<b>
                     <i>Lysyl Oxidase</i>
                  </b> Is a Tumor Suppressor Gene Inactivated by Methylation and Loss of Heterozygosity in Human Gastric Cancers

Kaneda, Atsushi; Wakazono, Kuniko; Tsukamoto, Tetsuya; Watanabe, Naoko; Yagi, Yukiko; Tatematsu, Masae; Kaminishi, Michio; Sügimura, Takashi; Ushijima, Toshikazu

doi:10.1158/0008-5472.can-04-1543

Cited by 155 publications

(137 citation statements)

References 38 publications

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“…Many studies have shown that increased LOX expression is associated with malignant progression of cancer cells [17,31,50], whereas some studies reported that 50-kDa pro-LOX or its cleaved 18-kDa product (LOX-PP) may have tumor-suppressive function [21][22][23][24]. One of the reasons responsible for the differences between these reports and our study might be the different the cell lines.…”

Section: Discussioncontrasting

confidence: 78%

“…Involvement of the LOX family is widely accepted as a poor prognostic factor for patients with cancer [15][16][17][18][19][20]. By contrast, Kaneda et al [21] reported that LOX is a tumor suppressor gene inactivated by heavy methylation of the 5 0 untranslated region and loss of heterozygosity in gastric cancers, and several studies have reported that LOX-PP has tumor suppressor activity [22][23][24]. Both downregulation and upregulation of LOX in tumor tissues and cancer cell lines have been described [25][26][27][28], suggesting a paradoxical role for LOX as a tumor suppressor [21,29] as well as a metastasis promoter gene [30,31].…”

Section: Introductionmentioning

confidence: 99%

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Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

et al. 2015

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Purpose It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelialmesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. Methods Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of LOX small interfering RNA (siRNA) on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by reverse transcription PCR, Western blot, a wound-healing assay, and an invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically.Results Hypoxic conditions increased the number of polygonal or spindle-shaped cells resulting from EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. The number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. Conclusion LOX affects the EMT of gastric cancer cells in hypoxic conditions. LOX expression is a useful prognostic factor for patients with gastric cancer.

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Section: Discussioncontrasting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

et al. 2015

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“…LOX upregulation was detected in breast and renal cell carcinomas (10,11), while LOX downregulation was observed in prostate, bronchogenic, gastric, and head and neck squamous cell carcinomas (HNSCC) (12)(13)(14)(15). LOXL2 expression was also downregulated in HNSCC (15) but upregulated in colon and esophageal and breast carcinomas ONCOLOGY REPORTS 22: 799-804, 2009 799 Differential expression of the LOX family genes in human colorectal adenocarcinomas (16,17).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Kim

2009

Oncol Rep

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Abstract. Lysyl oxidase (LOX) is an amine oxidase that catalyzes the cross-linking of collage or elastin in the extracellular matrix, regulating the tensile strength and structural integrity of connective tissues. Recently, four paralogues (LOXL, LOXL2, LOXL3 and LOXL4) of LOX have been identified in humans, each containing the functional domains required for the amine oxidase activity toward collagen and elastin. Paradoxical roles of the LOX family members have been reported in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and type. To address expression of the LOX family genes in colorectal adenocarcinomas, we performed real-time PCR analysis with matched tumor/normal tissue specimens from 104 patients. The expression of the LOX family genes was not statistically associated with tumor location, stage, growth type, or differentiation status. However, upregulation of LOX, LOXL2 and LOXL4 was significantly correlated with absence of lymphovascular invasion (P=0.012, 0.014 and 0.005, respectively), suggesting that the oxygen tension in or around the tumors may be an important regulator for the differential expression of LOX, LOXL2 and LOXL4 in colorectal cancer. Additionally, expression of LOX, but not the other LOX family genes, was significantly upregulated in patients with a diffuse cytoplasmic expression pattern of CEA, indicating that LOX upregulation may be associated with increased invasiveness and metastatic potential in colorectal cancer.

