Original Research
Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression

https://doi.org/10.1016/j.tranon.2021.101236Get rights and content
Under a Creative Commons license
open access

Highlights

  • TGF-β1 secreted from CAFs promote the migration and invasion of OSCC cells.

  • CAFs upregulate SOX9 expression of OSCC cells, possibly through inducing EMT.

  • The presence of CAFs is correlated with SOX9 expression in the invasive cancer nests.

  • The TGF-β/SOX9 axis between CAFs and OSCC cells facilitates cancer progression.

  • Targeting the TGF-β/SOX9 axis could be a potential novel target for OSCC.

Abstract

Cancer-associated fibroblasts (CAFs) have important roles in promoting cancer development and progression. We previously reported that high expression of sex-determining region Y (SRY)-box9 (SOX9) in oral squamous cell carcinoma (OSCC) cells was positively correlated with poor prognosis. This study developed three-dimensional (3D) in vitro models co-cultured with OSCC cells and CAFs to examine CAF-mediated cancer migration and invasion in vitro and in vivo. Moreover, we performed an immunohistochemical analysis of alpha-smooth muscle actin and SOX9 expression in surgical specimens from 65 OSCC patients. The results indicated that CAFs promote cancer migration and invasion in migration assays and 3D in vitro models. The invading OSCC cells exhibited significant SOX9 expression and changes in the expression of epithelial–mesenchymal transition (EMT) markers, suggesting that SOX9 promotes EMT. TGF-β1 signalling inhibition reduced SOX9 expression and cancer invasion in vitro and in vivo, indicating that TGF-β1-mediated invasion is dependent on SOX9. In surgical specimens, the presence of CAFs was correlated with SOX9 expression in the invasive cancer nests and had a significant impact on regional recurrence. These findings demonstrate that CAFs promote cancer migration and invasion via the TGF-β/SOX9 axis.

Keywords

Oral squamous cell carcinoma
CAFs
TGF-β
SOX9
3D in vitro model

Abbreviations

CAFs
cancer-associated fibroblasts
CIS
carcinoma in situ
CM
conditioned medium
ELISA
enzyme-linked immunosorbent assay
EMT
epithelial–mesenchymal transition
NOFs
normal oral fibroblasts
OED
oral epithelial dysplasia
OSCC
oral squamous cell carcinoma
SOX9
sex-determining region Y (SRY)-box9
siRNA
short interfering RNA
3D
three-dimensional
TGF-β
transforming growth factor-β
TME
tumour microenvironment
α-SMA
alpha-smooth muscle actin

Cited by (0)