High expression of the secreted protein dickkopf homolog 4: Roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene Corrigendum in /10.3892/ijmm.2023.5250

Zhai,Wei; Hu,Guang-Hui; Zheng,Jun-Hua; Peng,Bo; Liu,Min; Huang,Jian‑Hua; Wang,Guang-Chun; Yao,Xu-Dong; Xu,Yun-Fei

doi:10.3892/ijmm.2014.1673

May-2014 Volume 33 Issue 5

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

May-2014 Volume 33 Issue 5

Full Size Image

Article

High expression of the secreted protein dickkopf homolog 4: Roles in invasion and metastasis of renal cell carcinoma and its association with Von Hippel-Lindau gene

Corrigendum in: /10.3892/ijmm.2023.5250

Authors:
- Wei Zhai
- Guang-Hui Hu
- Jun-Hua Zheng
- Bo Peng
- Min Liu
- Jian‑Hua Huang
- Guang-Chun Wang
- Xu-Dong Yao
- Yun-Fei Xu
View Affiliations / Copyright

Affiliations: Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
Pages: 1319-1326
|
Published online on: February 25, 2014

https://doi.org/10.3892/ijmm.2014.1673
Expand metrics +

Abstract

The aim of this study was to investigate the effects of the dickkopf homolog 4 (DKK4)/Wnt/β-catenin signaling pathway on tumorigenesis and metastasis in clear cell renal cell carcinoma (ccRCC), as well as to elucidate the underlying mechanisms. We examined the expression of DKK4 in 30 cases of ccRCC and matched adjacent normal tissues, and investigated its correlation with clinicopathological characteristics. Stable DKK4-transfected cells were established, and DKK4 functional analyses were performed, including a T-cell factor/lymphoid enhancer factor (TCF/LEF) reporter assay, and experiments on cell viability, apoptosis, invasive capability and tumor growth in vivo. Finally, western blot analysis was performed to detect Von Hippel‑Lindau (VHL) expression in 50 clinical specimens. The expression levels of the DKK4, β-catenin and β-catenin downstream target genes, cyclin D1 and c-myc, were determined in the these specimens, as well as in RCC4(-), T3-14(+) cell lines by qRT-PCR and western blot analysis. The same tests were also performed in human embryonic kidney (HEK)293 cells which were transfected with the pCDH-DKK4 plasmid. After 6 weeks the tumor weight significantly increased in the mice transfected with the tumor cells. DKK4 mRNA and protein expression levels were significantly upregulated (p<0.001). DKK4 was distinctly overexpressed (68.0%) in all patient tissues. VHL(-) samples accounted for 60.0% of all samples, while DKK4 expression was significantly upregulated in 50% of these samples, indicating a correlation with VHL(-) expression (r=0.403, p<0.05). We also observed reduced expression levels of cyclin D1, c-myc and β-catenin (to a greater extent) in the VHL(-), RCC4(-) and T3-14(+) cells, as well as in the stably transfected HEK293 cells. DKK4 may be an oncogene, and its upregulated expression may be involved in the pathogenesis of ccRCC as a downstream gene of VHL. By activating other pathways apart from the Wnt/β-catenin pathway, DKK4 may play an important role in ccRCC tumorigenesis and metastasis.

