Abstract
Due to high levels of expression in aggressive tumors, high mobility group AT-hook 1 (HMGA1) has recently attracted attention as a potential anti-tumor target. However, HMGA1 is also expressed in normal somatic progenitor cells, raising the question: how might systemic anti-HMGA1 therapies affect the structure and function of normal tissue differentiation? In the present study, RNA sequencing data demonstrated HMGA1 is highly expressed in human airway basal stem/progenitor cells (BC), but decreases with BC differentiation in air-liquid interface cultures (ALI). BC collected from nonsmokers, healthy smokers, and smokers with chronic obstructive pulmonary disease (COPD) displayed a range of HMGA1 expression levels. Low initial expression levels of HMGA1 in BC were associated with decreased ability to maintain a differentiated ALI epithelium. HMGA1 down-regulation in BC diminished BC proliferation, suppressed gene expression related to normal proliferation and differentiation, decreased airway epithelial resistance, suppressed junctional and cell polarity gene expression, and delayed wound closure of airway epithelium following injury. Furthermore, silencing of HMGA1 in airway BC in ALI increased the expression of genes associated with airway remodeling in COPD including squamous, epithelial-mesenchymal transition (EMT), and inflammatory genes. Together, the data suggests HMGA1 plays a central role in normal airway differentiation, and thus caution should be used to monitor airway epithelial structure and function in the context of systemic HMGA1-targeted therapies.
Highlights
High mobility group AT-hook1 (HMGA1) codes for a 10 kDa protein that functions as a non-histone chromatin protein [1,2,3]
high mobility group AThook 1 (HMGA1) is expressed in normal somatic progenitor cells, raising the question: how might systemic anti-HMGA1 therapies affect the structure and function of normal tissue differentiation? In the present study, RNA sequencing data demonstrated HMGA1 is highly expressed in human airway basal stem/progenitor cells (BC), but decreases with BC differentiation in air-liquid interface cultures (ALI)
Since HMGA1 has functions that likely affect regeneration [3, 9, 10] we asked: is the level of HMGA1 expression in BC associated with the regeneration capacity of BC? Primary BC from human SAE of 17 of nonsmokers, 14 healthy smokers and 16 chronic obstructive pulmonary disease (COPD) smokers described by Staudt et al [52] were assessed for the capacity of the purified BC to differentiate in ALI culture
Summary
High mobility group AT-hook (HMGA1) codes for a 10 kDa protein that functions as a non-histone chromatin protein [1,2,3]. HMGA1 has recently become an anti-tumor target due to the correlation of high HMGA1 expression with tumor aggression and mortality [11,12,13,14,15,16,17,18,19]. A variety of anti-HMGA1 strategies, including small molecules, antisense mRNA expression, miRNA expression, and siRNA delivery, have demonstrated promising anti-tumor effects using transformed cells in in vitro systems and xenograft models [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]. Systemic use of anti-HMGA1 therapeutics may affect HMGA1 expression in nonmalignant cells, and the consequences of reduced HMGA1 www.impactjournals.com/oncotarget expression in human somatic progenitor cells have not been studied
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