Abstract
Lung cancer cells express different chemokines and chemokine receptors that modulate leukocyte infiltration within tumor microenvironment. In this study we screened several mediators/growth factors on CXCL1 release in human carcinoma epithelial cells. Of the tested mediators, VEGF was found to have a robust increase in causing CXCL1 release. VEGF stimulated CXCL1 release and mRNA expression in a time- and concentration-dependent manner. The release was inhibited by the VEGF receptor antagonists and the JNK, PI-3K, tyrosine kinase, and transcription inhibitors. In parallel, VEGF induced JNK, PI3K and Akt activation. Strikingly, among these inhibitors only the JNK inhibitor could reduce VEGF-induced CXCL1 mRNA expression, suggesting that JNK participated in VEGF-induced CXCL1 synthesis, whereas PI-3K was responsible for cellular CXCL1 secretory process. In addition, the steroid dexamethasone and TGF-β suppressed CXCL1 release through a transcriptional regulation. We also showed that cells stimulated with VEGF significantly attracted monocyte migration, which could be abolished by CXCL1 B/N Ab, CXC receptor 2 antagonist, TGF-β, and dexamethasone. In summary, we provide here evidence showing JNK activation for VEGF-induced CXCL1 DNA transcription and PI-3K pathway for extracellular CXCL1 release in human carcinoma epithelial cells. The released CXCL1 was functionally linked to recruiting monocytes into lung cancer cell microenvironment.
Highlights
CXCL1, known as growth-related oncogene protein-α (GRO-α) or melanoma growth stimulatory activity factor (MGSA), is a polypeptide which was initially isolated from Hs294 human melanoma cells
It is known that vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 are critical for development of haematopoietic cells, vascular endothelial cells, and lymphatic endothelial cells, respectively
We demonstrated that TGF-β affected VEGF-induced CXCL1 mRNA level and luciferase reporter activity, suggesting it might interfere with VEGF-induced CXCL1 release through a transcriptional mechanism
Summary
CXCL1, known as growth-related oncogene protein-α (GRO-α) or melanoma growth stimulatory activity factor (MGSA), is a polypeptide which was initially isolated from Hs294 human melanoma cells. The ELR+ chemokines are primarily chemotactic for endothelial cells and neutrophils. These chemokines are potent promoters of angiogenesis, as the recruited neutrophils are known to synthesize and store angiogenic molecules like vascular endothelial growth factors (VEGFs) [3,4]. It is known that VEGFR-1, VEGFR-2, and VEGFR-3 are critical for development of haematopoietic cells, vascular endothelial cells, and lymphatic endothelial cells, respectively. VEGF secreted by human A549 lung carcinoma cells facilitates tumor metastasis in a murine model [8]. Some reports have shown that VEGF is induced after irradiation both in vitro and in vivo in Lewis lung carcinomas (LLC) [10]
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