Cycling hypoxia affects cell invasion and proliferation through direct regulation of claudin1 / claudin7 expression, and indirect regulation of P18 through claudin7
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Hong Liu1, Feifei Jiang1, Xinshan Jia2, Jing Lan3, Hao Guo3, Erran Li4, Aihui Yan1, Yan Wang1
1Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
2Department of Pathology, China Medical University, Shenyang, Liaoning 110001, China
3Department of Dermatology, China Medical University, Shenyang, Liaoning 110001, China
4Institute of Respiratory Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China
Yan Wang, email: firstname.lastname@example.org
Hong Liu, email: email@example.com
Keywords: claudin1, claudin7, HIF1α, cycling hypoxia, nasopharyngeal carcinoma
Received: February 16, 2016 Accepted: December 05, 2016 Published: December 31, 2016
Claudins (CLDNs), the major integral membrane proteins at tight junction, play critical roles in apical cell-to-cell adhesion, maintenance of epithelial polarity, and formation of impermeable barriers between epithelial cells.
We investigated in this study the expression of CLDNs- Claudin1 (CLDN1) and Claudin7 (CLDN7), and their relation to tumor progression in nasopharyngeal cancer (NPC). CLDN7, rather than CLDN1, showed higher expression in both undifferentiated tumor tissue and the poorly differentiated CNE2 cells, compared with differentiated tissue and the highly differentiated CNE1 cells. Furthermore, knockdown of CLDN7 dramatically inhibited the metastasis and invasion of CNE2 cells suggesting that CLDN7 could act as a biomarker for NPC metastasis.
Cycling hypoxia could induce significant changes in CLDN1 and CLDN7 expression in NPC cells. Genetics analysis demonstrated that CLDN1/CLDN7 were not only regulated directly by HIF1a but also affected each other through a feedback mechanism. CLDN7 acted as a bridge to promote HIF1a-induced P18 expression and cell differentiation. Taken together, our results provide evidence that adjusting the oxygenation time and cycles in NPC might be an effective method to prevent / delay the metastasis of poorly differentiated NPC cells.
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