Identification of WISP1 as a novel oncogene in glioblastoma

Abstract

Glioblastoma is the most common and aggressive primary brain tumor and has a high mortality in humans. However, mechanisms and factors involved in the progression of glioblastoma remain elusive. WISP1 (WNT1 inducible signaling pathway protein 1), has been suggested to be a critical regulator of cancer development. The aim of this study was to investigate the role of WISP1 in regulating the progression of glioblastoma. Clinicopathological characteristics of glioblastoma were assessed, and higher levels of WISP1 were positively associated with advanced clinical stage and a poor prognosis. Consistently, WISP1 expression was significantly upregulated in glioblastoma tissue and cell lines compared with normal tissue and cells. Additionally, inhibition of WISP1 greatly suppressed cell proliferation, migration, and invasion and promoted apoptosis and cell cycle arrest of glioblastoma cells. Further study indicated that downregulation of WISP1 suppressed cell proliferation associated with the gene expression of c‑myc and cyclin D1 and cellular signaling such as through the ERK pathway, while inhibiting epithelial-mesenchymal transition and MMP9. Finally, knockdown of WISP1 markedly suppressed in vivo tumor growth and sensitized glioblastoma cells to temozolomide. This study identified WISP1 as an oncogene in glioblastoma and suggests that WISP1 may serve as a potential molecular marker and treatment target for glioblastoma.

WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial–mesenchymal transition

“…WISP1 activates AKT signaling pathway to promote a variety of cellular functions, such as proliferation, survival, migration, and invasion in normal tissue and cancer cells (25,27,29,32,36,47,48). It also stimulates the MEK/ERK pathway to enhance tumor migration and invasion (30,34,45,46), possibly through the induction of MEK/ERK signaling-induced EMT (44). Because AKT signaling and MEK/ERK signaling are the intracellular signaling cascades known to induce EMT and tumor metastasis (4 -6), we hypothesized that these two signaling pathways are essential for EMT in melanoma cells and that WISP1 activates these signaling pathways to promote EMT.…”

“…For its role in tumor cell dissemination, WISP1 was shown to induce EMT to promote cell migration and invasion in lung epithelial, gastric cancer, and breast cancer cells (40 -43). In human glioblastoma, the WISP1-activated MEK/ ERK pathway might be responsible for the EMT of the tumor cells (44). The activation of various signaling, including PI3K/ AKT, MEK/ERK, NF-B, or JNK/p38 pathways, has been shown to be essential for WISP1-induced cell migration and/or invasion in vascular smooth muscle cells, cholangiocarcinoma, chondrosarcoma, oral squamous cell carcinoma, osteosarcoma, and colorectal cancer cells (30,33,34,(45)(46)(47)(48).…”

The role of CCN4/WISP-1 in the cancerous phenotype

“…Jing et al published results concerning CCN4 in glioblastoma in 2017 51. CCN4 was overexpressed in glioblastoma tissues and cell lines as compared to normal tissues and cells.…”

Tp53 Mutation Inhibits Ubiquitination and Degradation of WISP1 via Down-Regulation of Siah1 in Pancreatic Carcinogenesis

“…Our previous study has also demonstrated that Tp53 mutation may promote WISP1 expression in mouse PDAC cells ( Wang et al, 2015 ). Recent studies had shown that WISP1 acts as a new oncogene in glioblastoma ( Jing et al, 2017 ), oral squamous cell carcinoma ( Jung et al, 2017 ), gastric cancer ( Jia et al, 2017 ), melanoma ( Shao et al, 2016 ), and colon cancer ( Wu et al, 2016 ). Also, Yang et al (2015) showed that patients with high expression of WISP-1 had a shorter survival time independent of clinical stage and lymphatic metastasis status in pancreatic cancer.…”

“…WISP1 is a matricellular protein and plays a significant role in regulation of cellular signaling networks ( Berschneider and Konigshoff, 2011 ). Recently, abnormal expression of WISP1 has been proven in various types of human malignancies ( Gurbuz and Chiquet-Ehrismann, 2015 ; Chahal et al, 2016 ; Wu et al, 2016 ; Jing et al, 2017 ). A previous study demonstrated that WISP1 protects human lung and breast cancer cells from p53-dependent cell death, suggesting that there could be a crosstalk between Tp53 and WISP1 signaling pathways ( Su et al, 2002 ).…”