School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
Cell Death Dis. 2022 Apr 5;13(4):304. doi: 10.1038/s41419-022-04756-2.
Partitioning-defective protein 6 (Par6) family proteins have been demonstrated to be closely associated with the occurrence and development of cancers. It is well accepted that dysregulation of epithelial-mesenchymal transition (EMT) greatly contributes to carcinogenesis and metastases of ovarian cancer. So far, the roles of Par6 in EMT of ovarian cancer are not clear. Functional experiments were carried out to study the roles of PARD6A in EMT of ovarian cancer in vitro and in vivo, and EMT pathways potentially affected by PARD6A expression were screened. We found that PARD6A was significantly highly expressed in tissues of ovarian cancer patients in III-IV stages, poorly differentiated or with lymphatic metastases versus I-II stages, moderately or well differentiated, or without lymphatic metastases, respectively. PARD6A knockdown suppressed EMT of SKOV3 and A2780 cells in vitro and ovarian cancer metastasis in vivo, while overexpression of PARD6A promoted EMT in HO8910 and OVCAR8 cells. It was indicated that PARD6A affected EMT of ovarian cancer cells through SNAIL1 signaling pathway and subsequently modulated the expression of VIMENTIN and E-cadherin, which was further confirmed by knockdown and overexpression of SNAIL1 experiments. PARD6A was also demonstrated to regulate expression of SNAIL1 by modulating integrin β1 and ILK proteins, specifically it was shown that the transcription of SNAIL1 was regulated by ILK in this study. In addition, expression of ILK in ovarian cancer tissues was demonstrated to be correlated with tumor stages and lymphatic metastases clinically. In this study, we identified a novel role of PARD6A as an inducer of cell migration and invasion, which is likely to play an important role in metastasis of ovarian cancer. The molecular pathways of EMT mediated by PARD6A-Integrin β1-ILK-SNAIL1 and finally implemented by E-cadherin and VIMENTIN may provide a novel strategy for drug development for ovarian cancer therapy in the near future.
Par6 家族蛋白已被证实与癌症的发生和发展密切相关。上皮-间质转化 (EMT) 的失调极大地促进了卵巢癌的发生和转移，这一观点已被广泛接受。迄今为止，Par6 在卵巢癌细胞 EMT 中的作用尚不清楚。本研究通过体外和体内功能实验研究了 PARD6A 在卵巢癌细胞 EMT 中的作用，并筛选了可能受 PARD6A 表达影响的 EMT 途径。我们发现，PARD6A 在 III-IV 期卵巢癌患者的组织中表达显著升高，与 I-II 期相比，组织分化差或有淋巴转移的患者 PARD6A 表达更高，而组织分化较好或无淋巴转移的患者 PARD6A 表达较低。PARD6A 敲低抑制 SKOV3 和 A2780 细胞的 EMT 以及体内卵巢癌转移，而过表达 PARD6A 则促进 HO8910 和 OVCAR8 细胞的 EMT。这表明 PARD6A 通过 SNAIL1 信号通路影响卵巢癌细胞 EMT，进而调节 VIMENTIN 和 E-cadherin 的表达，通过 SNAIL1 敲低和过表达实验进一步证实了这一点。PARD6A 还通过调节整合素 β1 和 ILK 蛋白来调节 SNAIL1 的表达，具体来说，本研究表明 SNAIL1 的转录受 ILK 调节。此外，卵巢癌组织中 ILK 的表达与临床肿瘤分期和淋巴转移有关。在本研究中，我们确定了 PARD6A 作为细胞迁移和侵袭诱导因子的新作用，这可能在卵巢癌转移中发挥重要作用。PARD6A-整合素 β1-ILK-SNAIL1 介导的 EMT 分子途径，最终通过 E-cadherin 和 VIMENTIN 实施，可能为卵巢癌治疗的药物研发提供新的策略。
