Investigation of bone invasion and underlying mechanisms of oral cancer using a cell line‑derived xenograft model

Qiusheng Shan, Kiyofumi Takabatake, Haruka Omori, Hotaka Kawai, May Wathone Oo, Shintaro Sukegawa, Masae Fujii, Yasunori Inada, Sho Sano, Keisuke Nakano, Hitoshi Nagatsuka

Research output: Contribution to journalArticlepeer-review


The cancer stroma regulates bone invasion in oral squamous cell carcinoma (OSCC). However, data on normal stroma are limited. In the present study, the effects of gingival and periodontal ligament tissue‑derived stromal cells (G‑SCs and P‑SCs, respectively) and human dermal fibroblasts (HDFs) on bone resorption and osteoclast activation were assessed using hematoxylin and eosin and tartrate‑resistant acid phosphatase staining in a cell line‑derived xenograft model. The results demonstrated that G‑SCs promoted bone invasion and osteoclast activation and inhibited osteoclast proliferation following crosstalk with the human OSCC HSC‑3 cell line, whereas P‑SCs inhibited bone resorp‑ tion and promoted osteoclast proliferation in vitro but had a minimal effect on osteoclast activation both in vitro and in vivo following crosstalk with HSC‑3 cells. Furthermore, the effects of G‑SCs, P‑SCs and HDFs on protein expression levels of matrix metalloproteinase (MMP)‑9, membrane type 1 MMP (MT1‑MMP), Snail, parathyroid hormone‑related peptide (PTHrP) and receptor activator of NF‑κB ligand (RANKL) in HSC‑3 cells in OSCC bone invasion regions were assessed using immunohistochemistry. The results demonstrated that G‑SCs had a more prominent effect on the expression of MMP‑9, MT1‑MMP, Snail, PTHrP, and RANKL, whereas P‑SCs only promoted RANKL and PTHrP expression and exerted a minimal effect on MMP‑9, MT1‑MMP and Snail expression. The potential genes underlying the differential effects of G‑SCs and P‑SCs on bone invasion in OSCC were evaluated using a microarray, which indicated that cyclin‑dependent kinase 1, insulin, aurora kinase A, cyclin B1 and DNA topoisomerase II alpha underlaid these differential effects. Therefore, these results demonstrated that G‑SCs promoted bone invasion in OSCC by activating osteoclasts on the bone surface, whereas P‑SCs exerted an inhibitory effect. These findings could indicate a potential regulatory mechanism for bone invasion in OSCC.

Original languageEnglish
Article number382
JournalOncology Letters
Issue number5
Publication statusPublished - Nov 2022
Externally publishedYes


  • bone invasion
  • gingival ligament tissue‑derived stromal cell
  • microarray
  • oral squamous cell carcinoma
  • periodontal ligament tissue‑derived stromal cell
  • xenograft model

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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