FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer
| Autor: | Bu Miin Huang, Chia Ching Wu, Ming-Min Chang, Chia Yih Wang, Su-Zhen Wu, Shang Hsun Yang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Tumor microenvironment MMP2 M2 macrophage infiltration Chemistry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Lewis lung carcinoma Epithelial-to-mesenchymal transition/EMT medicine.disease medicine.disease_cause Metastasis FGF9 stomatognathic diseases FGFR1 Oncology Tumor progression medicine Cancer research Epithelial–mesenchymal transition Lung cancer Carcinogenesis Liver metastasis RC254-282 Original Research |
| Zdroj: | Translational Oncology Translational Oncology, Vol 14, Iss 11, Pp 101208-(2021) |
| ISSN: | 1936-5233 |
| Popis: | Highlights • FGF9 induced cell proliferation, EMT, migration, and invasion of mouse Lewis lung cancer (LLC) cells, in vitro. • FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13) and reduced the expression of E-cadherin. • FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with tumor growth, angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. • The FGF9/LLC syngeneic animal model provides a useful tool for the mechanism studies of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis. Fibroblast growth factors 9 (FGF9) modulates cell proliferation, differentiation and motility for development and repair in normal cells. Abnormal activation of FGF9 signaling is associated with tumor progression in many cancers. Also, FGF9 may be an unfavorable prognostic indicator for non-small cell lung cancer patients. However, the effects and mechanisms of FGF9 in lung cancer remain elusive. In this study, we investigated the FGF9-induced effects and signal activation profiles in mouse Lewis lung carcinoma (LLC) in vitro and in vivo. Our results demonstrated that FGF9 significantly induced cell proliferation and epithelial-to-mesenchymal transition (EMT) phenomena (migration and invasion) in LLC cells. Mechanism-wise, FGF9 interacted with FGFR1 and activated FAK, AKT, and ERK/MAPK signal pathways, induced the expression of EMT key proteins (N-cadherin, vimentin, snail, MMP2, MMP3 and MMP13), and reduced the expression of E-cadherin. Moreover, in the allograft mouse model, intratumor injection of FGF9 to LLC-tumor bearing C57BL/6 mice enhanced LLC tumor growth which were the results of increased Ki67 expression and decreased cleaved caspase-3 expression compared to control groups. Furthermore, we have a novel finding that FGF9 promoted liver metastasis of subcutaneous inoculated LLC tumor with angiogenesis, EMT and M2-macrophage infiltration in the tumor microenvironment. In conclusion, FGF9 activated FAK, AKT, and ERK signaling through FGFR1 with induction of EMT to stimulate LLC tumorigenesis and hepatic metastasis. This novel FGF9/LLC allograft animal model may therefore be useful to study the mechanism of liver metastasis which is the worst prognostic factor for lung cancer patients with distant organ metastasis. |
| Databáze: | OpenAIRE |
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