TY - JOUR
T1 - FGF9/FGFR1 promotes cell proliferation, epithelial-mesenchymal transition, M2 macrophage infiltration and liver metastasis of lung cancer
AU - Chang, Ming Min
AU - Wu, Su Zhen
AU - Yang, Shang Hsun
AU - Wu, Chia Ching
AU - Wang, Chia Yih
AU - Huang, Bu Miin
N1 - Funding Information:
This research was funded by Ministry of Science and Technology, Taiwan, Republic of China (grant number: MOST 105-2320-B-006-001, and MOST 106-2320-B-006-001, MOST 110-2320-B-006-025 MY3 to BMH; grant number: MOST 106-2811-B-006-014, MOST 107-2811-B-006-0519, MOST 109-2811-B-006-555 to MMC; and grant number: CLFHR11025 to SZW and BMH). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. We are grateful for the support from the Core Research Laboratory, College of Medicine, National Cheng Kung University.
Funding Information:
We are grateful for the support from the Core Research Laboratory, College of Medicine, National Cheng Kung University.
Funding Information:
This research was funded by Ministry of Science and Technology , Taiwan, Republic of China (grant number: MOST 105-2320-B-006-001 , and MOST 106-2320-B-006-001 , MOST 110-2320-B-006-025 MY3 to BMH; grant number: MOST 106-2811-B-006-014 , MOST 107-2811-B-006-0519 , MOST 109-2811-B-006-555 to MMC; and grant number: CLFHR11025 to SZW and BMH). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Publisher Copyright:
© 2021
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.tranon.2021.101208
DO - 10.1016/j.tranon.2021.101208
M3 - Article
AN - SCOPUS:85113337875
SN - 1944-7124
VL - 14
JO - Translational Oncology
JF - Translational Oncology
IS - 11
M1 - 101208
ER -