Abstract
The mechanisms underlying the role of chemokines in tumor angiogenesis is still not fully understood. In this study, we detected the influence of CCL19 on colorectal cancer (CRC) angiogenesis. The expression of CCL19 and CD31 in CRC tissues were detected by immunohistochemistry. Human CRC cell lines SW1116 and SW620 stably transfected with CCL19 lentivirus and CCL19 shRNA, and HUVEC stably transfected with CCR7 shRNA were used in our study. Our study showed that CCL19 was significantly low-expressed in CRC tissues and positively related to highly tumor microvessel density. In vitro, we observed that CCL19 high-expressed SW1116 supernatant was able to inhibit proliferation, migration, and sprouting responses of HUVEC, whereas CCL19 low-expressed SW620 supernatant can promote HUVEC angiogenesis. Additionally, we further demonstrated that these functions maybe achieved through promoting miR-206 thus inhibiting Met/ERK/Elk-1/HIF-1α/VEGF-A pathway in a CCR7-dependent manner. Mice angiogenesis model also confirmed that elevated expression of CCL19 inhibit the angiogenesis of CRC in vivo. In summary, our results supported that CCL19 can inhibit CRC angiogenesis through promoting miR-206 thus inhibiting Met/ERK/Elk-1/HIF-1α/VEGF-A pathway. This may be a novel therapeutic option for anti-vascular treatment in CRC.
Highlights
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, with morbidity and mortality ranking third in the world[1]
To explore the clinicopathological significance of CC ligand 19 (CCL19) in CRC, we analyzed the correlation between CCL19 expression and CRC patients’ clinical and pathologic materials in the tissue microarray (TMA) cohort (Table 1)
The results showed that the SW1116/CCL19-CM, as well as the SW620/shCCL19-CM can either inhibit or promote the migration of HUVEC compared with the control group, which can be abrogated by anti-CCL19-neutralizing antibody (Fig. 2d)
Summary
Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, with morbidity and mortality ranking third in the world[1]. Despite a increasing number of proteins and signaling pathways have been found to be Chemokines belong to a superfamily that consists of small proteins, which are able to bind to G-proteincoupled receptors that activate downstream accesses and functions[5]. Chemokines and their receptors widely participate in tumorigenesis, metastasis, and angiogenesis[3,6]. Our previous studies revealed that CXCL5, CCR4, and CCR6 are overexpressed in CRC tissues compared with normal tissues, and elevated expression of these factors could promote cancer metastasis and angiogenesis[7,8,9]
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