View Figures

View References

1	Ljungberg B, Hanbury DC, Kuczyk MA, et al: Renal cell carcinoma guideline. Eur Urol. 51:1502–1510. 2007. View Article : Google Scholar : PubMed/NCBI
2	Zhang Z, Wondergem B and Dykema K: A comprehensive study of progressive cytogenetic alterations in clear cell renal cell carcinoma and a new model for ccRCC tumorigenesis and progression. Adv Bioinformatics. 2010:4283252010. View Article : Google Scholar
3	Lam JS, Leppert JT, Figlin RA and Belldegrun AS: Surveillance following radical or partial nephrectomy for renal cell carcinoma. Curr Urol Rep. 6:7–18. 2005. View Article : Google Scholar : PubMed/NCBI
4	Huang Y, Dai Y, Yang J, et al: Microarray analysis of microRNA expression in renal clear cell carcinoma. Eur J Surg Oncol. 35:1119–1123. 2009. View Article : Google Scholar : PubMed/NCBI
5	Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8 (+) selected tumor infiltrating lymphocytes from primary tumor. J Urol. 158:740–745. 1997.
6	Nelson WJ and Nusse R: Convergence of Wnt, β-catenin, and cadherin pathways. Science. 303:1483–1487. 2004.
7	Capurro MI, Xiang YY, Lobe C and Filmus J: Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res. 65:6245–6254. 2005. View Article : Google Scholar : PubMed/NCBI
8	Rask K, Nilsson A, Brännström M, et al: Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β. Br J Cancer. 89:1298–1304. 2003.
9	Chien AJ, Moore EC, Lonsdorf AS, et al: Activated Wnt/β-catenin signaling in melanoma is associated with decreased proliferation in patient tumors and a murine melanoma model. Proc Natl Acad Sci USA. 106:1193–1198. 2009.
10	Gilbertson RJ: Medulloblastoma: signalling a change in treatment. Lancet Oncol. 5:209–218. 2004. View Article : Google Scholar : PubMed/NCBI
11	Banumathy G and Cairns P: Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 10:658–664. 2010. View Article : Google Scholar : PubMed/NCBI
12	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
13	Fang D, Hawke D, Zheng Y, et al: Phosphorylation of β-catenin by AKT promotes β-catenin transcriptional activity. J Biol Chem. 282:11221–11229. 2007.
14	Jho EH, Zhang T, Domon C, Joo CK, Freund JN and Costantini F: Wnt/β-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol. 22:1172–1183. 2002.
15	Hirata H, Hinoda Y, Majid S, et al: DICKKOPF-4 activates the noncanonical c-Jun-NH2 kinase signaling pathway while inhibiting the Wnt-canonical pathway in human renal cell carcinoma. Cancer. 117:1649–1660. 2011. View Article : Google Scholar : PubMed/NCBI
16	Pfaff E, Becker S, Günther A and Königshoff M: Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis. Eur Respir J. 37:79–87. 2011. View Article : Google Scholar : PubMed/NCBI
17	Pendás-Franco N, García J, Peña C, et al: DICKKOPF-4 is induced by TCF/β-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1α, 25-dihydroxyvitamin D3. Oncogene. 27:4467–4477. 2008.PubMed/NCBI
18	Katoh Y and Katoh M: Comparative genomics on DKK2 and DKK4 orthologs. Int J Mol Med. 16:477–481. 2005.PubMed/NCBI
19	Peruzzi B, Athauda G and Bottaro DP: The von Hippel-Lindau tumor suppressor gene product represses oncogenic β-catenin signaling in renal carcinoma cells. Proc Natl Acad Sci USA. 103:14531–14536. 2006.PubMed/NCBI
20	Kim YS, Kang YK, Kim JB, Han S, Kim KI and Paik SR: β-catenin expression and mutational analysis in renal cell carcinomas. Pathol Int. 50:725–730. 2000.
21	Tanimoto K, Makino Y, Pereira T and Poellinger L: Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19:4298–4309. 2000.
22	Ma X, Yang K, Lindblad P, Egevad L and Hemminki K: VHL gene alterations in renal cell carcinoma patients: novel hotspot or founder mutations and linkage disequilibrium. Oncogene. 20:5393–5400. 2001. View Article : Google Scholar : PubMed/NCBI
23	Patel PH, Chadalavada RS, Chaganti R and Motzer RJ: Targeting von Hippel-Lindau pathway in renal cell carcinoma. Clin Cancer Res. 12:7215–7220. 2006. View Article : Google Scholar : PubMed/NCBI
24	Matsui A, Yamaguchi T, Maekawa S, et al: DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer. Cancer Sci. 100:1923–1930. 2009. View Article : Google Scholar : PubMed/NCBI
25	Fatima S, Lee N, Tsang F, et al: Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma. Oncogene. 31:4233–4244. 2012.
26	Krupnik VE, Sharp JD, Jiang C, et al: Functional and structural diversity of the human Dickkopf gene family. Gene. 238:301–313. 1999. View Article : Google Scholar : PubMed/NCBI
27	Aravind L and Koonin EV: A colipase fold in the carboxy-terminal domain of the Wnt antagonists-the Dickkopfs. Curr Biol. 8:R477–R478. 1998. View Article : Google Scholar : PubMed/NCBI
28	van Tilbeurgh H, Bezzine S, Cambillau C, Verger R and Carrière F: Colipase: structure and interaction with pancreatic lipase. Biochim Biophys Acta. 1441:173–184. 1999.PubMed/NCBI
29	Bazzi H, Fantauzzo KA, Richardson GD, Jahoda CA and Christiano AM: The Wnt inhibitor, Dickkopf 4, is induced by canonical Wnt signaling during ectodermal appendage morphogenesis. Dev Biol. 305:498–507. 2007. View Article : Google Scholar : PubMed/NCBI
30	Veeck J, Bektas N, Hartmann A, et al: Wnt signalling in human breast cancer: expression of the putative Wnt inhibitor Dickkopf-3 (DKK3) is frequently suppressed by promoter hypermethylation in mammary tumours. Breast Cancer Res. 10:R822008. View Article : Google Scholar
31	Zenzmaier C, Untergasser G, Hermann M, Dirnhofer S, Sampson N and Berger P: Dysregulation of Dkk-3 expression in benign and malignant prostatic tissue. Prostate. 68:540–547. 2008. View Article : Google Scholar : PubMed/NCBI
32	Baehs S, Herbst A, Thieme SE, et al: Dickkopf-4 is frequently down-regulated and inhibits growth of colorectal cancer cells. Cancer Lett. 276:152–159. 2009. View Article : Google Scholar : PubMed/NCBI
33	Morais C, Johnson DW and Gobe G: The VHL-HIF signaling in renal cell carcinoma: promises and pitfalls. Emerging Research and Treatments in Renal Cell Carcinoma. Amato RJ: InTech Publishers; Croatia: pp. 57–82. 2011
34	Linehan WM, Rubin JS and Bottaro DP: VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma. Int J Biochem Cell Biol. 41:753–756. 2009. View Article : Google Scholar : PubMed/NCBI
35	Mao B, Wu W, Davidson G, et al: Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 417:664–667. 2002. View Article : Google Scholar : PubMed/NCBI
36	Baldin V, Lukas J, Marcote M, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI
37	Wu JF, Shao JC, Wang DB, Qin R and Zhang H: Expression and significance of cell cycle regulators in gastric carcinoma. Ai Zheng. 24:175–179. 2005.PubMed/NCBI
38	Spencer CA and Groudine M: Control of c-myc regulation in normal and neoplastic cells. Adv Cancer Res. 56:1–48. 1991. View Article : Google Scholar : PubMed/NCBI
39	Hirata H, Hinoda Y, Ueno K, Nakajima K, Ishii N and Dahiya R: MicroRNA-1826 directly targets β-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis. 33:501–508. 2012.PubMed/NCBI
40	Chen L, Han L, Zhang K, et al: VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1α/VEGF and β-catenin/Tcf-4 signaling. Neuro Oncol. 14:1026–1036. 2012.PubMed/NCBI