Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Molecular Pathology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, Maryland.
Mol Cancer Res. 2019 Oct;17(10):2051-2062. doi: 10.1158/1541-7786.MCR-19-0310. Epub 2019 Jul 10.
High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecologic cancer-related death. We have previously shown that (also known as , rother f the egulator of mprinted ites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. -expressing cells exhibited increased motility and invasion, and expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECM-receptor interactions. Importantly, , a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, analyses provided evidence for and coexpression in several cancers. Finally, ChIP-seq demonstrated that expression of was associated with and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including . Taken together, our data indicate that may promote cell motility and invasion in HGSC via upregulation of , and suggests as a potential therapeutic target in this malignancy. IMPLICATIONS: These studies provide evidence that aberrant expression of BORIS may play a role in the progression to HGSC by enhancing the migratory and invasive properties of FTSEC.
高级别浆液性癌（HGSC）是最具侵袭性和主要的上皮性卵巢癌形式，也是妇科癌症相关死亡的主要原因。我们之前已经表明， （也称为 ，印迹调控因子的另一个）在大多数卵巢癌中表达，并与全球和启动子特异性 DNA 低甲基化、晚期肿瘤分期和不良预后相关。为了探索其在 HGSC 中的作用，我们在人输卵管分泌上皮细胞（FTSEC）中表达了 ，这是 HGSC 的假定起源细胞。表达 的细胞表现出增强的迁移和侵袭能力，并且 表达与几种与癌症相关的基因表达网络的改变相关，包括脂肪酸代谢、TNF 信号转导、细胞迁移和 ECM-受体相互作用。重要的是， ，一个参与癌细胞迁移和侵袭的糖基转移酶基因，被 BORIS 高度诱导，而 敲低显著阻断了 BORIS 诱导的细胞迁移和侵袭。此外， 分析提供了证据表明 和 在几种癌症中共同表达。最后，ChIP-seq 表明 表达与 和 CTCF 在数百个位点的增强结合相关，其中许多与靶基因的转录激活相关，包括 。总之，我们的数据表明， 可能通过上调 来促进 HGSC 中的细胞迁移和侵袭，并表明 是这种恶性肿瘤的潜在治疗靶点。 这些研究提供了证据表明，BORIS 的异常表达可能通过增强 FTSEC 的迁移和侵袭特性在向 HGSC 的进展中发挥作用。
