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
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 7/2016

01-07-2016 | Original Article

WAVE3 Induces EMT and Promotes Migration and Invasion in Intrahepatic Cholangiocarcinoma

Authors: Zebin Zhu, Wei Chen, Xiaoyu Yin, Jiaming Lai, Qian Wang, Lijian Liang, Wei Wang, Anxun Wang, Chaoxu Zheng

Published in: Digestive Diseases and Sciences | Issue 7/2016

Login to get access

Abstract

Background

Wiskott–Aldrich syndrome protein family verprolin-homologous protein 3 (WAVE3) plays a critical role in cancer progression and metastasis. However, the specific role of WAVE3 in intrahepatic cholangiocarcinoma (ICC) has not been studied.

Aims

This study aimed to explore the role and mechanism of WAVE3 in the progression and metastasis of ICC.

Methods

The expression of WAVE3 in ICC tissues and adjacent non-cancerous tissues was detected by immunohistochemistry. Western blot analysis was utilized to detect the expression of WAVE3 in ICC cells. A transwell assay was used to assess the potential for migration and invasion. The expression of WAVE3 in CC-LP-1 cells was knocked down by small interfering RNA (siRNA) interference.

Results

The expression of WAVE3 in ICC tissues was significantly higher than that in adjacent non-cancerous tissues. The overall survival was lower in the subgroup of ICC patients with higher WAVE3 expression compared to the subgroup with a lower level of WAVE3 expression. WAVE3 expression was an adverse prognostic factor for ICC patients. CC-LP-1 cells expressed higher levels of WAVE3 protein compared to RBE cells and human intrahepatic biliary epithelial cells, which correlated with greater migration and invasion capabilities compared with the RBE cells. After the transfection of CC-LP-1 cells with WAVE3 siRNA, the level of WAVE3 protein was significantly decreased, accompanied by a marked reduction in migration, invasion and proliferation. Moreover, after the knockdown of WAVE3 expression in CC-LP-1 cells, the protein levels of Slug and Vimentin were significantly decreased, while that of E-cadherin was significantly increased.

