Abstract
Ovarian cancer is the leading cancer-related cause of death in women worldwide. It is of great relevance to understand the mechanism responsible for tumor progression and identify unique oncogenesis markers for a higher chance of preventing this malignant disease. The high-expression OC-2 gene has been shown to be a potential candidate for regulating oncogenesis and angiogenesis in ovarian cancer. Hence, we wished to investigate the impact of OC-2 gene on ovarian cancer aggressiveness. CRISPR/Cas9, a gene editing tool, allows for direct ablation of OC-2 at the genomic level, and we successfully generated OC-2 KO cell lines from SKOV3 and CAOV3 cells. In an apoptosis assay, OC-2 KO induced the apoptosis activation of tumor cells, with the up-regulation of Bax/Caspase-8 and the down-regulation of Bcl-2. Consequently, the proliferation, migration, and invasion of OC-2 KO cell lines were significantly inhibited. Assays of qRT-PCR and Western blotting showed that the expression levels of pro-angiogenic growth factors VEGFA, FGF2, HGF, and HIF-1α and the activation of Akt/ERK pathways were significantly down-regulated at the loss of OC-2. In the xenograft model, OC-2 KO potently suppressed the subcutaneous tumor growth, with the inhibition exceeding 56%. The down-regulation of CD31 and relevant pro-angiogenic growth factors were observed in OC-2 KO tumor tissues. Taken together, OC-2 depletion negatively regulated the ovarian cancer progression possibly by apoptosis activation and angiogenesis inhibition. This work revealed a pivotal regulator of apoptosis and angiogenesis networks in ovarian cancer, and we applied the CRISPR/Cas9 system to the transcription factor pathway for developing a broad-acting anti-tumor gene therapy.
Highlights
The double-strand DNA of the target area can be cleaved by Cas9 rabbit polyclonal anti-OC-2 (1:500) and anti-CD31
The results indicated that OC-2 could positively regulate relevant proangiogenic growth factor expression and the Akt/ERK pathways
By using CRISPR/Cas9 technology, we proved that OC-2 played a key role in cell apoptosis, proliferation, migration, invasion, and tumor angiogenesis of ovarian cancer
Summary
Inhibits the Tumor Growth and Angiogenesis of Ovarian Cancer. Ovarian cancer is one of the most common types of malignancy for females, after cervical and endometrial cancer [1, 2]. Since there are little typical symptoms at the early stage of ovarian cancer, patients at the late stage will be extremely hard to treat due to extensive abdominal metastasis [3]. The key biomarkers for ovarian cancer diagnosis and treatment are demanded in spite of different heterogeneity and genotypes [4, 5]. The development of ovarian cancer would be inconceivable without microvessels providing nutrients and transferring metabolins [6]. Tumor and endothelial cells secrete various vascular factors to aggravate tumor
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