Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
J Gynecol Oncol. 2023 Nov;34(6):e71. doi: 10.3802/jgo.2023.34.e71. Epub 2023 Jun 27.
More than 75% of ovarian cancer patients are diagnosed at advanced stages and die of tumor cell metastasis. This study aimed to identify new epigenetic and transcriptomic alterations associated with ovarian cancer metastasis.
Two cell sublines with low- and high-metastasis potentials were derived from the ovarian cancer cell line A2780. Genome-wide DNA methylome and transcriptome profiling were carried out in these two sublines by Reduced Representation Bisulfite Sequencing and RNA-seq technologies. Cell-based assays were conducted to support the clinical findings.
There are distinct DNA methylation and gene expression patterns between the two cell sublines with low- and high-metastasis potentials. Integrated analysis identified 33 methylation-induced genes potentially involved in ovarian cancer metastasis. The DNA methylation patterns of two of them (i.e., SFRP1 and LIPG) were further validated in human specimens, indicating that they were hypermethylated and downregulated in peritoneal metastatic ovarian carcinoma compared to primary ovarian carcinoma. Patients with lower SFRP1 and LIPG expression tend to have a worse prognosis. Functionally, knockdown of SFRP1 and LIPG promoted cell growth and migration, whereas their overexpression resulted in the opposite effects. In particular, knockdown of SFRP1 could phosphorylate GSK3β and increase β-catenin expression, leading to deregulated activation of the Wnt/β-catenin signaling.
Many systemic and important epigenetic and transcriptomic alterations occur in the progression of ovarian cancer. In particular, epigenetic silencing of SFRP1 and LIPG is a potential driver event in ovarian cancer metastasis. They can be used as prognostic biomarkers and therapeutic targets for ovarian cancer patients.
超过 75%的卵巢癌患者在晚期被诊断，死于肿瘤细胞转移。本研究旨在鉴定与卵巢癌转移相关的新的表观遗传和转录组改变。
从卵巢癌细胞系 A2780 中衍生出具有低转移和高转移潜能的两个细胞亚系。通过 Reduced Representation Bisulfite Sequencing 和 RNA-seq 技术对这两个亚系进行全基因组 DNA 甲基化组和转录组谱分析。进行细胞基础检测以支持临床发现。
具有低转移和高转移潜能的两个细胞亚系之间存在明显的 DNA 甲基化和基因表达模式。整合分析鉴定了 33 个可能参与卵巢癌转移的甲基化诱导基因。其中两个基因（SFRP1 和 LIPG）的 DNA 甲基化模式在人类标本中进一步得到验证，表明它们在腹膜转移性卵巢癌中比原发性卵巢癌中呈高甲基化和下调。SFRP1 和 LIPG 表达水平较低的患者预后较差。功能上，SFRP1 和 LIPG 的敲低促进细胞生长和迁移，而它们的过表达则产生相反的效果。特别是，SFRP1 的敲低可以使 GSK3β 磷酸化并增加β-catenin 的表达，导致 Wnt/β-catenin 信号通路的失调激活。
在卵巢癌的进展过程中发生了许多系统性和重要的表观遗传和转录组改变。特别是，SFRP1 和 LIPG 的表观遗传沉默是卵巢癌转移的潜在驱动事件。它们可以用作卵巢癌患者的预后生物标志物和治疗靶点。
