Induction of cellular senescence in fibroblasts through β1-integrin activation by tenascin-C-derived peptide and its protumor effect

Motomichi Fujita; Manabu Sasada; Mayu Eguchi; Takuya Iyoda; Shin Okuyama; Takuro Osawa; Kenta Tsuzuranuki; Mamoru Sakamoto; Yu Hagihara; Masaki Matsumura; Satoshi Osada; Hiroaki Kodama; Yoshikazu Higami; Fumio Fukai

Induction of cellular senescence in fibroblasts through β1-integrin activation by tenascin-C-derived peptide and its protumor effect

Am J Cancer Res. 2021 Sep 15;11(9):4364-4379. eCollection 2021.

Authors

Affiliations

¹ Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science Chiba, Japan.
² Clinical Research Center in Hiroshima, Hiroshima University Hospital Hiroshima, Japan.
³ Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University Yamaguchi, Japan.
⁴ Faculty of Science and Engineering, Saga University Saga, Japan.
⁵ Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science Chiba, Japan.

PMID: 34659892
PMCID: PMC8493383

Abstract

Tenascin-C is upregulated during inflammation and tumorigenesis, and its expression level is correlated with a poor prognosis in several malignancies. Nevertheless, the substantial role of tenascin-C in cancer progression is poorly understood. Previously, we found that a peptide derived from tenascin-C, termed TNIIIA2, acts directly on tumor cells to activate β1-integrin and induce malignant progression. Here, we show that β1-integrin activation by TNIIIA2 in human fibroblasts indirectly contributes to cancer progression through the induction of cellular senescence. Prolonged treatment of fibroblasts with TNIIIA2 induced cellular senescence, as characterized by the suppression of cell growth and the induction of senescence-associated-β-galactosidase and p16^INK4a expression. The production of reactive oxygen species and subsequent DNA damage were responsible for the TNIIIA2-induced senescence of fibroblasts. Interestingly, peptide FNIII14, which inactivates β1-integrin, inhibited fibroblast senescence induced not only by TNIIIA2 but also by H₂O₂, suggesting that β1-integrin activation plays a critical role in the induction of senescence in fibroblasts. Moreover, TNIIIA2-induced senescent fibroblasts secreted heparin-binding epidermal growth factor-like growth factor (HB-EGF), which caused preneoplastic epithelial HaCaT cells to acquire malignant properties, including colony-forming and focus-forming abilities. Thus, our study demonstrates that tenascin-C-derived peptide TNIIIA2 induces cellular senescence in fibroblasts through β1-integrin activation, causing cancer progression via the secretion of humoral factors such as HB-EGF.

Keywords: SASP; Tenascin-C; cancer-associated fibroblast; cellular senescence; heparin-binding epidermal growth factor-like growth factor; β1-integrin.