PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1

Ken Saito, Ayaka Mitsui, I. Wayan Sumardika, Yusuke Yokoyama, Masakiyo Sakaguchi, Eisaku Kondo

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

We previously reported that high expression of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin β1 to promote the invasion and metastasis of oral squa- mous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2-integrin β1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)-6 in the tumor microenvironment acts as a key molecule that triggers PLOD2-integrin β1 axis-derived acceleration of tumor invasion and metastasis. It was found using the dual-luciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL-6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL-6 stimulation did not contribute to integrin β1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL-6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL-6 expres- sion occurred in CD163-positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL-6 significantly increases STAT3-mediated PLOD2 promoter activity, IL-6 released by M2-type tumor-associated macrophages is a crucial factor that promotes PLOD2-integrin β1 axis-enhanced invasion and metastasis of oral SCC cells.

Original languageEnglish
Article number29
JournalInternational journal of oncology
Volume58
Issue number6
DOIs
Publication statusPublished - Jun 1 2021

Keywords

  • Integrin β1
  • Interleukin-6
  • Invasion
  • Procollagen-lysine 2-oxoglutarate 5-dioxygenase 2
  • Squamous cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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