Expression of Hoxb‐5 during human lung development and in congenital lung malformations

Volpe, MaryAnn V.; Pham, Lucia D.; Lessin, Marc S.; Ralston, Steven J.; Bhan, Ina; Cutz, Ernest; Nielsen, Heber C.

doi:10.1002/bdra.10086

Cited by 110 publications

(88 citation statements)

References 33 publications

(53 reference statements)

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“…In mice, we have reported that regulated spatial and temporal expression of the Hox protein, Hoxb5, helps regulate airway branching patterns partially through regulation of cell matrix molecules (57,60,61). We have also shown that HoxB5 (nomenclature for human Hoxb5) is expressed in human lung development in a similar pattern to that seen in mouse and that human BPS and CCAM tissue has abnormally high levels of HoxB5 protein, analogous to the canalicular stage of lung development and significantly increased over age and lung development stage-matched controls (59,64). The persistent overexpression of HoxB5 in BPS and CCAM tissues may have deleterious effects on downstream genes governing mesenchymal-epithelial cell adhesion and cellular interactions, but whether Hox gene regulation and altered cell adhesion coexist in BPS and CCAM has not been studied.…”

supporting

confidence: 52%

“…We evaluated ␣ 2 -integrin protein levels in mouse fetal lung fibroblasts in which we have previously reported siRNA-specific downregulation of Hoxb5 protein. This was done to further understand the potential relationship between altered ␣ 2 -integrin protein expression in BPS and CCAM and the aberrant expression of HoxB5 protein that we have previously reported in these same tissue samples (59,60). Compared with mouse fetal lung fibroblasts treated with scramble siRNA (50 nM) (negative control), the 150-kDa protein isoform of ␣ 2 -integrin was significantly decreased in fetal mouse lung fibroblasts treated with Hoxb5 siRNA (50 nM) in association with the previously described decrease in Hoxb5 protein levels ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…BPS and CCAM tissue from children up to 3 years of age was obtained at surgical resection. CCAM tissue specimens used in this study were pathologically defined by our institution's Department of Pathology as type II CCAM (1,54).Tissue from each specimen was separated for Western blot and immunostaining studies as previously described (59). Mouse lung fibroblasts cultures.…”

Section: Methodsmentioning

confidence: 99%

“…Normal lung, BPS, and CCAM tissue samples in which we have previously studied HoxB5 protein expression were used for this study (59). Western blot analysis using methodology we have previously described was used to identify temporal and quantitative changes in ␣2-, ␣3-, and ␤1-integrins and E-cadherin protein levels in human lung tissue from the canalicular period (17-to 22-wk gestation, n ϭ 7) and the alveolar period (term gestation to 1.5 years, n ϭ 3) and in BPS (1-3 yr of age, n ϭ 4) and CCAM tissue (1-3 yr of age, n ϭ 7) (58).…”

Section: Methodsmentioning

confidence: 99%

“…We hypothesized that integrin and E-cadherin expression would be altered in BPS and CCAM tissue that we have previously shown to have increased levels of HoxB5 protein (59).…”

mentioning

confidence: 99%

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

Volpe

Chung²,

Ulm³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Volpe MV, Chung E, Ulm JP, Gilchrist BF, Ralston S, Wang KT, Nielsen HC. Aberrant cell adhesion molecule expression in human bronchopulmonary sequestration and congenital cystic adenomatoid malformation. Am J Physiol Lung Cell Mol Physiol 297: L143-L152, 2009. First published May 1, 2009 doi:10.1152/ajplung.90618.2008.-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 ␣ 2-, ␣3-, and ␤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. ␣ 2-, ␣3-, and ␤ 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 ␣ 2-integrin protein levels by Western blot. Compared with normal human lung, a previously undetected ␣ 2-integrin isoform potentially lacking essential cytoplasmic sequences was significantly increased in BPS and CCAM, and ␣ 2-integrin spatial and cellular expression was more intense. Ecadherin protein levels were also significantly increased, whereas ␣ 3 increased in CCAM compared with canalicular, but not with alveolar, stage lung. ␤ 1-integrin levels were unchanged. We conclude that in BPS and CCAM, altered ␣ 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.

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supporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…We hypothesized that integrin and E-cadherin expression would be altered in BPS and CCAM tissue that we have previously shown to have increased levels of HoxB5 protein (59).…”

mentioning

confidence: 99%

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

Volpe

Chung²,

Ulm³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Development and Cancer: TheHOXGene Connection

James

Grier

Thompson

et al. 2007

The Cancer Handbook

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Homeobox genes nave been identified in the genomes of all animals mapped so far. The Human Class 1 homeobox ( HOX ) genes are clustered on four different chromosomes, 7p15, 17q21, 12q123 and 2q31. The proteins encoded by these genes act as master regulators of transcription. During embryogenesis they define axial patterning and developmental cues. The discovery that genes initially expressed in embryogenesis are often re‐expressed in neoplasia has led to the concept that ‘Oncology recapitulates Ontogeny’. Individual HOX genes have been identified in specific developmetal processes, e.g. downregulation of HOXB5 appears necessary for normal lung development. In other processes such as haematopoiesis sub‐sets of HOX genes are associated with lineage commitment and differentiation. Generally higher HOX gene expression is associated with a more primitive phenotype. The oncogenic potential of HOX proteins has been linked with leukaemia and solid tumours. Chromosomal translocations involving several HOX genes indicate they play a direct role in leukaemogenesis. Known regulators of HOX expression such as MLL are also directly involved in the onset and maintenance of leukaemia. Current investigations of HOX gene expression in various cancers indicate their potential for disease classification and prediction of clinical outcome. Model systems of dysregulated HOX expression suggest a functional role for these master regulators in cancer, often associated with a more aggressive phenotype, such as high metastatic potential. Future work to test the concept that ‘Oncology recapitulates Ontogeny’ will involve elucidation of the upstream regulators and downstream targets within the HOX‐axis.

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Prenatal Diagnosis and Management of Abnormal Fetal Development with Emphasis on the Third Trimester of Pregnancy

Wladimiroff

Cohen–Overbeek

2009

Genetic Disorders and the Fetus

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Expression of Hoxb‐5 during human lung development and in congenital lung malformations

Cited by 110 publications

References 33 publications

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

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

Development and Cancer: TheHOXGene Connection

Prenatal Diagnosis and Management of Abnormal Fetal Development with Emphasis on the Third Trimester of Pregnancy

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