Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion

Authors: Shizhuo Wang, Heng Wei, Shulan Zhang

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Dickkopf-4 (DKK4), a member of DKK family, appears to be a divergent protein. It remained multi-biological functions in carcinogenesis. The effect of DKK4 on the ovarian cancer cells remains unclear. This study detected the clinical significance of DKK4 in epithelial ovarian cancer (EOC) patients and its role in invasion.

Methods

QRT-PCR and western blot analysis were used to examine the levels of DKK4 mRNA and protein in 33 EOC tissues and 33 benign ovarian tumors. Immunohistochemical analysis was performed to assess DKK4 expression in 239 EOC samples. siRNA-mediated DKK4 silence was conducted. Transwell assay was used to detect the invasive ability. Phalloidin was used to stain the formations of actin filaments.

Results

The expressions of DKK4 mRNA and protein were elevated in EOC tissues as compared with those in benign ovarian tumors (p = 0.001 and <0.0001 respectively). Immunohistochemical results showed the strong expression of DKK4 protein was positively associated with late FIGO stage (p = 0.005) and poor disease free survival in univariate and multivariate analysis (p < 0.0001 and p = 0.001, respectively). SiRNA-mediated DKK4 knockdown inhibited cell invasive ability (all p < 0.0001) and the formations of actin filaments. DKK4 could promote the phosphration of c-JUN and JNK (p < 0.0001 and p = 0.001, respectively).

