Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation

Abstract

In many organs, integrins and cadherins are partly regulated by Hox genes, but their interactions in airway morphogenesis and congenital lung diseases are unknown. We previously showed that the Hox protein HoxB5 is abnormally increased in bronchopulmonary sequestration (BPS) and congenital cystic adenomatoid malformation (CCAM), congenital lung lesions with abnormal airway branching. We now report on α2-, α3-, and β1-integrin and E-cadherin expression in normal human lung and in BPS and CCAM tissue previously shown to have abnormal HoxB5 expression and on the relationship of cell adhesion molecule expression to Hoxb5 regulation. α2-, α3-, and β1-integrins and E-cadherin expression in normal human lung and BPS and CCAM were evaluated using Western blot and immunohistochemistry. Fetal mouse lung fibroblasts with Hoxb5-specific siRNA downregulation were evaluated for α2-integrin protein levels by Western blot. Compared with normal human lung, a previously undetected α2-integrin isoform potentially lacking essential cytoplasmic sequences was significantly increased in BPS and CCAM, and α2-integrin spatial and cellular expression was more intense. E-cadherin protein levels were also significantly increased, whereas α3increased in CCAM compared with canalicular, but not with alveolar, stage lung. β1-integrin levels were unchanged. We conclude that in BPS and CCAM, altered α2-integrin cytoplasmic signaling contributes to abnormal cellular behavior in these lung lesions. Aberrant cell adhesion molecule and Hox protein regulation are likely part of the mechanism involved in the development of BPS and CCAM.