Downregulation of P-cadherin Expression in Hepatocellular Carcinoma Induces Tumorigenicity

Overview

Journal Int J Clin Exp Pathol

Specialty Pathology

Date 2014 Oct 23

PMID 25337260

Citations 18

Authors

Richard Bauer

Daniela Valletta

Karin Bauer

Wolfgang E Thasler

Arndt Hartmann

Martina Muller

Torsten E Reichert

Claus Hellerbrand

Affiliations

Soon will be listed here.

Abstract

P-cadherin is a major contributor to cell-cell adhesion in epithelial tissues, playing pivotal roles in important morphogenetic and differentiation processes and in maintaining tissue integrity and homeostasis. Alterations of P-cadherin expression have been observed during the progression of several carcinomas where it appears to act as tumor suppressive or oncogenic in a context-dependent manner. Here, we found a significant downregulation of P-cadherin in hepatocellular carcinoma (HCC) cell lines and tissues compared to primary human hepatocytes and non-malignant liver tissues. Combined immunohistochemical analysis of a tissue microarray containing matched pairs of HCC tissue and corresponding non-tumorous liver tissue of 69 patients confirmed reduced P-cadherin expression in more than half of the cases. In 35 human HCC tissues, the P-cadherin immunosignal was completely lost which correlated with tumor staging and proliferation. Also in vitro, P-cadherin suppression in HCC cells via siRNA induced proliferation compared to cells transfected with control-siRNA. In summary, downregulation of P-cadherin expression appears to induce tumorigenicity in HCC. Therefore, P-cadherin expression may serve as a prognostic marker and therapeutic target of this highly aggressive tumor.

Citing Articles

Alteration of Cadherin 3 Expression and DNA Methylation in Association with Aggressive Renal Cell Carcinoma.

Faraj Tabrizi P, Peters I, Schimansky I, Dubrowinskaja N, Reese C, Tezval H Int J Mol Sci. 2023; 24(22).

PMID: 38003666 PMC: 10670999. DOI: 10.3390/ijms242216476.

Construction and validation of a prognostic risk model for breast cancer based on protein expression.

Huang B, Zhang X, Cao Q, Chen J, Lin C, Xiang T BMC Med Genomics. 2022; 15(1):148.

PMID: 35787690 PMC: 9252042. DOI: 10.1186/s12920-022-01299-5.

Placental-Cadherin, a biomarker for local immune status and poor prognosis among patients with tongue squamous cell carcinoma.

Wang H, Yu T, Mao L Eur Arch Otorhinolaryngol. 2021; 279(7):3597-3609.

PMID: 34825969 DOI: 10.1007/s00405-021-07181-x.

Identification of novel targets of miR-622 in hepatocellular carcinoma reveals common regulation of cooperating genes and outlines the oncogenic role of zinc finger CCHC-type containing 11.

Gaza A, Fritz V, Malek L, Wormser L, Treiber N, Danner J Neoplasia. 2021; 23(5):502-514.

PMID: 33901943 PMC: 8099721. DOI: 10.1016/j.neo.2021.04.001.

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma.

Fritz V, Malek L, Gaza A, Wormser L, Appel M, Kremer A Cancers (Basel). 2021; 13(5).

PMID: 33803354 PMC: 7967205. DOI: 10.3390/cancers13051183.

References

Kirovski G, Stevens A, Czech B, Dettmer K, Weiss T, Wild P . Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5'-deoxy-5'-methylthioadenosine (MTA). Am J Pathol. 2011; 178(3):1145-52. PMC: 3069916. DOI: 10.1016/j.ajpath.2010.11.059. View

Faria G, Cardoso M, Martins D, Bettencourt H, Amendoeira I, Schimitt F . P-cadherin as prognostic factor for loco-regional relapse in breast cancer. Acta Med Port. 2012; 25(2):97-105. View

Farazi P, DePinho R . Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006; 6(9):674-87. DOI: 10.1038/nrc1934. View

Bruix J, Sala M, Llovet J . Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004; 127(5 Suppl 1):S179-88. DOI: 10.1053/j.gastro.2004.09.032. View

Kudo S, Caaveiro J, Goda S, Nagatoishi S, Ishii K, Matsuura T . Identification and characterization of the X-dimer of human P-cadherin: implications for homophilic cell adhesion. Biochemistry. 2014; 53(11):1742-52. DOI: 10.1021/bi401341g. View