Conclusions

Our results indicated that DKK4 might be contributed to predicting EOC progression and prognosis. DKK4 could promote the invasion of EOC through JNK activation.
Literature
1.
Feeley KM, Wells M. Precursor lesions of ovarian epithelial malignancy. Histopathology. 2001;38:87–95.CrossRefPubMed
2.
3.
Salamanca CM, Maines-Bandiera SL, Leung PC, Hu YL, Auersperg N. Effects of epidermal growth factor/hydrocortisone on the growth and differentiation of human ovarian surface epithelium. J Soc Gynecol Investig. 2004;11:241–51.CrossRefPubMed
4.
Hsieh JC, Kodjabachian L, Rebbert ML, Rattner A, Smallwood PM, Samos CH, Nusse R, Dawid IB, Nathans J. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 1999;398(6726):431–6.CrossRefPubMed
5.
Kawano Y, Kypta R. Secreted antagonists of the Wnt signalling pathway. J Cell Sci. 2003;116:2627–34.CrossRefPubMed
6.
Roth W, Wild-Bode C, Platten M, Grimmel C, Melkonyan HS, Dichgans J, et al. Secreted frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. Oncogene. 2000;19:4210–20.CrossRefPubMed
7.
Niehrs C. Function and biological roles of the Dickkopf family of Wnt modulators. Oncogene. 2006;25:7469–81.CrossRefPubMed
8.
Sato H, Suzuki H, Toyota M, Nojima M, Maruyama R, Sasaki S, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis. 2007;28:2459–66.CrossRefPubMed
9.
Hiramitsu S, Terauchi M, Kubota T. The effects of Dickkopf-4 on the proliferation, differentiation, and apoptosis of osteoblasts. Endocrinology. 2013;154(12):4618–26.CrossRefPubMed
10.
Sima J, Piao Y, Chen Y, Schlessinger D. Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development. Development. 2016;143(24):4723–35.CrossRefPubMed
11.
Fatima S, Lee NP, Tsang FH, Kolligs FT, Ng IO, Poon RT, et al. Dickkopf 4 (DKK4) acts on Wnt/β-catenin pathway by influencing β-catenin in hepatocellular carcinoma. Oncogene. 2012;31:4233–44.CrossRefPubMed
12.
Baehs S, Herbst A, Thieme SE, Perschl C, Behrens A, Scheel S, et al. Dickkopf-4 is frequently down-regulated and inhibits growth of colorectal cancer cells. Cancer Lett. 2009;276:152–9.CrossRefPubMed
13.
Liao CH, Yeh CT, Huang YH, Wu SM, Chi HC, Tsai MM, et al. Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells. Hepatology. 2012;55:910–20.CrossRefPubMed
14.
Sato H, Suzuki H, Toyota M, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors. Carcinogenesis. 2007;28:2459–66.CrossRefPubMed
15.
Matsui A, Yamaguchi T, Maekawa S, Miyazaki C, Takano S, Uetake T, et al. DICKKOPF-4 and -2 genes are upregulated in human colorectal cancer. Cancer Sci. 2009;100:1923–30.CrossRefPubMed
16.
Pendas-Franco N, Garcia JM, Pena C, et al. DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha, 25-dihydroxyvitamin D3. Oncogene. 2008;27:4467–77.CrossRefPubMed
17.
Ouyang Y, Pan J, Tai Q, Ju J, Wang H. Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA-Seq. Tumour Biol. 2016;37(8):10827–38.CrossRefPubMed
18.
Hirata H, Hinoda Y, Majid S, Chen Y, Zaman MS, Ueno K, 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. 2011;117:1649–60.CrossRefPubMed
19.
Shizhuo W, Tao J, Shulan Z, Bing Z. The expression and significance of Dickkopf-1 in epithelial ovarian carcinoma. Int J Biol Markers. 2009;24:165–70.CrossRefPubMed
20.
Jarboe JS, Johnson KR, Choi Y, Lonser RR, Park JK. Expression of interleukin-13 receptor alpha2 in glioblastoma multiforme: implications for targeted therapies. Cancer Res. 2007;67:7983–6.CrossRefPubMed
21.
Hao XP, Pretlow TG, Rao JS, Pretlow TP. Beta-catenin expression is altered in human colonic aberrant crypt foci. Cancer Res. 2001;61:8085–8.PubMed
22.
Gonzalez-Villasana V, Gutiérrez-Puente Y, Tari AM. Cyclooxygenase-2 utilizes Jun N-terminal kinases to induce invasion, but not tamoxifen resistance, in MCF-7 breast cancer cells. Oncol Rep. 2013;30(3):1506–10.PubMed
23.
Vivas-Mejia P, Benito JM, Fernandez A, Han HD, Mangala L, Rodriguez-Aguayo C, et al. C-Jun-NH2-kinase-1 inhibition leads to antitumor activity in ovarian cancer. Clin Cancer Res. 2010;16(1):184–94.CrossRefPubMed
24.
Liu H, Liang SL, Kumar S, Weyman CM, Liu W, Zhou A. Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression. Cancer Chemother Pharmacol. 2009;63(6):997–1005.CrossRefPubMed
25.
Davidson B, Givant-Horwitz V, Lazarovici P, Risberg B, Nesland JM, Trope CG, Schaefer E, Reich R. Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis. 2003;20(7):621–31.CrossRefPubMed
26.
Ødegaard E, Staff AC, Abeler VM, Kopolovic J, Onsrud M, Lazarovici P, Davidson B. The activated nerve growth factor receptor p-TrkA is selectively expressed in advanced-stage ovarian carcinoma. Hum Pathol. 2007;38(1):140–6.CrossRefPubMed
27.
Dingemans KP. What's new in the ultrastructure of tumor invasion in vivo? Pathol Res Pract. 1988;183:792–808.CrossRefPubMed
28.
Edwards BS, Dang AK, Murtazina DA, Dozier MG, Whitesell JD, Khan SA, et al. Dynamin is required for GnRH signaling to L-type calcium channels and activation of ERK. Endocrinology. 2016;157:831–43.CrossRefPubMed
29.
Zhou H, Zhang Y, Chen Q, Lin Y. AKT and JNK signaling pathways increase the metastatic potential of colorectal cancer cells by altering Transgelin expression. Dig Dis Sci. 2016;61:1091–7.CrossRefPubMed
30.
Xia Y, Karin M. The control of cell motility and epithelial morphogenesis by Jun kinases. Trends Cell Biol. 2004;14:94–101.CrossRefPubMed
31.
Zhai W, Hu GH, Zheng JH, Peng B, Liu M, Huang JH, et al. 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. Int J Mol Med. 2014;33:1319–26.PubMed
32.
Bazzi H, Fantauzzo KA, Richardson GD, Jahoda CA, Christiano AM. The Wnt inhibitor, Dickkopf 4, is induced by canonical Wnt signaling during ectodermal appendage morphogenesis. Dev Biol. 2007;305:498–507.CrossRefPubMed
33.
Diep DB, Hoen N, Backman M, Machon O, Krauss S. Characterisation of the Wnt antagonists and their response to conditionally activated Wnt signalling in the developing mouse forebrain. Brain Res Dev Brain Res. 2004;153:261–70.CrossRefPubMed
34.
Rask K, Nilsson A, Brännström M, Carlsson P, Hellberg P, Janson PO, et al. Wnt-signalling pathway in ovarian epithelial tumours: increased expression of Beta-catenin and GSK3beta. Br J Cancer. 2003;89:1298–04.CrossRefPubMedPubMedCentral
35.
Korb T, Schlüter K, Enns A, Spiegel HU, Senninger N, Nicolson GL, et al. Integrity of actin fibers and microtubules influences metastatic tumor cell adhesion. Exp Cell Res. 2004;299:236–47.CrossRefPubMed
36.
Wang S, Zhang S. Dickkopf-1 is frequently overexpressed in ovarian serous carcinoma and involved in tumor invasion. Clin Exp Metastasis. 2011;28:581–91.CrossRefPubMed
37.
Xia Y, Karin M. The control of cell motility and epithelial morphogenesis by Jun kinases. Trends Cell Biol. 2004;14(2):94–101.CrossRefPubMed
Metadata
Title
Dickkopf-4 is frequently overexpressed in epithelial ovarian carcinoma and promotes tumor invasion
Authors
Shizhuo Wang
Heng Wei
Shulan Zhang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3407-1

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Research article

Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study

Research article

A nationwide multi-institutional retrospective study to identify prognostic factors and develop a graded prognostic assessment system for patients with brain metastases from uterine corpus and cervical cancer

Research article

Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study

Research article

Palliative external beam radiotherapy for the treatment of tumor bleeding in inoperable advanced gastric cancer

Case report

Gastric hepatoid adenocarcinoma resulting in a spontaneous gastric perforation: a case report and review of the literature

Research article

Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits