenesis, tumor progression and response to therapy remains incompletely understood. In this study, we investigated the effects of STAT5 activation in squamous epithelial carcinogenesis and respond to therapy. Experimental Design The functional consequences of STAT5 activation in squamous epithelial carcinogenesis were examined using cells derived from normal (Het-1A) and transformed mucosal epithelial cells engineered to express constitutive-active mutants of STAT5. Results The growth rate of stable clones derived from both normal and transformed squamous epithelial cells expressing the constitutive-active STAT5 were increased. In SCCHN xenografts, tumor volumes were increased in constitutive-active STAT5 mutant cells compared to vector-transfected controls. Constitutive activation of STAT5 significantly increased cell migration and invasion through Matrigel as well as the transforming efficiency of SCCHN cells in vitro as assessed by soft agar assays. The constitutive-active STAT5 clones derived from SCCHN cells demonstrated changes consistent with an epithelial-mesenchymal transition (EMT) including decreased expression of E-cadherin and increased vimentin, in comparison to control transfectants. In these cells, STAT5 activation was associated with resistance to cisplatin-mediated apoptosis and growth inhibition induced by the EGFR tyrosine kinase inhibitor (TKI), erlotinib. Conclusions These results suggest that constitutive STAT5 signaling enhances tumor growth, invasion and EMT in squamous epithelial carcinogenesis and may contribute to resistance to EGFR TKI and chemotherapy.

Head and neck squamous cell carcinomas

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