Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma

Daisuke Yamada, Shinji Kikuchi, Yuko N. Williams, Mika Sakurai-Yageta, Mari Masuda, Tomoko Maruyama, Kyoichi Tomita, David H. Gutmann, Tadao Kakizoe, Tadaichil Kitamura, Yae Kanai, Yoshinori Murakami

Research output: Contribution to journalArticle

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Abstract

Renal clear cell carcinoma (RCCC) is a malignant tumor with poor prognosis caused by the high incidence of metastasis to distal organs. Although metastatic RCCC cells frequently show aberrant cytoskeletal organization, the underlying mechanism has not been elucidated. DAL-1/4.1B is an actin-binding protein implicated in the cytoskeleton-associated processes, while its inactivation is frequently observed, in lung and breast cancers and meningiomas, suggesting that 4.1B is a potential tumor suppressor. We studied a possible involvement of 4.1B in RCCCs and evaluated it as a clinical indicator. 4.1B protein was detected in the proximal convoluted tubules of human kidney, the presumed cell of origin of RCCC. On the other hand, loss or marked reduction of its expression was observed in 10 of 19 (53%) renal cell carcinoma (RCC) cells and 12 of 19 (63%) surgically resected RCCC by reverse transcription-PCR. Bisulfite sequencing or bisulfite SSCP analyses revealed that the 4.1B promoter was methylated in 9 of 19 (47%) RCC cells and 25 of 55 (45%) surgically resected RCCC, and inversely correlated with 4.1B expression (p < 0.0001). Aberrant methylation appeared to be a relatively early event because more than 40% of the tumors with pT1a showed hypermethylation. Furthermore, 4.1B methylation correlated with a nuclear grade (p = 0.017) and a recurrence-free survival (p = 0.0036) and provided an independent prognostic factor (p = 0.038, relative risk 10.5). These results indicate that the promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC.

Original languageEnglish
Pages (from-to)916-923
Number of pages8
JournalInternational Journal of Cancer
Volume118
Issue number4
DOIs
Publication statusPublished - 2006 Feb 15
Externally publishedYes

Fingerprint

Renal Cell Carcinoma
Genes
Neoplasms
Methylation
Kidney Tubules
Recurrence
Single-Stranded Conformational Polymorphism
Microfilament Proteins
Meningioma
Cytoskeleton
Epigenomics
Reverse Transcription
Lung Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Polymerase Chain Reaction
Survival
Incidence
Proteins

Keywords

  • Bi-sulfite sequencing
  • Independent prognostic factor
  • Recurrence-free survival rate
  • Tumor suppressor gene
  • Two-hit inactivation

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Yamada, D., Kikuchi, S., Williams, Y. N., Sakurai-Yageta, M., Masuda, M., Maruyama, T., ... Murakami, Y. (2006). Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. International Journal of Cancer, 118(4), 916-923. https://doi.org/10.1002/ijc.21450

Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. / Yamada, Daisuke; Kikuchi, Shinji; Williams, Yuko N.; Sakurai-Yageta, Mika; Masuda, Mari; Maruyama, Tomoko; Tomita, Kyoichi; Gutmann, David H.; Kakizoe, Tadao; Kitamura, Tadaichil; Kanai, Yae; Murakami, Yoshinori.

In: International Journal of Cancer, Vol. 118, No. 4, 15.02.2006, p. 916-923.

Research output: Contribution to journalArticle

Yamada, D, Kikuchi, S, Williams, YN, Sakurai-Yageta, M, Masuda, M, Maruyama, T, Tomita, K, Gutmann, DH, Kakizoe, T, Kitamura, T, Kanai, Y & Murakami, Y 2006, 'Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma', International Journal of Cancer, vol. 118, no. 4, pp. 916-923. https://doi.org/10.1002/ijc.21450
Yamada, Daisuke ; Kikuchi, Shinji ; Williams, Yuko N. ; Sakurai-Yageta, Mika ; Masuda, Mari ; Maruyama, Tomoko ; Tomita, Kyoichi ; Gutmann, David H. ; Kakizoe, Tadao ; Kitamura, Tadaichil ; Kanai, Yae ; Murakami, Yoshinori. / Promoter hypermethylation of the potential tumor suppressor DAL-1/4.1B gene in renal clear cell carcinoma. In: International Journal of Cancer. 2006 ; Vol. 118, No. 4. pp. 916-923.
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abstract = "Renal clear cell carcinoma (RCCC) is a malignant tumor with poor prognosis caused by the high incidence of metastasis to distal organs. Although metastatic RCCC cells frequently show aberrant cytoskeletal organization, the underlying mechanism has not been elucidated. DAL-1/4.1B is an actin-binding protein implicated in the cytoskeleton-associated processes, while its inactivation is frequently observed, in lung and breast cancers and meningiomas, suggesting that 4.1B is a potential tumor suppressor. We studied a possible involvement of 4.1B in RCCCs and evaluated it as a clinical indicator. 4.1B protein was detected in the proximal convoluted tubules of human kidney, the presumed cell of origin of RCCC. On the other hand, loss or marked reduction of its expression was observed in 10 of 19 (53{\%}) renal cell carcinoma (RCC) cells and 12 of 19 (63{\%}) surgically resected RCCC by reverse transcription-PCR. Bisulfite sequencing or bisulfite SSCP analyses revealed that the 4.1B promoter was methylated in 9 of 19 (47{\%}) RCC cells and 25 of 55 (45{\%}) surgically resected RCCC, and inversely correlated with 4.1B expression (p < 0.0001). Aberrant methylation appeared to be a relatively early event because more than 40{\%} of the tumors with pT1a showed hypermethylation. Furthermore, 4.1B methylation correlated with a nuclear grade (p = 0.017) and a recurrence-free survival (p = 0.0036) and provided an independent prognostic factor (p = 0.038, relative risk 10.5). These results indicate that the promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC.",
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AU - Masuda, Mari

AU - Maruyama, Tomoko

AU - Tomita, Kyoichi

AU - Gutmann, David H.

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