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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients
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p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients

机译：p21激活的激酶4调节卵巢癌细胞的增殖，迁移和侵袭，并导致患者预后不良

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摘要

Ovarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser~(474), with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear ceil histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clin-icopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.
机译：卵巢癌是一种致命的妇科恶性肿瘤，为了提高生存率，重要的是确定新的预后和治疗靶标。在这项研究中，我们介绍了p21激活激酶4（Pak4）在卵巢癌进展中的作用。我们显示Pak4表达及其激活形式，磷酸化（p）-Pak4 Ser〜（474）与卵巢癌转移，更短的总体生存率和无病生存率，晚期和高级别癌症，浆液性之间存在显着关联/清除细胞组织学亚型，降低化学敏感性。在卵巢癌细胞系中也观察到Pak4过表达。在体外和体内均在卵巢癌细胞的细胞核和细胞质中检测到Pak4和p-Pak4的表达。卵巢癌细胞系中Pak4的稳定敲低导致细胞迁移，侵袭和增殖减少，以及c-Src，ERK1 / 2和表皮生长因子受体（EGFR）激活降低，基质金属蛋白酶2（MMP2）表达降低。相反，Pak4过表达以c-Src，MEK-1，MMP2和激酶依赖性方式促进卵巢癌细胞迁移和侵袭，并通过控制cyclin D1和CDC25A表达的Pak4 / c-Src / EGFR途径诱导细胞增殖。 。 Pak4的稳定敲低也阻碍了裸鼠中肿瘤的生长和扩散。该报告揭示了Pak4与重要的临床病理学参数之间的关联，表明Pak4是卵巢癌的重要预后标志物和潜在的治疗分子靶标。 Pak4和EGFR之间可能暗含的串扰表明，将EGFR和Pak4双重靶向是治疗癌症的独特疗法。

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    Michelle K. Y. Siu; Hoi Yan Chan; Daniel S. H. Kong; Esther S. Y. Wong; Oscar G. W. Wong; Hextan Y. S. Ngan; Kar Fai Tam; Hongquan Zhang; Zhilun Li; Queeny K. Y. Chan; Sai Wah Tsao; Staffan Stroemblad; Annie N. Y. Cheung;

  • 作者单位

    Departments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Obstetrics and Gynecology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Obstetrics and Gynecology, University of Hong Kong, Pokfulam, Hong Kong;

    rnCenter for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Stockholm, Sweden;

    rnCenter for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Stockholm, Sweden;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

    rnDepartments of Anatomy, University of Hong Kong, Pokfulam, Hong Kong;

    rnCenter for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83, Stockholm, Sweden;

    rnDepartments of Pathology, University of Hong Kong, Pokfulam, Hong Kong;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    prognostic marker; therapeutic target;

    机译：预后指标治疗目标;

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