Wu Yuxian, Zheng Yaqun, Jin Zhijun
Department of Obstetrics and Gynaecology, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201803, PR China.
Department of Obstetrics and Gynaecology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, PR China.
Heliyon. 2023 Jul 28;9(8):e18799. doi: 10.1016/j.heliyon.2023.e18799. eCollection 2023 Aug.
High metastatic potential and resistance to immunotherapy lead to poor survival in patients with ovarian cancer. Angiopoietin-like protein 3 is aberrantly expressed and exerts diverse roles in the progression of several cancers. However, its function in ovarian cancer is unknown. Here, decreased expression of angiopoietin-like protein 3 was observed in ovarian cancer tissues and cells. Moreover, patients with high expression of angiopoietin-like protein 3 had longer overall survival and progression-free survival, indicating a good prognosis for patients. Furthermore, angiopoietin-like protein 3 overexpression inhibited ovarian cancer cell proliferation. Concomitantly, high invasion and the occurrence of epithelial-to-mesenchymal transition of cancer cells were restrained after angiopoietin-like protein 3 elevation. Up-regulation of angiopoietin-like protein 3 expression further increased interleukin 2-treated natural killer cell activation by increasing CD69 expression and production of interferon gamma and tumor necrosis factor-alpha when natural killer cells were co-cultured with ovarian cancer cells. Importantly, angiopoietin-like protein 3 overexpression enhanced natural killer cell-evoked cytotoxicity and apoptosis of cancer cells, indicating the pro-tumor killing ability of angiopoietin-like protein 3 for natural killer cells. Mechanistically, angiopoietin-like protein 3 elevation inhibited activation of the Janus Kinase/Signal transducer and activator of transcription 3 signaling in ovarian cancer cells by inhibiting protein expression of phospho-Janus Kinase 2, phospho-Signal transducer and activator of transcription 3, downstream matrix metallopeptidase 2 and programmed cell death 1. Moreover, blocking the Janus Kinase/Signal transducer and activator of transcription 3 pathway via their inhibitor Stattic restrained ovarian cancer cell proliferation, invasion, epithelial-to-mesenchymal transition, and promoted natural killer cell killing to ovarian cancer cells. Thus, these findings reveal that angiopoietin-like protein 3 may act as an anti-oncogenic regulator to inhibit the metastatic potential and enhance the susceptibility of ovarian cancer cells to natural killer cell-mediated killing. Consequently, angiopoietin-like protein 3 may regulate metastatic potential and immune escape from natural killer cells, indicating a promising therapeutic strategy for ovarian cancer.
高转移潜能和对免疫疗法的抗性导致卵巢癌患者生存率低下。血管生成素样蛋白3异常表达，并在多种癌症进展中发挥多种作用。然而，其在卵巢癌中的功能尚不清楚。在此，研究人员观察到卵巢癌组织和细胞中血管生成素样蛋白3的表达降低。此外，血管生成素样蛋白3高表达的患者总生存期和无进展生存期更长，提示患者预后良好。此外，血管生成素样蛋白3过表达抑制卵巢癌细胞增殖。同时，血管生成素样蛋白3水平升高后，癌细胞的高侵袭性和上皮-间质转化的发生受到抑制。当自然杀伤细胞与卵巢癌细胞共培养时，血管生成素样蛋白3表达上调通过增加CD69表达以及干扰素γ和肿瘤坏死因子-α的产生，进一步增强了白细胞介素2处理的自然杀伤细胞的活化。重要的是，血管生成素样蛋白3过表达增强了自然杀伤细胞诱发的癌细胞细胞毒性和凋亡，表明血管生成素样蛋白3对自然杀伤细胞具有促肿瘤杀伤能力。机制上，血管生成素样蛋白3水平升高通过抑制磷酸化的Janus激酶2、磷酸化的信号转导子和转录激活子3、下游基质金属肽酶2和程序性细胞死亡蛋白1的蛋白表达，抑制卵巢癌细胞中Janus激酶/信号转导子和转录激活子3信号通路的激活。此外，通过其抑制剂Stattic阻断Janus激酶/信号转导子和转录激活子3通路可抑制卵巢癌细胞增殖、侵袭、上皮-间质转化，并促进自然杀伤细胞对卵巢癌细胞的杀伤。因此，这些发现揭示血管生成素样蛋白3可能作为一种抗癌调节因子，抑制转移潜能并增强卵巢癌细胞对自然杀伤细胞介导杀伤的敏感性。因此，血管生成素样蛋白3可能调节转移潜能和自然杀伤细胞介导的免疫逃逸，提示其在卵巢癌治疗中具有广阔前景。
