Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma

Our plain-English summary of Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma, by H. Kohno, V.J. Amatya, Y. Takeshima, et al (Oncology Reports, 2010).

The study

• Authors: H. Kohno, V.J. Amatya, Y. Takeshima, K. Kushitani, N. Hattori, N. Kohno, K. Inai
• Journal: Oncology Reports
• Published: 2010;24(2):423-31
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

WIF-1 is a negative regulator of the Wnt-signaling pathway that may have important implications for tumorigenesis. Microarray analysis of whole genome expression in mesothelioma tissue revealed down-regulation of 491 genes and up-regulation of 167 genes involved mainly in Jak-STAT signaling (8 genes), MAPK signaling (16 genes) and Wnt signaling (13 genes) pathways. Of these, WIF-1 gene was down-regulated in mesothelioma 72-fold compared to normal tissue. We also analyzed WIF-1 and SFRPs promoter methylations in 46 mesothelioma tissues, 8 mesothelioma cell lines by methylation-specific polymerase chain reaction (MSP). WIF-1 promoter methylation was observed in 34 of 46 mesothelioma tissues (73.9%) and in all 8 mesothelioma cell lines. SFRP1, 2 and 4 promoter methylation was observed in 21 of 37 (56.8%), 26 of 42 (61.9%) and 17 of 36 (47.2%) mesothelioma tissues, respectively. Promoter methylation of any WIF-1 and/or SFRP genes was observed in 44 of 46 (95.6%) mesothelioma tissues. The treatment of mesothelioma cell lines with 5-aza-2'-deoxycytidine (5-aza-2dC) showed WIF-1 promoter methylation recovery followed by restoration of WIF-1 expression in 6 of 8 mesothelioma cell lines. The cytoplasmic expression of beta-catenin was observed in 38 of 43 cases of mesothelioma without any nuclear reactivity. The eight mesothelioma cell lines and 27 cases of mesothelioma examined showed no mutation in exon 3 of beta-catenin suggesting no alteration of canonical Wnt signaling pathway. Our data suggest that WIF-1 promoter methylation is a common event in mesothelioma.

In plain English

This Japanese laboratory study measured promoter methylation, a chemical DNA change that can silence genes, in four genes that restrain a cell signaling pathway called Wnt: WIF-1 and SFRP1, 2 and 4. Only for WIF-1 did it test whether methylation went with lower gene activity. A gene-activity scan found WIF-1 activity 72-fold lower in tumor than normal tissue. In tumor samples from 46 patients at Hiroshima University, WIF-1 methylation was found in 34 of 46 (73.9%). In comparison, it was found in 4 of 24 (16.7%) non-cancerous lung tissue samples including the lung lining (pleura), a statistically significant difference. Methylation of any of the four genes was found in 44 of 46 tumors (95.6%) and 12 of 24 controls (50%). SFRP methylation was more frequent in tumors, but the differences were not statistically significant. All 8 mesothelioma cell lines showed WIF-1 methylation. A drug that removes methylation restored WIF-1 in 6 of them. No mutations were found in the examined part of the beta-catenin gene. Asbestos exposure was not studied. The authors concluded that WIF-1 promoter methylation is a common event in mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human mesothelioma tissue samples and mesothelioma cell lines: gene-expression microarray, methylation-specific PCR, treatment of cell lines with a demethylating drug (5-aza-2dC), immunohistochemistry and beta-catenin mutation analysis
• Who was studied: 46 mesothelioma tissue samples from the Department of Pathology, Hiroshima University, Japan. They came from 38 male and 8 female patients, mean age 62.3 years, range 26 to 83, and were 24 epithelioid, 9 biphasic and 13 sarcomatoid. The comparison group was 24 non-cancerous peripheral lung tissues containing visceral pleura, 12 of them from lung cancer patients. The study also used 8 commercially obtained mesothelioma cell lines. The microarray used frozen tissue from four mesotheliomas.
• Exposure: Not studied. The article does not report the patients' asbestos or other exposures. It examined gene methylation and gene activity in tumors.
• Main results:
  • In the microarray of mesothelioma tissue, 491 genes were less active and 167 genes more active than in normal tissue. WIF-1 activity was 72-fold lower in mesothelioma than in normal tissue.
  • The microarray did not show altered SFRP gene activity. The SFRP genes were tested for methylation only.
  • WIF-1 promoter methylation was found in 34 of 46 (73.9%) mesothelioma tissues and in 4 of 24 (16.7%) non-cancerous control tissues (P<0.01). All 4 methylated control samples came from lung cancer cases.
  • SFRP1, 2 and 4 methylation was found in 21 of 37 (56.8%), 26 of 42 (61.9%) and 17 of 36 (47.2%) mesothelioma tissues. In control tissues the figures were 37.5%, 54.5% and 26.7%. The differences were not statistically significant.
  • Methylation of any of WIF-1 or SFRP1, 2 and 4 was found in 44 of 46 (95.6%) mesothelioma tissues and in 12 of 24 (50%) control tissues (P<0.01).
  • All 8 mesothelioma cell lines showed WIF-1 promoter methylation. After treatment with the demethylating drug 5-aza-2dC, WIF-1 protein increased in 6 of the 8 cell lines. The other 2 showed no WIF-1 regardless of treatment.
  • In tissue staining, WIF-1 protein was seen in 3 of 28 (10.7%) mesothelioma cases with WIF-1 methylation and in 5 of 9 (55.6%) cases without it (P=0.011).
  • Beta-catenin was not seen in the cell nucleus in any of 43 mesothelioma cases, and it was seen in the cytoplasm in 38 cases. No mutation was found in the GSK-3 beta phosphorylation sites of exon 3 of the beta-catenin gene, in either the 27 tissue cases or the 8 cell lines.
• The authors' conclusion: The authors concluded that WIF-1 promoter methylation is a common event in mesothelioma.
• Limitations the authors state:
  • The authors suggested that mesothelioma involves a different branch of the Wnt pathway (Wnt-Ca2+) rather than the canonical beta-catenin pathway. They said this is a hypothesis that needs further study to confirm.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Carcinogenesis.

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