Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition.
BACKGROUND
Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis.


OBJECTIVE
To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT).


METHODS
Immunoblotting, immunofluorescence, flow cytometry, and real-time polymerase chain reaction were performed to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1α inhibitors on nasal polypogenesis were investigated in a murine model.


RESULTS
E-cadherin and α-smooth muscle actin (α-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (α-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and β-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1α and decreased in normoxia by expressing HIF-1α. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and up-regulate pSmad3, which led to α-SMA induction. In CRS sinonasal specimens, HIF-1α expression was found to correlate with E-cadherin loss and α-SMA expression. Finally, HIF-1α inhibitors suppressed nasal polypogenesis in a murine model.


CONCLUSIONS
hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1α and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1α be viewed as a therapeutic target for nasal polyposis.
Department of Pharmacology and Biomedical Science, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Hyun-Woo
HW
Shin
Kumsun
K
Cho
Dae Woo
DW
Kim
Doo Hee
DH
Han
Roza
R
Khalmuratova
Sang-Wook
SW
Kim
Sea-Yuong
SY
Jeon
Yang-Gi
YG
Min
Chul Hee
CH
Lee
Chae-Seo
CS
Rhee
Jong-Wan
JW
Park
D000199:Actins / Q000502:physiology; D000818:Animals; D015820:Cadherins / Q000502:physiology; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D000860:Hypoxia / Q000150:complications; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D009298:Nasal Polyps / Q000209:etiology* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology
C541116:ACTA2 protein, human; D000199:Actins; D015820:Cadherins; D051793:Hypoxia-Inducible Factor 1; D053773:Transforming Growth Factor beta1