nach oben

Erschienen in:

10.12.2015 | Original Article

Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells

verfasst von: Yong Qin, Sheng-qian Xu, De-biao Pan, Guan-xiong Ye, Cheng-jun Wu, Shi Wang, Chao-jun Wang, Jin-yan Jiang, Jing Fu

Erschienen in: Tumor Biology | Ausgabe 5/2016

Einloggen, um Zugang zu erhalten

Abstract

The role and clinical implication of the WWP2 E3 ubiquitin ligase in liver cancer are poorly understood. In the current study, we investigated the expression level of WWP2 and its functions in cell adhesion, invasion, and migration in liver cancer. We used real-time PCR to detect the expression of WWP2 in liver cancer and adjacent samples from the People’s Hospital of Lishui and also analyzed The Cancer Genome Atlas (TCGA) RNA-seq data by bioinformatics. Migration and invasion were detected by transwell analysis. We detected a strong WWP2 expression in tumor tissues of the People’s Hospital of Lishui, and the survival rate was significantly higher in patients with lower WWP2-expressing tumors. WWP2 small hairpin RNA (shRNA) lentivirus stably infected cells (shWWP2), Huh7, showed slower growth speed compared with scramble control-infected cells in a xenograft mouse model. Knockdown of WWP2 Huh7 and BEL-7404 cells demonstrated a reduction in adhesion, invasion, and migration. Gene set enrichment analysis (GSEA) showed that WWP2 is positively correlated to cancer-related pathways including the chemokine signaling pathway. WWP2 also regulated MMP-9, caspase-9, CXCR3, and CCR5 expression in liver cancer cells. In addition, knockdown of CXCR3 and CCR5 significantly inhibited cell proliferation, adhesion, invasion, and migration in Huh7 and BEL-7404 cells. Our data suggest that targeting of WWP2 may be a therapeutic strategy for liver cancer treatment.

Nur mit Berechtigung zugänglich

Okuda K. Hepatocellular carcinoma. J Hepatol. 2000;32:225–37.CrossRefPubMed

del Pozo AC, López P. Management of hepatocellular carcinoma. Clin Liver Dis. 2007;11:305–21.CrossRefPubMed

Kudo M, Okanoue T. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice manual proposed by the Japan Society of Hepatology. Oncology. 2007;72:2–15.CrossRefPubMed

Nakakura EK, Choti MA. Management of hepatocellular carcinoma. Oncol Huntingt. 2000;14:1085–97.

Huang S, He X. The role of microRNAs in liver cancer progression. Br J Cancer. 2010;104:235–40.CrossRefPubMedPubMedCentral

Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48:2047–63.CrossRefPubMed

Qian YW, Chen Y, Yang W, Fu J, Cao J, Ren YB, et al. P28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis. Gastroenterology. 2012;142:1547. e1514–58. e1514.CrossRef

Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, et al. Identification of novel human WW domain-containing proteins by cloning of ligand targets. J Biol Chem. 1997;272:14611–6.CrossRefPubMed

Xu H, Wang W, Li C, Yu H, Yang A, Wang B, et al. WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells. Cell Res. 2009;19:561–73.CrossRefPubMed

10.

Maddika S, Kavela S, Rani N, Palicharla VR, Pokorny JL, Sarkaria JN, et al. WWP2 is an E3 ubiquitin ligase for PTEN. Nat Cell Biol. 2011;13:728–33.CrossRefPubMedPubMedCentral

11.

Chantry A. WWP2 ubiquitin ligase and its isoforms: new biological insight and promising disease targets. Cell Cycle. 2011;10:2437–9.CrossRefPubMedPubMedCentral

12.

Yang Y, Liao B, Wang S, Yan B, Jin Y, Shu H-B, et al. E3 ligase WWP2 negatively regulates TLR3-mediated innate immune response by targeting TRIF for ubiquitination and degradation. Proc Natl Acad Sci. 2013;110:5115–20.CrossRefPubMedPubMedCentral

13.

Fukumoto C, Nakashima D, Kasamatsu A, Unozawa M, Shida-Sakazume T, Higo M, et al. WWP2 is overexpressed in human oral cancer, determining tumor size and poor prognosis in patients: downregulation of WWP2 inhibits the AKT signaling and tumor growth in mice. Oncoscience. 2014;1:807.CrossRefPubMedPubMedCentral

14.

Zou W, Chen X, Shim J-H, Huang Z, Brady N, Hu D, et al. The E3 ubiquitin ligase WWP2 regulates craniofacial development through mono-ubiquitylation of goosecoid. Nat Cell Biol. 2011;13:59–65.CrossRefPubMed

15.

Nakamura Y, Yamamoto K, He X, Otsuki B, Kim Y, Murao H, et al. WWP2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25. Nat Commun. 2011;2:251.CrossRefPubMedPubMedCentral

16.

O’Hayre M, Salanga C, Handel T, Allen S. Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J. 2008;409:635–49.CrossRefPubMed

17.

Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med. 2010;16:133–44.CrossRefPubMedPubMedCentral

18.

Rollins BJ. Inflammatory chemokines in cancer growth and progression. Eur J Cancer. 2006;42:760–7.CrossRefPubMed

19.

Yu T, Wu Y, Helman JI, Wen Y, Wang C, Li L. CXCR4 promotes oral squamous cell carcinoma migration and invasion through inducing expression of MMP-9 and MMP-13 via the ERK signaling pathway. Mol Cancer Res. 2011;9:161–72.CrossRefPubMed

20.