Conclusions

WAVE3 may represent a new adverse prognostic factor for patients with ICC. This protein enhances migration and invasion capabilities in ICC, most likely through the induction of an epithelial-mesenchymal transition.
Appendix
Available only for authorised users
Literature
1.
2.
Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.CrossRefPubMed
3.
Hirashita T, Iwashita Y, Ohta M, et al. Expression of matrix metalloproteinase-7 is an unfavorable prognostic factor in intrahepatic cholangiocarcinoma. J Gastrointest Surg. 2012;16:842–848.CrossRefPubMedPubMedCentral
4.
Ding YB, Deng B, Huang YS, et al. A high level of integrin α6 expression in human intrahepatic cholangiocarcinoma cells is associated with a migratory and invasive phenotype. Dig Dis Sci. 2013;58:1627–1635.CrossRefPubMed
5.
Zhao S, Wang J, Qin C. Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway. J Exp Clin Cancer Res. 2014;33:103.CrossRefPubMedPubMedCentral
6.
Fabris L, Cadamuro M, Moserle L, et al. Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization. Hepatology. 2011;54:890–899.CrossRefPubMedPubMedCentral
7.
Wang J, Zhang K, Wang J, et al. Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma. Oncotarget. 2015;6:18905–18920.CrossRefPubMedPubMedCentral
8.
Chen MH, Chiang KC, Cheng CT, et al. Antitumor activity of the combination of an HSP90 inhibitor and a PI3K/mTOR dual inhibitor against cholangiocarcinoma. Oncotarget. 2014;5:2372–2389.CrossRefPubMedPubMedCentral
9.
Millard TH, Sharp SJ, Machesky LM. Signalling to actin assembly via the WASP (Wiskott–Aldrich syndrome protein)-family proteins and the Arp2/3 complex. Biochem J. 2004;380:1–17.CrossRefPubMedPubMedCentral
10.
Machesky LM, Mullins RD, Higgs HN, et al. Scar, a WASp-related protein, activates nucleation of actin filaments by the Arp2/3 complex. Proc Natl Acad Sci USA. 1999;96:3739–3744.CrossRefPubMedPubMedCentral
11.
Mullins RD, Heuser JA, Pollard TD. The interaction of Arp2/3 complex with actin: nucleation, high affinity pointed end capping, and formation of branching networks of filaments. Proc Natl Acad Sci USA. 1998;95:6181–6186.CrossRefPubMedPubMedCentral
12.
Sossey-Alaoui K, Safina A, Li X, et al. Down-regulation of WAVE3, a metastasis promoter gene, inhibits invasion and metastasis of breast cancer cells. Am J Pathol. 2007;170:2112–2121.CrossRefPubMedPubMedCentral
13.
Fernando HS, Sanders AJ, Kynaston HG, Jiang WG. WAVE3 is associated with invasiveness in prostate cancer cells. Urol Oncol. 2010;28:320–327.CrossRefPubMed
14.
Ji Y, Li B, Zhu Z, et al. Overexpression of WAVE3 promotes tumor invasiveness and confers an unfavorable prognosis in human hepatocellular carcinoma. Biomed Pharmacother. 2015;69:409–415.CrossRefPubMed
15.
Yue Z, Feng W, Xiangke L, Liuxing W, Qingxia F, Jianbo G. WAVE3 promotes epithelial-mesenchymal transition of gastric cancer through upregulation of snail. Cancer Gene Ther. 2014;21:499–506.CrossRefPubMed
16.
Chang B, Li S, He Q, et al. Deregulation of Bmi-1 is associated with enhanced migration, invasion and poor prognosis in salivary adenoid cystic carcinoma. Biochim Biophys Acta. 2014;1840:3285–3291.CrossRefPubMed
17.
Kamihira T, Shimoda S, Harada K, et al. Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis. Gastroenterology. 2003;125:1379–1387.CrossRefPubMed
18.
Spolverato G, Vitale A, Cucchetti A, et al. Can hepatic resection provide a long-term cure for patients with intrahepatic cholangiocarcinoma? Cancer. 2015;121:3998–4006.CrossRefPubMed
19.
Sossey-Alaoui K. Surfing the big WAVE: insights into the role of WAVE3 as a driving force in cancer progression and metastasis. Semin Cell Dev Biol. 2013;24:287–297.PubMed
20.
Teng Y, Ghoshal P, Ngoka L, Mei Y, Cowell JK. Critical role of the WASF3 gene in JAK2/STAT3 regulation of cancer cell motility. Carcinogenesis. 2013;34:1994–1999.CrossRefPubMedPubMedCentral
21.
Sossey-Alaoui K, Ranalli TA, Li X, Bakin AV, Cowell JK. WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression. Exp Cell Res. 2005;308:135–145.CrossRefPubMed
22.
Teng Y, Mei Y, Hawthorn L, Cowell JK. WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells. Oncogene. 2014;33:203–211.CrossRefPubMed
23.
Zhang Y, Guan XY, Dong B, et al. Expression of MMP-9 and WAVE3 in colorectal cancer and its relationship to clinicopathological features. J Cancer Res Clin Oncol. 2012;138:2035–2044.CrossRefPubMed
24.
Wu J, Wang G, Chen X, Xue Z. Expression of WASF3 in patients with non-small cell lung cancer: correlation with clinicopathological features and prognosis. Oncol Lett. 2014;8:1169–1174.PubMedPubMedCentral
25.
Teng Y, Ren MQ, Cheney R, Sharma S, Cowell JK. Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases. Br J Cancer. 2010;103:1066–1075.CrossRefPubMedPubMedCentral
26.
Taylor MA, Davuluri G, Parvani JG, et al. Upregulated WAVE3 expression is essential for TGF-beta-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat. 2013;142:341–353.CrossRefPubMedPubMedCentral
27.
Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFβ in cancer. FEBS Lett. 2012;586:1959–1970.CrossRefPubMed
28.
Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.CrossRefPubMed
29.
Yang LX, Gao Q, Shi JY, et al. Mitogen-activated protein kinase kinase kinase 4 deficiency in intrahepatic cholangiocarcinoma leads to invasive growth and epithelial-mesenchymal transition. Hepatology. 2015;62:1804–1816.CrossRefPubMed
30.
Huang XY, Zhang C, Cai JB, et al. Comprehensive multiple molecular profile of epithelial mesenchymal transition in intrahepatic cholangiocarcinoma patients. PLoS ONE. 2014;9:e96860.CrossRefPubMedPubMedCentral
31.
Yao X, Wang X, Wang Z, et al. Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma. Onco Targets Ther. 2012;5:255–261.CrossRefPubMedPubMedCentral
32.
Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes in cancer invasion? Cancer Sci. 2010;101:2093–2104.CrossRefPubMed
33.
Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–5828.CrossRefPubMedPubMedCentral
34.
Gu MJ, Choi JH. Epithelial-mesenchymal transition phenotypes are associated with patient survival in intrahepatic cholangiocarcinoma. J Clin Pathol. 2014;67:229–234.CrossRefPubMed
35.
Teng Y, Xie X, Walker S, White DT, Mumm JS, Cowell JK. Evaluating human cancer cell metastasis in zebrafish. J Clin Pathol. 2014;67:229–234.CrossRef
Metadata
Title
WAVE3 Induces EMT and Promotes Migration and Invasion in Intrahepatic Cholangiocarcinoma
Authors
Zebin Zhu
Wei Chen
Xiaoyu Yin
Jiaming Lai
Qian Wang
Lijian Liang
Wei Wang
Anxun Wang
Chaoxu Zheng
Publication date
01-07-2016
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 7/2016
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-016-4102-9

Other articles of this Issue 7/2016

Digestive Diseases and Sciences 7/2016 Go to the issue

Review

The Genetics of Barrett’s Esophagus: A Familial and Population-Based Perspective

Original Article

Esophageal Epithelial Resistance and Lower Esophageal Sphincter Muscle Contraction Increase in a Chronic Diabetic Rabbit Model

Original Article

Time to Relapse in Children with Crohn’s Disease Treated with Azathioprine and Nutritional Therapy or Corticosteroids

Original Article

Knockdown of Astrocyte Elevated Gene-1 Inhibits Activation of Hepatic Stellate Cells

Stanford Multidisciplinary Seminars

Biliary Cystadenoma: A Suggested “Cystamatic” Approach?

UNM Clinical Case Conferences

Rewards of Persistence: Manometric Clues to Cancer
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits