ABSTRACT

Piwi-interacting RNAs (piRNAs/piRs) are small non-coding RNAs that play important roles in stablizing genome through silencing transposable genetic elements. The piR-651 was reported to be dysregulated in several human solid cancer tissues, such as gastric and lung cancers. However, the role of piRNA-651 in carcinogenesis of breast cancer has not been defined. We found that piR-651 was highly expressed in breast cancer tissues and cell lines. Overexpression of piR-651 facilitated cell proliferation and invasion, restrained cell apoptosis and the percentage of arrested cells in G0/G1 phase, accompanied by upregulated expression of oncogenes (MDM2, CDK4 and Cyclin D1), whereas piR-651 downregulation showed the opposite effects. Additionally, piR-651 could promote phosphatase and tensin homolog (PTEN) methylation and its downregulated expression by recruiting DNA methyltransferase 1 (DNMT1) to the PTEN promoter region through complex formation with PIWIL2. PTEN overexpression reversed the effects of upregulated piR-651 on cell functions. This study reveals that piR-651 promotes proliferation and migration and induces apoptosis of breast cancer cells by facilitating DNMT1-mediated PTEN promoter methylation, which may provide a potential therapeutic mechanism for breast cancer.

摘要

Piwi 相互作用 RNA (piRNAs/piRs) 是小的非编码 RNA，它们通过沉默转座基因元件在稳定基因组中发挥重要作用。据报道，piR-651 在几种人类实体癌组织中失调，例如胃癌和肺癌。然而，piRNA-651在乳腺癌发生中的作用尚未明确。我们发现 piR-651 在乳腺癌组织和细胞系中高度表达。piR-651过表达促进细胞增殖和侵袭，抑制细胞凋亡和G0/G1期停滞细胞百分比，伴随癌基因（MDM2、CDK4和Cyclin D1）表达上调，而piR-651下调显示相反的效果. 此外，piR-651 可以通过与 PIWIL2 形成复合物将 DNA 甲基转移酶 1 (DNMT1) 募集到 PTEN 启动子区域来促进磷酸酶和张力蛋白同源物 (PTEN) 甲基化及其下调的表达。PTEN 过表达逆转了上调的 piR-651 对细胞功能的影响。本研究表明，piR-651通过促进DNMT1介导的PTEN启动子甲基化促进乳腺癌细胞的增殖和迁移并诱导其凋亡，这可能为乳腺癌提供潜在的治疗机制。