FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer

Ming-Min Chang; Su-Zhen Wu; Shang-Hsun Yang; Chia-Ching Wu; Chia-Yih Wang; Bu-Miin Huang

doi:10.1016/j.tranon.2021.101208

FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer

Transl Oncol. 2021 Nov;14(11):101208. doi: 10.1016/j.tranon.2021.101208. Epub 2021 Aug 23.

Authors

Ming-Min Chang¹, Su-Zhen Wu², Shang-Hsun Yang³, Chia-Ching Wu¹, Chia-Yih Wang⁴, Bu-Miin Huang⁵

Affiliations

¹ Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China.
² Department of Anesthesiology, Chi Mei Medical Center, Liouying, Tainan 73657, Taiwan, Republic of China.
³ Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China.
⁴ Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China. Electronic address: b89609046@gmail.com.
⁵ Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40406, Taiwan, Republic of China. Electronic address: bumiin@mail.ncku.edu.tw.

Abstract

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.

Keywords: Epithelial-to-mesenchymal transition/EMT; FGF9; FGFR1; Lewis lung carcinoma; Liver metastasis; M2 macrophage infiltration.