Claudin-3 inhibits tumor-induced lymphangiogenesis via regulating the PI3K signaling pathway in lymphatic endothelial cells

  • Sci Rep. 2022 Oct 19;12(1):17440. doi: 10.1038/s41598-022-22156-6.
Ningjing Lei  1  2 ,  Yanru Cheng  1 ,  Jiajia Wan  1 ,  Rosel Blasig  3 ,  Anqi Li  1 ,  Yueyue Bai  1  2 ,  Reiner F Haseloff  3 ,  Ingolf E Blasig  3 ,  Linyu Zhu  4 ,  Zhihai Qin  5
Affiliations
  • 1. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, 450052, Henan, China.
  • 2. School of Basic Medical Sciences, Zhengzhou University, No. 100 Kexue Road, Zhengzhou, 450001, China.
  • 3. Leibniz-Forschungsinstitut Für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125, Berlin, Germany.
  • 4. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, 450052, Henan, China. [email protected].
  • 5. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, 450052, Henan, China. [email protected].
PMID: 36261482 DOI: 10.1038/s41598-022-22156-6
Abstract

Claudin-3 is a tight junction protein that has often been associated with the progression and metastasis of various tumors. Here, the role of claudin-3 in tumor-induced lymphangiogenesis is investigated. We found an increased lymphangiogenesis in the B16F10 tumor in claudin-3 knockout mice, accompanied by augmented melanoma cell metastasis into sentinel lymph nodes. In vitro, the overexpression of claudin-3 on lymphatic endothelial cells inhibited tube formation by suppressing cell migration, resulting in restricted lymphangiogenesis. Further experiments showed that claudin-3 inhibited lymphatic endothelial cell migration by regulating the PI3K signaling pathway. Interestingly, the expression of claudin-3 in lymphatic endothelial cells is down-regulated by vascular endothelial growth factor C that is often present in the tumor microenvironment. This study indicates that claudin-3 plays an important role as a signaling molecule in lymphatic endothelial cell activity associated with tumor lymphangiogenesis, which may further contribute to melanoma metastasis.

Products