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“…To make a genome-wide screening for novel aberrant methylation, restriction landmark genomic scanning (RLGS), methylation-sensitive-representational difference analysis (MS-RDA) and cDNA microarrays combined with treatment with a demethylating agent have been used. [6][7][8] Most studies, including our previous analysis of human breast cancers, 9,10 have attempted to identify genes silenced in cancers. These studies have paid little attention to the other CGI that are potentially useful as tumor biomarkers even if not related with gene silencing.…”

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confidence: 99%

Identification of 20 genes aberrantly methylated in human breast cancers

Miyamoto

Fukutomi

Akashi‐Tanaka

et al. 2005

Intl Journal of Cancer

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Aberrant methylation of CpG islands (CGI) not only plays a role in gene silencing, but is also a potential cancer biomarker. To identify more CGI aberrantly methylated in human breast cancers, we carried out a genome-wide search for aberrant methylation, using methylation-sensitive-representational difference analysis. CGI in 5 0 upstream regions of 20 genes, TSPAN-2, AK5, LOC284999, HOXD11, FLJ25161, XT3, PCDH10, PCDHGB6, SIM1, LOC346978, COE2, TDH (FLJ25033), LOC346419, FLJ33790, GJB2, AMN, LOC201164, DLX4, DCC and FOXA2, were found to be methylated in at least one of 8 breast cancer cell lines. Fifteen of the 20 genes were methylated in more than one of 21 primary breast cancers in Stages I or II, and especially, those of LOC346978, HOXD11, SIM1, PCDHGB6 and FLJ25161 were methylated in more than 10 cancers. All the breast cancers had some aberrant methylation. Key words: MS-RDA; breast cancer; CpG island; methylation Aberrant methylation of CpG islands (CGI) in promoter regions is known to be involved in silencing of tumor-suppressor genes. 1,2Because the aberrant methylation of tumor-suppressor genes is specific to cancer cells, its detection in biopsy specimens and free DNA in the blood is drawing attention as a tumor marker.3 Aberrantly methylated DNA molecules embedded in the vast majority of normal, unmethylated DNA molecules can be sensitively detected by various techniques, such as methylation-specific PCR (MSP) and quantitative MSP.4,5 Detection of aberrant methylation is more advantageous than detection of mutation in terms of sensitivity. One of the current limitations to the use of aberrant methylation as a tumor marker is the lack of target CGI specifically methylated in cancer cells.Uncovering novel aberrantly methylated CGI is important not only for discovery of novel tumor-suppressor genes, but also for identification of tumor markers. To make a genome-wide screening for novel aberrant methylation, restriction landmark genomic scanning (RLGS), methylation-sensitive-representational difference analysis (MS-RDA) and cDNA microarrays combined with treatment with a demethylating agent have been used.6-8 Most studies, including our previous analysis of human breast cancers, 9,10 have attempted to identify genes silenced in cancers. These studies have paid little attention to the other CGI that are potentially useful as tumor biomarkers even if not related with gene silencing.In our study, to search for aberrantly methylated 5 0 CGI as candidate tumor markers, we analyzed a human breast cancer cell line, MDA-MB-468, by MS-RDA with recent modifications for efficient isolation of CGI. 11,12Material and methods Cell lines, tumor samples, and DNA/RNA extraction MCF-7, ZR-75-1, BT474, T-47D, MDA-MB-231, MDA-MB-468 and SK-BR-3 were purchased from the American Type Culture Collection (Rockville, MD), and YMB-1-E was obtained from the Japanese Collection of Research Bioresources (Tokyo, Japan). Human mammary epithelial cells (HMEC) were purchased from Cambrex (East Rutherford, NJ). Breast cancers (1 carcinom...

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Lysyl Oxidase Is a Tumor Suppressor Gene Inactivated by Methylation and Loss of Heterozygosity in Human Gastric Cancers

Cited by 155 publications

References 38 publications

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia

Differential expression of the LOX family genes in human colorectal adenocarcinomas

Identification of 20 genes aberrantly methylated in human breast cancers

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