This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-07-0012v1 67/9/4123    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, G. Articles by Sidransky, D. Search for Related Content PubMed PubMed Citation Articles by Wu, G. Articles by Sidransky, D.

LOXL1 and LOXL4 Are Epigenetically Silenced and Can Inhibit Ras/Extracellular Signal-Regulated Kinase Signaling Pathway in Human Bladder Cancer

¹ Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins University School of Medicine, and ² Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; ³ Karmanos Cancer Institute, Department of Pathology, Wayne State University, Detroit, Michigan; and ⁴ The Collagen Research Unit, Biocenter Oulu and Department of Medical Biochemistry, University of Oulu, Oulu, Finland

Requests for reprints: David Sidransky and Barry Trink, Department of Otolaryngology–Head and Neck Surgery, Head and Neck Cancer Research Division, 1550 Orleans Street 5N.03, Baltimore, MD 21231. Phone: 410-502-5153; Fax: 410-614-1411; E-mail: dsidrans{at}jhmi.edu and btrink{at}jhmi.edu and Guojun Wu, Karmanos Cancer Institute, Department of Pathology, Wayne State University, HWCRC Room 831, 4100 John R Street, Detroit, MI 48201. E-mail: wugu{at}karmanos.org.

Promoter hypermethylation is one of the common mechanisms leading to gene silencing in various human cancers. Using a combination of pharmacologic unmasking and microarray techniques, we identified 59 candidate hypermethylated genes, including LOXL1, a lysyl oxidase-like gene, in human bladder cancer cells. We further showed that LOXL1 and LOXL4 are commonly silenced genes in human bladder cancer cells, and this silence is predominantly related to promoter methylation. We also found LOXL1 and LOXL4 gene methylation and loss of expression in primary bladder tumors. In addition, somatic mutations were identified in LOXL4, but not in LOXL1 in bladder cancer. Moreover, reintroduction of LOXL1 and LOXL4 genes into human bladder cancer cells leads to a decrease of colony formation ability. Further studies indicated that the overexpression of LOXL1 and LOXL4 could antagonize Ras in activating the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, our current study suggests for the first time that lysyl oxidase-like genes can act as tumor suppressor genes and exert their functions through the inhibition of the Ras/ERK signaling pathway in human bladder cancer. [Cancer Res 2007;67(9):4123–9]

This article has been cited by other articles:

				U. Schlotzer-Schrehardt, F. Pasutto, P. Sommer, I. Hornstra, F. E. Kruse, G. O.H. Naumann, A. Reis, and M. Zenkel Genotype-Correlated Expression of Lysyl Oxidase-Like 1 in Ocular Tissues of Patients with Pseudoexfoliation Syndrome/Glaucoma and Normal Patients Am. J. Pathol., December 1, 2008; 173(6): 1724 - 1735. [Abstract] [Full Text] [PDF]

				N. Wakamatsu, J. B. Collins, J. S. Parker, M. Tessema, N. P. Clayton, T.-V. T. Ton, H.-H. L. Hong, S. Belinsky, T. R. Devereux, R. C. Sills, et al. Gene Expression Studies Demonstrate that the K-ras/Erk MAP Kinase Signal Transduction Pathway and Other Novel Pathways Contribute to the Pathogenesis of Cumene-induced Lung Tumors Toxicol Pathol, July 1, 2008; 36(5): 743 - 752. [Abstract] [Full Text] [PDF]