Overexpression of REIC/Dkk-3 suppresses the expression of CD147 and inhibits the proliferation of human bladder cancer cells

Abstract

Abstract. Our group previously developed an adenoviral vector encoding the REIC/Dkk-3 gene (Ad-REIC), a tumor suppressor, for cancer gene therapy. The Ad-REIC agent induces apoptosis and inhibits invasion in a number of cancer cell lines; however, the molecular mechanisms underlying its effects remain unclear. Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a key molecule that promotes cancer proliferation and invasion. In order to elucidate the therapeutic mechanism of Ad-REIC, its effect on the expression of CD147 in human bladder cancer KK47 cells was investigated. Treatment with Ad-REIC markedly downregulated the expression of CD147 and significantly inhibited cellular proliferation. Since the expression of CD147 is reported to be under the positive control of mitogen-activated protein kinase (MAPK) signaling and the c-Myc protein, the correlations between the expression of CD147 and the activation of MAPKs or the expression of c-Myc were examined. Unexpectedly, no positive correlation was observed between the level of CD147 and the potential regulators that were assessed, indicating that another signaling pathway is responsible for the downregulation of CD147. The results from the present study demonstrate that Ad-REIC treatment can significantly downregulate the expression of CD147 in bladder cancer cells. Downregulation of the cancer-progression factor CD147 may be a novel mechanism that underlies the therapeutic effects of Ad-REIC treatment.

DKK3, Downregulated in Invasive Epithelial Ovarian Cancer, Is Associated with Chemoresistance and Enhanced Paclitaxel Susceptibility via Inhibition of the β-Catenin-P-Glycoprotein Signaling Pathway

“…As the 3D spheroid structure mimics the physical and biochemical features of a natural solid tumor mass, it may be similar to cells growing in vivo. Thus, our result suggested that secreted DKK3 may effectively penetrate the tumor mass, resulting in fractional killing, which is consistent with the results of previous reports showing that an adenovirus carrying DKK3 induced apoptosis in bladder, prostate, biliary, and liver cancers [ 34 , 35 , 40 , 41 , 42 ]. Taken together, we believe that DKK3 may be a promising cancer therapeutic for overcoming drug resistance, which may be utilized in various types of biopharmaceutics.…”

“…Taken together with the results of a previous report showing the absence of DKK3 in 63% cases of 56 ovarian carcinoma tissue samples [ 20 ], we concluded that >50% invasive epithelial ovarian cancers lose DKK3 during carcinogenesis. DKK3 is frequently downregulated in various cancers [ 6 , 10 , 14 , 16 , 17 , 18 , 34 , 35 , 36 ], and therefore, this study supports the hypothesis that downregulation of DKK3 occurs commonly during carcinogenesis.…”

The Suppressing Effects of Dkk3 Expression on Aggressiveness and Tumorigenesis of Colorectal Cancer

“…Horikawa et al (25) found that Dkk3 overexpression suppressed the proliferation of human bladder cancer cells by downregulating CD147 expression. Here, it was observed that both recombinant Dkk3 protein and Dkk3 overexpression might inhibit cell proliferation and trigger G 2 phase arrest in both colorectal cancer cell types.…”

Inhibition of EMMPRIN by microRNA‑124 suppresses the growth, invasion and tumorigenicity of gliomas

“…EMMPRIN is a type of transmembrane glycoprotein and is a member of the immunoglobulin superfamily due to having Ig-like domains. It is critical for cell invasion, angiogenesis, and glycolysis ( 20 , 21 ). Jia et al ( 22 ) demonstrated that hepatocellular carcinoma cell lines with higher highly/lowly glycosylated ratios of EMMPRIN expression showed higher lymphatic metastasis preferences.…”