TY - JOUR
T1 - Aberrant cell adhesiveness due to DNA hypermethylation of KLF11 in papillary urothelial carcinomas
AU - Tsumura, Koji
AU - Fujimoto, Mao
AU - Tian, Ying
AU - Kawahara, Toru
AU - Fujimoto, Hiroyuki
AU - Maeshima, Akiko Miyagi
AU - Nakagawa, Tohru
AU - Kume, Haruki
AU - Yoshida, Teruhiko
AU - Kanai, Yae
AU - Arai, Eri
N1 - Publisher Copyright:
© 2023
PY - 2024/6
Y1 - 2024/6
N2 - Purpose: The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas. Methods: Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines. Results: The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5′-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected. Conclusion: These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane.
AB - Purpose: The aim of this study was to clarify DNA methylation profiles determining the clinicopathological diversity of urothelial carcinomas. Methods: Genome-wide DNA methylation analysis was performed using the Infinium HumanMethylation450 BeadChip in 46 paired samples of non-cancerous urothelium (N) and corresponding cancerous tissue (T), and 26 samples of normal control urothelium obtained from patients without urothelial carcinomas (C). For genes of interest, correlation between DNA methylation and mRNA expression was examined using the Cancer Genome Atlas database. In addition, the role of a selected target for cancer-relevant endpoints was further examined in urothelial carcinoma cell lines. Results: The genes showing significant differences in DNA methylation levels between papillary carcinomas and more aggressive non-papillary (nodular) carcinomas were accumulated in signaling pathways participating in cell adhesion and cytoskeletal remodeling. Five hundred ninety-six methylation sites showed differences in DNA methylation levels between papillary and nodular carcinomas. Of those sites, that were located in CpG-islands around transcription start site, 5′-untranslated region or 1st exon, 16 genes exhibited inverse correlations between DNA methylation and mRNA expression levels. Among the latter, only the KLF11 gene showed papillary T sample-specific DNA hypermethylation in comparison to C and N samples. The DNA methylation levels of KLF11 were not significantly different between T samples and N samples or T samples and C samples for patients with papillo-nodular or nodular carcinomas. Knockdown experiments using the urothelial carcinoma cell lines HT1376 and 5637, which are considered models for papillary carcinoma, revealed that KLF11 participates in altering the adhesiveness of cells to laminin-coated dishes, although cell growth was not affected. Conclusion: These data indicate that DNA hypermethylation of KLF11 may participate in the generation of papillary urothelial carcinomas through induction of aberrant cancer cell adhesion to the basement membrane.
KW - Clinicopathological diversity
KW - DNA methylation
KW - KLF11
KW - Morphological configuration
KW - Papillary carcinoma
KW - Urothelial carcinoma
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U2 - 10.1016/j.yexmp.2024.104908
DO - 10.1016/j.yexmp.2024.104908
M3 - Article
C2 - 38824688
AN - SCOPUS:85194721118
SN - 0014-4800
VL - 137
JO - Experimental and Molecular Pathology
JF - Experimental and Molecular Pathology
M1 - 104908
ER -
