Effects of connective tissue growth factor on prostate cancer bone metastasis and osteoblast differentiation

Abstract

Previous studies have demonstrated that connective tissue growth factor (CTGF) is expressed at increased levels in prostate cancer bone metastasis mouse models and patients with prostate cancer which metastasizes to the bone; however, the underlying molecular mechanism(s) remain unknown. The present study investigated the function of CTGF in osteoblast differentiation and its effect on prostate cancer bone metastasis by analyzing CTGF gene expression and transcription at different levels of invasion, metastasis of prostate cancer cells, and the influence of CTGF on proliferation and xenotransplantation. A mouse model demonstrating bone metastasis was used to investigate the function(s) of CTGF in bone metastasis and osteoblast differentiation. Results demonstrated that CTGF expression was increased in association with high bone metastasis in prostate cancer cells, and its expression was significantly decreased in whole cell lysates. CTGF expression in prostate cancer cells with high levels of bone metastasis was increased 1.9-fold compared with prostate cancer cells with low levels of bone metastasis. The expression of CTGF in mesenchymal cells was markedly increased compared with epithelial cells. Results indicated that the increased expression of CTGF does not affect the proliferation of tumor cells and possesses no influence on tumor volume. Control and CTGF plasmids were transfected into RM1 cells and led to 4 and 17% bone lesions, respectively. Increased expression of CTGF significantly enlarged the tumor area in the bone metastatic position compared with the control. Positive areas of alkaline phosphatase were significantly decreased as the concentration of CTGF increased. The results of the present study demonstrated that CTGF promotes prostate carcinoma to metastasize in the bone by dysregulating osteoblast differentiation.

Ras and Wnt Interaction Contribute in Prostate Cancer Bone Metastasis

“…Siu et al demonstrated that KLF4 functions as a transcription factor to activate the AR-miR-1 signaling pathway to constrain the tumor-suppressive role of miR-1 [50]. CTCF, a downstream transcription activator of Smad and Myc signaling, contributes to slowing down metastasis in PCa through directly interacting with the miR-127-3p promoter, in which the downregulation of miR-127-3p accompanies proteasome subunit beta type-5 (PSMB5) elevation and subsequently leads to the activation of BM [55][56][57]. All of the above research draws a large picture of the regulatory mechanism of BM in PCa cells, and Figure 1 summarizes these signaling cascades.…”

Identification of Signature Genes and Construction of an Artificial Neural Network Model of Prostate Cancer

“…In the early stage of PCa, most patients have no obvious symptoms due to the insidious onset and slow growth of the tumor [ 3 ]. Once PCa is advanced, it can cause symptoms such as abnormal urination, pelvic discomfort, erectile dysfunction, and even bone pain and spinal cord compression, which can greatly affect the quality of life of patients [ 4 , 5 ]. Accordingly, there is an urgent need to develop effective biological approaches to improve diagnosis and prognosis of PCa.…”

CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology

“…CCN2, as observed in breast cancer, CCN3 and CCN4 levels are up regulated in prostate cancer and bone-metastatic cells or corresponding bone metastasis (Dankner et al 2019 ; Kim et al 2020 ; Ono et al 2013 ). Consistently, exogenous administration of CCN2 prior to in vivo injection increases number and size of bone metastases, whereas its inhibition reduces bone metastasis and related osteosclerosis (Kim et al 2020 ; Zhang et al 2018 ). CCN3 in conditioned medium from prostate cancer cells favours osteoclastogenesis via both RANKL-dependent and RANKL-independent pathways in vitro and forced overexpression of CCN3 in PCa and LnCAP C4-2 cells enhances osteolytic potential and TRAP-staining in metastatic lesions (Chen et al 2013b ).…”