Bauer R, Dowejko A, Driemel O, Bosserhoff A, Reichert T . Truncated P-cadherin is produced in oral squamous cell carcinoma. FEBS J. 2008; 275(16):4198-210. DOI: 10.1111/j.1742-4658.2008.06567.x. View

Cheung L, Leung P, Wong A . Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. Oncogene. 2010; 29(16):2427-40. DOI: 10.1038/onc.2009.523. View

Mandeville J, Silva Neto B, Vanni A, Smith G, Rieger-Christ K, Zeheb R . P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells. BJU Int. 2008; 102(11):1707-14. DOI: 10.1111/j.1464-410X.2008.08115.x. View

Hay E, Laplantine E, Geoffroy V, Frain M, Kohler T, Muller R . N-cadherin interacts with axin and LRP5 to negatively regulate Wnt/beta-catenin signaling, osteoblast function, and bone formation. Mol Cell Biol. 2008; 29(4):953-64. PMC: 2643807. DOI: 10.1128/MCB.00349-08. View

10.

Vlahova L, Doerflinger Y, Houben R, Becker J, Schrama D, Weiss C . P-cadherin expression in Merkel cell carcinomas is associated with prolonged recurrence-free survival. Br J Dermatol. 2012; 166(5):1043-52. DOI: 10.1111/j.1365-2133.2012.10853.x. View

11.

Law P, Ching A, Chan A, Wong Q, Wong C, To K . MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma. Carcinogenesis. 2012; 33(6):1134-41. DOI: 10.1093/carcin/bgs130. View

12.

Van Marck V, Stove C, Jacobs K, Van den Eynden G, Bracke M . P-cadherin in adhesion and invasion: opposite roles in colon and bladder carcinoma. Int J Cancer. 2010; 128(5):1031-44. DOI: 10.1002/ijc.25427. View

13.

Munoz-Guerra M, Marazuela E, Fernandez-Contreras M, Gamallo C . P-cadherin expression reduced in squamous cell carcinoma of the oral cavity: an indicatior of poor prognosis. Cancer. 2005; 103(5):960-9. DOI: 10.1002/cncr.20858. View

14.

Bauer R, Hein R, Bosserhoff A . A secreted form of P-cadherin is expressed in malignant melanoma. Exp Cell Res. 2005; 305(2):418-26. DOI: 10.1016/j.yexcr.2005.01.024. View

15.

Hussain K, El-Serag H . Epidemiology, screening, diagnosis and treatment of hepatocellular carcinoma. Minerva Gastroenterol Dietol. 2009; 55(2):123-38. View

16.

Kim M, Jung E, Lee H, Lee H, Yang H, Oh D . P-cadherin expression in gastric carcinoma: its regulation mechanism and prognostic significance. Hum Pathol. 2010; 41(6):877-85. DOI: 10.1016/j.humpath.2009.04.031. View

17.

Wheelock M, Johnson K . Cadherins as modulators of cellular phenotype. Annu Rev Cell Dev Biol. 2003; 19:207-35. DOI: 10.1146/annurev.cellbio.19.011102.111135. View

18.

Jacobs K, Feys L, Vanhoecke B, Van Marck V, Bracke M . P-cadherin expression reduces melanoma growth, invasion, and responsiveness to growth factors in nude mice. Eur J Cancer Prev. 2011; 20(3):207-16. DOI: 10.1097/CEJ.0b013e3283429e8b. View

19.

Thasler W, Weiss T, Schillhorn K, Stoll P, Irrgang B, Jauch K . Charitable State-Controlled Foundation Human Tissue and Cell Research: Ethic and Legal Aspects in the Supply of Surgically Removed Human Tissue For Research in the Academic and Commercial Sector in Germany. Cell Tissue Bank. 2004; 4(1):49-56. DOI: 10.1023/A:1026392429112. View

20.

Bauer K, Gosau M, Bosserhoff A, Reichert T, Bauer R . P-cadherin controls the differentiation of oral keratinocytes by regulating cytokeratin 1/10 expression via C/EBP-beta-mediated signaling. Differentiation. 2012; 84(5):345-54. DOI: 10.1016/j.diff.2012.09.002. View