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

Horikawa,Yuhei; Watanabe,Masami; Sadahira,Takuya; Ariyoshi,Yuichi; Kobayashi,Yasuyuki; Araki,Motoo; Wada,Koichiro; Ochiai,Kazuhiko; Li,Shun‑Ai; Nasu,Yasutomo

doi:10.3892/ol.2017.6548

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

Authors:
- Yuhei Horikawa
- Masami Watanabe
- Takuya Sadahira
- Yuichi Ariyoshi
- Yasuyuki Kobayashi
- Motoo Araki
- Koichiro Wada
- Kazuhiko Ochiai
- Shun‑Ai Li
- Yasutomo Nasu
View Affiliations

Affiliations: Department of Urology, Okayama University, Okayama 700‑8558, Japan, Department of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Musashino, Tokyo 180‑8602, Japan
Published online on: July 8, 2017 https://doi.org/10.3892/ol.2017.6548
Pages: 3223-3228

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Dobruch J and Herr H: Should all patients receive single chemotherapeutic agent instillation after bladder tumour resection? BJU Int. 104:170–174. 2009. View Article : Google Scholar : PubMed/NCBI
2	Hirata T, Watanabe M, Kaku H, Kobayashi Y, Yamada H, Sakaguchi M, Takei K, Huh NH, Nasu Y and Kumon H: REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic agent for bladder cancer. Int J Oncol. 41:559–564. 2012.PubMed/NCBI
3	Watanabe M, Sakaguchi M, Kinoshita R, Kaku H, Ariyoshi Y, Ueki H, Tanimoto R, Ebara S, Ochiai K, Futami J, et al: A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector. Oncol Rep. 31:1089–1095. 2014.PubMed/NCBI
4	Watanabe M, Nasu Y and Kumon H: Adenovirus-mediated REIC/Dkk-3 gene therapy: Development of an autologous cancer vaccination therapy (Review). Oncol Lett. 7:595–601. 2014.PubMed/NCBI
5	Abarzua F, Sakaguchi M, Takaishi M, Nasu Y, Kurose K, Ebara S, Miyazaki M, Namba M, Kumon H and Huh NH: Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer Res. 65:9617–9622. 2005. View Article : Google Scholar : PubMed/NCBI
6	Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J and Kikuchi M: Emmprin (basigin/CD147): Matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int. 56:359–367. 2006. View Article : Google Scholar : PubMed/NCBI
7	Zhong WD, Chen QB, Ye YK, Han ZD, Bi XC, Dai QS, Liang YX, Zeng GH, Wang YS, Zhu G, et al: Extracellular matrix metalloproteinase inducer expression has an impact on survival in human bladder cancer. Cancer Epidemiol. 34:478–482. 2010. View Article : Google Scholar : PubMed/NCBI
8	Pan Y, He B, Chen J, Sun H, Deng Q, Wang F, Ying H, Liu X, Lin K, Peng H, et al: Gene therapy for colorectal cancer by adenovirus-mediated siRNA targeting CD147 based on loss of the IGF2 imprinting system. Int J Oncol. 47:1881–1889. 2015.PubMed/NCBI
9	Bovenzi CD, Hamilton J, Tassone P, Johnson J, Cognetti DM, Luginbuhl A, Keane WM, Zhan T, Tuluc M, Bar-Ad V, et al: Prognostic indications of elevated MCT4 and CD147 across cancer types: A meta-analysis. Biomed Res Int. 2015:2424372015. View Article : Google Scholar : PubMed/NCBI
10	Hatanaka M, Higashi Y, Kawai K, Su J, Zeng W, Chen X and Kanekura T: CD147-targeted siRNA in A375 malignant melanoma cells induces the phosphorylation of EGFR and downregulates cdc25C and MEK phosphorylation. Oncol Lett. 11:2424–2428. 2016.PubMed/NCBI
11	Liang YX, Lu JM, Mo RJ, He HC, Xie J, Jiang FN, Lin ZY, Chen YR, Wu YD, Luo HW, et al: E2F1 promotes tumor cell invasion and migration through regulating CD147 in prostate cancer. Int J Oncol. 48:1650–1658. 2016.PubMed/NCBI
12	Le Floch R, Chiche J, Marchiq I, Naiken T, Ilc K, Murray CM, Critchlow SE, Roux D, Simon MP and Pouysségur J: CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA. 108:16663–16668. 2011. View Article : Google Scholar : PubMed/NCBI
13	Aït-Ali N, Fridlich R, Millet-Puel G, Clérin E, Delalande F, Jaillard C, Blond F, Perrocheau L, Reichman S, Byrne LC, et al: Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell. 161:817–832. 2015. View Article : Google Scholar : PubMed/NCBI
