Aberrant cell adhesiveness due to DNA hypermethylation of KLF11 in papillary urothelial carcinomas

IF 2.8 4区医学 Q2 PATHOLOGY Experimental and molecular pathology Pub Date : 2024-06-01 DOI:10.1016/j.yexmp.2024.104908

Koji Tsumura , Mao Fujimoto , Ying Tian , Toru Kawahara , Hiroyuki Fujimoto , Akiko Miyagi Maeshima , Tohru Nakagawa , Haruki Kume , Teruhiko Yoshida , Yae Kanai , Eri Arai

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Abstract

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.

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乳头状尿路上皮癌中 KLF11 的 DNA 高甲基化导致细胞粘附性异常。

目的：本研究旨在阐明决定尿路癌临床病理多样性的DNA甲基化图谱：方法：使用Infinium HumanMethylation450 BeadChip对46份非癌尿路上皮（N）和相应癌组织（T）的配对样本，以及26份来自无尿路上皮癌患者（C）的正常对照尿路上皮样本进行全基因组DNA甲基化分析。对于感兴趣的基因，DNA 甲基化与 mRNA 表达之间的相关性通过癌症基因组图谱数据库进行了检验。此外，还在尿路上皮癌细胞系中进一步研究了所选靶点对癌症相关终点的作用：结果：乳头状癌和侵袭性更强的非乳头状（结节性）癌之间的DNA甲基化水平存在明显差异的基因，都累积在参与细胞粘附和细胞骨架重塑的信号通路中。乳头状癌和结节性癌之间有596个甲基化位点的DNA甲基化水平存在差异。这些位点位于转录起始位点、5'-非翻译区或第一外显子周围的CpG区，其中16个基因的DNA甲基化与mRNA表达水平呈反相关。与C和N样本相比，后者中只有KLF11基因表现出乳头状T样本特异性DNA甲基化水平过高。在乳头状结节性癌或结节性癌患者中，T样本与N样本、T样本与C样本之间的KLF11基因DNA甲基化水平没有明显差异。使用被认为是乳头状癌模型的尿路上皮癌细胞系 HT1376 和 5637 进行的基因敲除实验显示，KLF11 参与改变细胞与层粘连蛋白涂层平皿的粘附性，但细胞生长不受影响：这些数据表明，KLF11的DNA高甲基化可能通过诱导癌细胞对基底膜的异常粘附而参与乳头状尿路上皮癌的生成。

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来源期刊

Experimental and molecular pathology 医学-病理学

CiteScore

8.90

自引率

0.00%

发文量

审稿时长

11.5 weeks

期刊介绍： Under new editorial leadership, Experimental and Molecular Pathology presents original articles on disease processes in relation to structural and biochemical alterations in mammalian tissues and fluids and on the application of newer techniques of molecular biology to problems of pathology in humans and other animals. The journal also publishes selected interpretive synthesis reviews by bench level investigators working at the "cutting edge" of contemporary research in pathology. In addition, special thematic issues present original research reports that unravel some of Nature''s most jealously guarded secrets on the pathologic basis of disease. Research Areas include: Stem cells; Neoangiogenesis; Molecular diagnostics; Polymerase chain reaction; In situ hybridization; DNA sequencing; Cell receptors; Carcinogenesis; Pathobiology of neoplasia; Complex infectious diseases; Transplantation; Cytokines; Flow cytomeric analysis; Inflammation; Cellular injury; Immunology and hypersensitivity; Athersclerosis.