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Role of cystic fibrosis transmembrane conductance regulator in FHC colon epithelial cell dysfunction and colon cancer
Author(s) -
Grant Garett J.,
Mogan Cara A.,
Liou Theodore G.,
Helms My N.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03534
Subject(s) - cystic fibrosis transmembrane conductance regulator , colorectal cancer , medicine , cystic fibrosis , inflammation , cancer research , population , cancer , immunology , environmental health
Objective To determine the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in colon cancer development, with a focus on cell migration, EGFR signaling, and inflammation using model FHC colon epithelial cells. Background Our clinical observations indicate that individuals with cystic fibrosis (CF) over the age of 40 are 4–8 times more likely to get colon cancer than the general population. Moreover, the likelihood of getting colon cancer increases to over 30 times the general population’s risk in CF patients who have had an organ transplant. The mechanism(s) leading to increased colon cancer in CF patients is not fully understood, but dysfunctional Cl − and Na + transport are highly implicated. Chronic inflammation has also been shown to play an important role in the development and progression of many cancers. We hypothesize that dysregulated ion transport in CF patients leads to chronic inflammation and increased incidence of colon cancer via altered epidermal growth factor receptor (EGFR) signaling. Methods We performed scratch assays on cultured human colon epithelial cells (FHC) and measured the rate of cell migration every 24 hours for 5 days in the presence of either CFTR activating or inhibiting compounds. EGFR signaling was analyzed using standard immunohistochemical labeling techniques and commercially available reagents in similarly treated FHC cells. Results Cells treated with 500 μM IBMX and 5 μM forskolin (CFTR activators) had significantly decreased rates of cell migration (26 μm 2 /24 hours) compared to the control group (51 μm 2 /24 hours) n=3; p<0.05. Control and colon cells treated with 500 μM IBMX and 5 μM forskolin showed low levels of EGFR labelling (restricted to cell periphery), whereas cells treated with 5 mM CFTR(inh)‐172 (CFTR inhibitor) showed more robust EGFR signal throughout the cytoplasm in 3 independent observations. Conclusion Our data indicates that suppressed CFTR activity impacts colon epithelial cell migration and EGFR localization in FHC cells. Additional research on CFTR and EGFR signaling is needed to better understand and improve treatment options for both colon cancer and CF patients. Support or Funding Information Funding: NIH R01 HL137033‐01 awarded to MNH.