Fibroblast activation protein-α in tumor cells promotes colorectal cancer angiogenesis via the Akt and ERK signaling pathways

Cao,Feng; Wang,Songsong; Wang,Huanqin; Tang,Wei

doi:10.3892/mmr.2017.8155

Fibroblast activation protein-α in tumor cells promotes colorectal cancer angiogenesis via the Akt and ERK signaling pathways

Authors:
- Feng Cao
- Songsong Wang
- Huanqin Wang
- Wei Tang
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Affiliations: Department of Medicine 13, Xintai People's Hospital, Taian, Shandong 271000, P.R. China, Department of Anesthesiology, 88 Hospital of PLA, Taian, Shandong 271000, P.R. China
Published online on: November 27, 2017 https://doi.org/10.3892/mmr.2017.8155
Pages: 2593-2599

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Abstract

Fibroblast activation protein-α (FAP-α) is a cell surface serine protease of the post-prolyl peptidase family, and stromal FAP-α expression may serve important functions in tumor occurrence and progression. In recent years, FAP-α expression in tumor cells has been detected in a number of types of tumor, and its roles in tumor growth and metastasis have been reported. However, the presence of FAP-α in colorectal cancer (CRC) cells lacks sufficient evidence and its role in angiogenesis remains unknown. The present study confirmed FAP-α expression in CRC cells at the tissue and cellular level, using immunohistochemistry and western blot analysis, respectively; it additionally identified that FAP-α in CRC cells was positively associated with vascular endothelial growth factor (VEGF)-A expression and microvessel density in stained tissue samples for the first time. In addition, western blotting identified that FAP-α overexpression in SW1116 cells significantly upregulated VEGF-A expression, and silencing of FAP-α in HT29 cells markedly inhibited VEGF-A expression. Survival analysis demonstrated that patients with high expression of FAP-α and VEGF-A had the shortest survival time. To detect the effects of FAP-α on human umbilical vein endothelial cells (HUVECs), conditioned medium (CM) from CRC cell lines was used and it was identified that CM from SW1116 cells with overexpressed FAP-α exhibited significantly increased VEGF-R2, phosphorylated extracellular signal-regulated kinase (p-ERK) and p-RAC-α serine/threonine-protein kinase (Akt) in HUVECs, in addition to the proliferation rate. Conversely, CM from HT29 cells with FAP-α silenced exhibited a significantly inhibited proliferation rate. Molecular mechanism analysis demonstrated that p-ERK and p-Akt in SW1116 and HT29 cells were affected by alterations in FAP-α expression, and treatment with a p-ERK inhibitor (U0126) and p-Akt inhibitor (LY294002) ameliorated VEGF-A upregulation induced by FAP-α overexpression. All the results confirmed the presence of FAP-α in CRC cells and suggested that FAP-α may effectively promote angiogenesis in CRC via the Akt and ERK signaling pathways.

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