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

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 squamous 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 expression 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.

SUBMITTER: Saito K

PROVIDER: S-EPMC8057293 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PLOD2 Is Essential to Functional Activation of Integrin β1 for Invasion/Metastasis in Head and Neck Squamous Cell Carcinomas.

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Project description:HoxB9, as a HOX family member, is known to play important roles in embryonic development. Recent studies have shown that HoxB9 is involved in cancer progression. However, little is known about the role of HoxB9 and the underlying mechanisms that suppress oral squamous cell carcinoma (OSCC) progression. In the present study, we used immunohistochemical staining to demonstrate that HoxB9 is over-expressed in OSCC cells and found that high levels of HoxB9 were significantly associated with shorter overall survival in patients with OSCC. Functional studies revealed that knocking down HoxB9 in OSCC cells using RNA interference decreased the migration and invasion of OSCC cells in vitro. Our mechanistic studies suggested that HoxB9 could stimulate the migration and invasion of OSCC cells by targeting EMT via the TGF-β1/Smad2/Slug signaling pathway. Collectively, these findings suggest the vital roles of HoxB9 in OSCC progression through its effects in promoting EMT.

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