Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells

Jung Min Suh, Yelin Son, Jung Yeon Yoo, Yookyung Goh, Nabil G. Seidah, Sanghyuk Lee, Yun Soo Bae

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Previously we demonstrated that Ahnak mediates transforming growth factor-β (TGFβ)-induced epithelial-mesenchymal transition (EMT) during tumor metastasis. It is well-known that circulating tumor cells (CTCs) invade the vasculature of adjacent target tissues before working to adapt to the host environments. Currently, the molecular mechanism by which infiltrated tumor cells interact with host cells to survive within target tissue environments is far from clear. Here, we show that Ahnak regulates tumor metastasis through PCSK9 expression. To validate the molecular function of Ahnak in metastasis, B16F10 melanoma cells were injected into WT and Ahnak knockout (Ahnak−/−) mice. Ahnak−/− mice were more resistant to the pulmonary metastasis of B16F10 cells compared to wild-type (WT) mice. To investigate the host function of Ahnak in recipient organs against metastasis of melanoma cells, transcriptomic analyses of primary pulmonary endothelial cells from WT or Ahnak−/− mice in the absence or presence of TGFβ stimulation were performed. We found PCSK9, along with several other candidate genes, was involved in the invasion of melanoma cells into lung tissues. PCSK9 expression in the pulmonary artery was higher in WT mice than Ahnak−/− mice. To evaluate the host function of PCSK9 in lung tissues during the metastasis of melanoma cells, we established lung epithelial cell-specific tamoxifen-induced PCSK9 conditional KO mice (Scgb1a1-Cre/PCSK9fl/fl). The pulmonary metastasis of B16F10 cells in Scgb1a1-Cre/PCSK9fl/fl mice was significantly suppressed, indicating that PCSK9 plays an important role in the metastasis of melanoma cells. Taken together, our data demonstrate that Ahnak regulates metastatic colonization through the regulation of PCSK9 expression.

Original languageEnglish
Pages (from-to)993-1001
Number of pages9
JournalNeoplasia
Volume23
Issue number9
DOIs
StatePublished - Sep 2021

Keywords

  • Ahnak
  • Extravasation
  • Metastasis
  • PCSK9
  • TGFβ

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