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 alpha(2)-, alpha(3)-, and beta(1)-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. alpha(2)-, alpha(3)-, and beta(1)-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 alpha(2)-integrin
protein levels by Western blot. Compared with normal human lung, a previously undetected alpha(2)-integrin
isoform potentially lacking essential cytoplasmic sequences was significantly increased in BPS and CCAM, and alpha(2)-integrin spatial and cellular expression was more intense.
E-cadherin protein levels were also significantly increased, whereas alpha(3) increased in CCAM compared with canalicular, but not with alveolar, stage lung. beta(1)-integrin levels were unchanged. We conclude that in BPS and CCAM, altered alpha(2)-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.