14	Marchiq I, Albrengues J, Granja S, Gaggioli C, Pouysségur J and Simon MP: Knock out of the BASIGIN/CD147 chaperone of lactate/H+ symporters disproves its pro-tumour action via extracellular matrix metalloproteases (MMPs) induction. Oncotarget. 6:24636–24648. 2015. View Article : Google Scholar : PubMed/NCBI
15	Kimiya K, Naito S, Soejima T, Sakamoto N, Kotoh S, Kumazawa J and Tsuruo T: Establishment and characterization of doxorubicin-resistant human bladder cancer cell line, KK47/ADM. J Urol. 148:441–445. 1992. View Article : Google Scholar : PubMed/NCBI
16	Ueki H, Watanabe M, Kaku H, Huang P, Li SA, Ochiai K, Hirata T, Noguchi H, Yamada H, Takei K, et al: A novel gene expression system for detecting viable bladder cancer cells. Int J Oncol. 41:135–140. 2012.PubMed/NCBI
17	Mori A, Watanabe M, Sadahira T, Kobayashi Y, Ariyoshi Y, Ueki H, Wada K, Ochiai K, Li SA and Nasu Y: The downregulation of the expression of CD147 by tumor suppressor REIC/Dkk-3, and its implication in human prostate cancer cell growth inhibition. Acta Med Okayama. 71:135–142. 2017.PubMed/NCBI
18	Hagemann T, Wilson J, Kulbe H, Li NF, Leinster DA, Charles K, Klemm F, Pukrop T, Binder C and Balkwill FR: Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. J Immunol. 175:1197–1205. 2005. View Article : Google Scholar : PubMed/NCBI
19	Huang Z, Wang C, Wei L, Wang J, Fan Y, Wang L, Wang Y and Chen T: Resveratrol inhibits EMMPRIN expression via P38 and ERK1/2 pathways in PMA-induced THP-1 cells. Biochem Biophys Res Commun. 374:517–521. 2008. View Article : Google Scholar : PubMed/NCBI
20	Ge H, Zhang JF, Guo BS, He Q, Wang BY, He B and Wang CQ: Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma. Vascul Pharmacol. 46:114–121. 2007. View Article : Google Scholar : PubMed/NCBI
21	Liu H, Xu XF, Zhao Y, Tang MC, Zhou YQ and Gao FH: NS-398 promotes pancreatic cancer cell invasion by CD147 and MMP-2 via the activation of P38. Mol Med Rep. 13:2208–2214. 2016.PubMed/NCBI
22	Kong LM, Liao CG, Zhang Y, Xu J, Li Y, Huang W, Zhang Y, Bian H and Chen ZN: A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res. 74:3764–3778. 2014. View Article : Google Scholar : PubMed/NCBI
23	Liang L, Major T and Bocan T: Characterization of the promoter of human extracellular matrix metalloproteinase inducer (EMMPRIN). Gene. 282:75–86. 2002. View Article : Google Scholar : PubMed/NCBI
24	Baba M, Inoue M, Itoh K and Nishizawa Y: Blocking CD147 induces cell death in cancer cells through impairment of glycolytic energy metabolism. Biochem Biophys Res Commun. 374:111–116. 2008. View Article : Google Scholar : PubMed/NCBI
25	Huang Q, Li J, Xing J, Li W, Li H, Ke X, Zhang J, Ren T, Shang Y, Yang H, et al: CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway. J Hepatol. 61:859–866. 2014. View Article : Google Scholar : PubMed/NCBI
26	Marchiq I, Le Floch R, Roux D, Simon MP and Pouyssegur J: Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res. 75:171–180. 2015. View Article : Google Scholar : PubMed/NCBI
27	Muramatsu T: Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem. 159:481–490. 2016. View Article : Google Scholar : PubMed/NCBI
28	Fu ZG, Wang L, Cui HY, Peng JL, Wang SJ, Geng JJ, Liu JD, Feng F, Song F, Li L, et al: A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells. Oncotarget. 7:9429–9447. 2016. View Article : Google Scholar : PubMed/NCBI
29	Walter M, Simanovich E, Brod V, Lahat N, Bitterman H and Rahat MA: An epitope-specific novel anti-EMMPRIN polyclonal antibody inhibits tumor progression. Oncoimmunology. 5:e10780562015. View Article : Google Scholar : PubMed/NCBI
30	Kumon H, Ariyoshi Y, Sasaki K, Sadahira T, Araki M, Ebara S, Yanai H, Watanabe M and Nasu Y: Adenovirus vector carrying REIC/Dkk-3 gene: Neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy. Cancer Gene Ther. 23:400–409. 2016. View Article : Google Scholar : PubMed/NCBI
31	Kumon H, Sasaki K, Ariyoshi Y, Sadahira T, Ebara S, Hiraki T, Kanazawa S, Yanai H, Watanabe M and Nasu Y: Ad-REIC gene therapy: Promising results in a patient with metastatic CRPC following chemotherapy. Clin Med Insights Oncol. 9:31–38. 2015. View Article : Google Scholar : PubMed/NCBI