Yi Yuyin, Tsai Shu-Huei, Cheng Jung-Chien, Wang Evan Y, Anglesio Michael S, Cochrane Dawn R, Fuller Megan, Gibb Ewan A, Wei Wei, Huntsman David G, Karsan Aly, Hoodless Pamela A
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada; Cell and Developmental Biology Program, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
Gynecol Oncol. 2017 Dec;147(3):663-671. doi: 10.1016/j.ygyno.2017.10.016. Epub 2017 Oct 24.
APELA is a small, secreted peptide that can function as a ligand for the G-protein coupled receptor, Apelin Receptor (APLNR, APJ). APELA plays an essential role in endoderm differentiation and cardiac development during embryogenesis. We investigated whether APELA exerts any functions in cancer progression.
The Cancer Genome Atlas (TCGA) RNA sequencing datasets, microarray from an OCCC mouse model, and RNA isolated from fresh frozen and FFPE patient tissue were used to assess APELA expression. APELA knockout ovarian clear cell carcinoma (OCCC) cell lines were generated using CRISPR/Cas9.
APELA was expressed in various ovarian cancer histotypes and was especially elevated in OCCC. Disruption of APELA expression in OCCC cell lines suppressed cell growth and migration, and altered cell-cycle progression. Moreover, addition of human recombinant APELA peptide to the OCCC cell line OVISE promoted cell growth and migration. Interestingly, OVISE cells do not express APLNR, suggesting that APELA can function through an APLNR-independent pathway. Furthermore, APELA affected cell growth and cell cycle progression in a p53-dependent manner. In addition, APELA knockdown induced p53 expression in cancer cell lines.
Our findings uncover a potential oncogenic role for APELA in promoting ovarian tumour progression and provide a possible therapeutic strategy in ovarian cancer by targeting APELA.
APELA是一种小分子分泌肽，可作为G蛋白偶联受体Apelin受体（APLNR，APJ）的配体发挥作用。APELA在胚胎发育过程中的内胚层分化和心脏发育中起重要作用。我们研究了APELA在癌症进展中是否发挥任何作用。
使用癌症基因组图谱（TCGA）RNA测序数据集、来自OCCC小鼠模型的微阵列以及从新鲜冷冻和福尔马林固定石蜡包埋（FFPE）患者组织中分离的RNA来评估APELA的表达。使用CRISPR/Cas9构建APELA基因敲除的卵巢透明细胞癌（OCCC）细胞系。
APELA在各种卵巢癌组织类型中均有表达，在OCCC中尤其升高。OCCC细胞系中APELA表达的破坏抑制了细胞生长和迁移，并改变了细胞周期进程。此外，向OCCC细胞系OVISE中添加人重组APELA肽可促进细胞生长和迁移。有趣的是，OVISE细胞不表达APLNR，这表明APELA可以通过不依赖APLNR的途径发挥作用。此外，APELA以p53依赖的方式影响细胞生长和细胞周期进程。此外，APELA敲低可诱导癌细胞系中p53的表达。
我们的研究结果揭示了APELA在促进卵巢肿瘤进展中的潜在致癌作用，并为通过靶向APELA治疗卵巢癌提供了一种可能的治疗策略。
