Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. Implications: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.

中文翻译：

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来自转移生态位的信号通过 miR-4454 下调调节早期和晚期卵巢癌转移


卵巢癌的治疗因广泛转移而受到限制，但人们对此仍知之甚少。我们在与转移微环境的有效相互作用的背景下研究了转移定植的关键步骤，目的是确定关键的调节因子。通过使用早期卵巢癌转移的器官型 3D 培养模型与 42 名卵巢癌患者的匹配原发性和转移性肿瘤的 miRNA 表达分析相结合，我们确定 miR-4454 是卵巢癌患者早期定植和晚期转移的关键调节因子。卵巢癌。 miR-4454通过微环境成纤维细胞的旁分泌信号在转移性卵巢癌细胞中下调，促进卵巢癌细胞的迁移、侵袭、增殖和克隆生长以及穿透大网膜外层的能力。 miR-4454 的稳定过表达可减少卵巢癌异种移植物的转移。其作用机制是通过上调其靶标、富含半胱氨酸的酸性分泌蛋白 (SPARC) 和 BCL2 相关的 athanogene 5 (BAG5)，激活粘着斑激酶 (FAK) 信号传导，通过其稳定性促进突变型 p53 获得功能，并抑制细胞凋亡。由于微环境诱导的 miR-4454 下调对于早期和晚期转移至关重要，因此靶向它可能是一种有前途的治疗方法。意义：本研究鉴定了一种 miRNA，miR-4454，它会被微环境信号下调，并通过其对 FAK 激活、突变 p53 稳定和细胞凋亡抑制的影响促进早期和晚期卵巢癌转移。