Lai K-C, Huang A-C, Hsu S-C, Kuo C-L, Yang J-S, Wu S-H, et al. Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J Agric Food Chem. 2010;58:2935–42.CrossRefPubMed

21.

Srinivas G, Anto RJ, Srinivas P, Vidhyalakshmi S, Senan VP, Karunagaran D. Emodin induces apoptosis of human cervical cancer cells through poly (ADP-ribose) polymerase cleavage and activation of caspase-9. Eur J Pharmacol. 2003;473:117–25.CrossRefPubMed

22.

de Lemos C, Christensen JE, Nansen A, Moos T, Lu B, Gerard C, et al. Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice. J Immunol. 2005;175:1767–75.CrossRefPubMed

23.

Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov JP. GSEA-P: a desktop application for gene set enrichment analysis. Bioinformatics. 2007;23:3251–3.CrossRefPubMed

24.

Hu Y, Chen H-Y, Yu C-Y, Xu J, Wang J-L, Qian J, et al. A long non-coding RNA signature to improve prognosis prediction of colorectal cancer. Oncotarget. 2014;5:2230.CrossRefPubMedPubMedCentral

25.

Xiong S, Zheng Y, Jiang P, Liu R, Liu X, Chu Y. MicroRNA-7 inhibits the growth of human non-small cell lung cancer A549 cells through targeting BCL-2. Int J Biol Sci. 2011;7:805.CrossRefPubMedPubMedCentral

26.

Payton JE, Grieselhuber NR, Chang L-W, Murakami M, Geiss GK, Link DC, et al. High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples. J Clin Invest. 2009;119:1714–26.CrossRefPubMedPubMedCentral

27.

Chen H-W, Yu S-L, Chen JJ, Li H-N, Lin Y-C, Yao P-L, et al. Anti-invasive gene expression profile of curcumin in lung adenocarcinoma based on a high throughput microarray analysis. Mol Pharmacol. 2004;65:99–110.CrossRefPubMed

28.

Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989;24:148–54.CrossRefPubMed

29.

Xu M, Qian G, Xie F, Shi C, Yan L, Yu L, et al. Expression of epithelial cell adhesion molecule associated with elevated ductular reactions in hepatocellar carcinoma. Clin Res Hepatol Gastroenterol. 2014;38:699–705.CrossRefPubMed

30.

Yamada S, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Arakawa Y, et al. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy. Ann Surg Oncol. 2014;21 Suppl 3:S436–42.CrossRefPubMed

31.

Soond SM, Smith PG, Wahl L, Swingler TE, Clark IM, Hemmings AM, et al. Novel WWP2 ubiquitin ligase isoforms as potential prognostic markers and molecular targets in cancer. Biochim Biophys Acta (BBA) Mol Basis Dis. 2013;1832:2127–35.CrossRef

32.

Nguyen Huu NS, Ryder WDJ, Zeps N, Flasza M, Chiu M, Hanby A, et al. Tumour‐promoting activity of altered WWP1 expression in breast cancer and its utility as a prognostic indicator. J Pathol. 2008;216:93–102.CrossRefPubMed

33.

Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, et al. Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer. 2009;9:240.CrossRefPubMedPubMedCentral

34.

Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor-beta up‐regulates E‐cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology. 2008;47:1557–66.CrossRefPubMed

35.

Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009;275:44–53.CrossRefPubMed

36.

Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9:582–9.CrossRefPubMedPubMedCentral

37.

Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25:977–88.CrossRefPubMed

38.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44.CrossRefPubMed

39.

Dagan-Berger M, Feniger-Barish R, Avniel S, Wald H, Galun E, Grabovsky V, et al. Role of CXCR3 carboxyl terminus and third intracellular loop in receptor-mediated migration, adhesion and internalization in response to CXCL11. Blood. 2006;107:3821–31.CrossRefPubMed

40.

Ma X, Norsworthy K, Kundu N, Rodgers WH, Gimotty PA, Goloubeva O, et al. CXCR3 expression is associated with poor survival in breast cancer and promotes metastasis in a murine model. Mol Cancer Ther. 2009;8:490–8.CrossRefPubMed

41.

Wu Q, Dhir R, Wells A. Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion. Mol Cancer. 2012;11.

42.

Velasco-Velázquez M, Jiao X, De La Fuente M, Pestell TG, Ertel A, Lisanti MP, et al. CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res. 2012;72:3839–50.CrossRefPubMed

Titel: Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells
verfasst von: Yong Qin
Sheng-qian Xu
De-biao Pan
Guan-xiong Ye
Cheng-jun Wu
Shi Wang
Chao-jun Wang
Jin-yan Jiang
Jing Fu
Publikationsdatum: 10.12.2015
Verlag: Springer Netherlands
Erschienen in: Tumor Biology / Ausgabe 5/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-015-4547-z

Neu im Fachgebiet Onkologie

23.04.2024 | Medikamente in Schwangerschaft und Stillzeit | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells

Abstract

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2016

miR-874 suppresses the proliferation and metastasis of osteosarcoma by targeting E2F3

Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis

Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype

MicroRNA-144 mediates metabolic shift in ovarian cancer cells by directly targeting Glut1

Combination of miR-125b and miR-27a enhances sensitivity and specificity of AFP-based diagnosis of hepatocellular carcinoma

Downregulation of microRNA-217 and microRNA-646 acts as potential predictor biomarkers in progression, metastasis, and unfavorable prognosis of human osteosarcoma

Neu im Fachgebiet Onkologie

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Stufenschema weist Prostatakarzinom zuverlässig nach

Update Onkologie