CTGF promotes osteosarcoma angiogenesis by regulating miR-543/angiopoietin 2 signaling

Abstract

Osteosarcoma is the most common primary solid tumor of bone. It has a high metastatic potential and occurs predominantly in adolescents and young adults. Angiopoietin 2 (Angpt2) is a key regulator in tumor angiogenesis, facilitating tumor growth and metastasis. Connective tissue growth factor (CTGF, also known as CCN2), is a cysteine-rich protein that has been reported to promote metastasis of osteosarcoma. However, the effect of CTGF on Angpt2 regulation and angiogenesis in human osteosarcoma remains largely unknown. We found that overexpression of CTGF in osteosarcoma cells increased Angpt2 production and induced angiogenesis, in vitro and in vivo. Our findings demonstrate that CTGF-enhanced Angpt2 expression and angiogenesis is mediated by the phospholipase C (PLC)/protein kinase C (PKCδ) signaling pathway. Moreover, endogenous microRNA-543 (miR-543) expression was negatively regulated by CTGF via the PLC/PKCδ pathway. We also provide evidence showing clinical significance between CTGF, Angpt2, and miR-543 as well as tumor staging in human osteosarcoma tissue. CTGF may serve as a therapeutic target in the process of osteosarcoma metastasis and angiogenesis.

Anlotinib, a novel small molecular tyrosine kinase inhibitor, suppresses growth and metastasis via dual blockade of VEGFR2 and MET in osteosarcoma

“…The occurrence and development of malignant osteosarcoma are driven by genetic effects and pathological alterations. Angiogenesis is involved in osteosarcoma proliferation, migration, invasion, metastasis and accumulating evidence shows that angiogenesis inhibition may be used as a strategy for treating osteosarcoma . Multiple angiogenesis inhibitors, such as sorafenib, sunitinib and cediranib, have been used to treat advanced osteosarcoma .…”

“…Angiogenesis is involved in osteosarcoma proliferation, migration, invasion, metastasis and accumulating evidence shows that angiogenesis inhibition may be used as a strategy for treating osteosarcoma. 9,10 Multiple angiogenesis inhibitors, such as sorafenib, sunitinib and cediranib, have been used to treat advanced osteosarcoma. 11 However, the results of recent studies support the idea that angiogenesis inhibitors can elicit tumor adaptation and disease progression, resulting in the development of tumors with high invasive and metastatic potential.…”

Clinical significance of CCN2/connective tissue growth factor in Behçet's disease patients

“…CCN2 regulates the vascular endothelium through the production of endothelial basement membrane components and is considered as an essential mediator of vascular remodeling by regulating endothelial‐pericyte interactions . The overexpression of CCN2 in osteosarcoma cells induces angiogenesis both in vitro and in vivo through the increased production of angiopiotin‐2 . Vascular endothelial growth factor, another angiogenic factor known to be increased in BD, can directly induce CCN2 gene expression .…”

MicroRNA‐543 promotes ovariectomy‐induced osteoporosis through inhibition of AKT/p38 MAPK signaling pathway by targeting YAF2

“…In recent years, accumulating evidence indicates that miR‐543 has a variety of functional roles. It was shown that endogenous miR‐543 expression was negatively regulated by connective tissue growth factor, making miR‐543 a therapeutic target in osteosarcoma metastasis and angiogenesis . Also, miR‐543 mimics was shown to promote the invasion and migration of non‐small–cell lung cancer cells .…”

“…Herein, the aim of the study is to determine the roles of miR‐543 in osteoporosis. MiR‐543 has been demonstrated to regulate a number of diseases, including osteosarcoma, lung cancer, gastric cancer, and renal cancer . More importantly, miR‐543 was shown to be associated with a number of aging‐related diseases .…”