Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.
Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.
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DOI：
10.1158/1535-7163.mct-14-0077
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发表时间：
2014-12
影响因子：
5.7
通讯作者：
Jove R
中科院分区：
文献类型：
--
作者：
Wen W;Liang W;Wu J;Kowolik CM;Buettner R;Scuto A;Hsieh MY;Hong H;Brown CE;Forman SJ;Horne D;Morgan R;Wakabayashi M;Dellinger TH;Han ES;Yim JH;Jove R
JAK/STAT3是卵巢癌中异常激活的主要信号通路之一，与卵巢癌患者的肿瘤进展和预后不良有关。在这项研究中，我们使用腹膜播散性小鼠模型评估了靶向JAK/STAT3信号转导在卵巢癌中的治疗潜力。我们将转移性人卵巢癌细胞株SKOV3-M-Luc注射到免疫缺陷小鼠的腹膜腔内，从而建立了这种小鼠模型。该模型表现出类似于晚期卵巢癌的表型，包括广泛的腹膜转移和腹水产生。STAT3在人卵巢癌细胞中的结构性激活似乎是由涉及细胞因子IL-6家族和JAK1激酶的自分泌-细胞因子环介导的。ShRNA介导的JAK1或STAT3在卵巢癌细胞中的敲除导致肿瘤生长减少，腹膜播散减少，腹水产生减少，提示STAT3在卵巢癌进展中起关键作用。在这个模型中，当JAK1激酶的小分子抑制剂(JAKI)用于治疗卵巢癌时，也得到了类似的结果。此外，我们还发现在体内外卵巢癌细胞中IL-6的表达水平与STAT3的激活有关，提示IL-6作为一种生物标志物具有潜在的应用前景。总之，我们的结果表明，靶向JAK1/STAT3，使用shRNA敲除或小分子抑制剂，有效地抑制卵巢肿瘤的进展，因此，可能成为治疗晚期卵巢癌的一种潜在的新的治疗方法。
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine-cytokine loop involving the IL-6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL-6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL-6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.