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

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.

miR‐155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16‐bearing mice at the premetastatic stage

“…Angiogenin secreted by breast tumour cells triggers angiogenic activity in endothelial cells . Vascular remodelling is considered to be one of the key events in metastasis development . MicroRNAs associated with pro‐ and antiangiogenic events include miR‐155, miR‐21, miR‐205 and miR‐let7b .…”

“…14 Vascular remodelling is considered to be one of the key events in metastasis development. 15,16 MicroRNAs associated with pro-and antiangiogenic events include miR-155, miR-21, miR-205 and miR-let7b. [17][18][19][20][21][22] Among those, miR-155 is significantly increased in cutaneous melanoma and acts as an oncogene.…”

Correlation of Fibroblast Activation Protein (Fap) Immuohistochemical Expression With Histopathological Grading and Tumor-Stroma Ratio (Tsr) in Colorectal Adenocarcinoma

“…This study has analyzed the intensity and proportion of FAP expression by immunohistochemical examination. This study suggested that the expression of FAP in the stroma improves tumor prognosis and poor survival in some patients with solid tumor types, including colorectal cancer, but other studies on colorectal cancer did not get statistically significant results, both on the overall survival value, tumor cell invasion, lymph node involvement and distant metastases [26][27][28][29]. Therefore, further exploration is needed to validate the presence of Fibroblast Activation Protein (FAP) in relation to the activity of the stroma in influencing tumorigenesis, angiogenesis, and prognosis, and in the future, it can be used as an adequate treatment in colorectal cancer patients.…”

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling

“…The phosphorylation of ERK 1/2 and Smad 2/3, however, was unaffected. Meanwhile, the inhibited phosphorylation of AKT [59,[63][64][65]. Thus, the exact relationships among VEGFA, AKT and p38 in NPC cells merit further exploration.…”