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

藤黄蛋白C 衰老 癌变 细胞生物学 成纤维细胞 生物 整合素 癌症研究 下调和上调 细胞培养 细胞 癌症 细胞外基质 生物化学 遗传学 基因
作者
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
出处
期刊:American Journal of Cancer Research 卷期号:11 (9): 4364-4379 被引量:3
标识
摘要

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 p16INK4a 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.

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