Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.
Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.
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DOI：
10.3390/cancers14215400
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发表时间：
2022-11-02
期刊：
影响因子：
5.2
通讯作者：
Viswanadhapalli, Suryavathi
中科院分区：
文献类型：
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作者：
Blankenship, Logan;Pratap, Uday P.;Yang, Xue;Liu, Zexuan;Altwegg, Kristin A.;Santhamma, Bindu;Ramasamy, Kumaraguruparan;Konda, Swapna;Chen, Yidong;Lai, Zhao;Zheng, Siyuan;Sareddy, Gangadhara R.;Valente, Philip T.;Kost, Edward R.;Nair, Hareesh B.;Tekmal, Rajeshwar R.;Vadlamudi, Ratna K.;Viswanadhapalli, Suryavathi
关键词：
在这项研究中，我们利用全局 RNA 测序来阐明肥胖状况促进子宫内膜样子宫内膜癌 (EEC) 进展的分子机制。我们的结果表明，肥胖状况上调 LIF/LIFR 信号传导，并且从肥胖患者收集的 EEC 肿瘤具有高水平的 LIF。机制研究表明，LIF/LIFR 信号在肥胖驱动的 EEC 进展中发挥着重要作用，而 LIFR 抑制剂 EC359 有潜力抑制肥胖患者中由肥胖增加驱动的肿瘤进展。子宫内膜癌（EC）是女性第四大常见癌症，一半的子宫内膜样癌（EEC）病例可归因于肥胖。然而，肥胖驱动的 EEC 的潜在机制仍不清楚。在这项研究中，我们研究了 LIF 信号传导是否在肥胖驱动的 EEC 进展中发挥作用。对脂肪条件培养基 (ADP-CM) 刺激的 EEC 细胞的 RNA-seq 分析显示，LIF/LIFR 介导的信号通路（包括 JAK/STAT 和白细胞介素通路）上调。对从肥胖患者收集的正常和 EEC 组织进行的免疫组织化学分析表明，与正常子宫内膜相比，EEC 组织中 LIF 的表达上调。用 ADP-CM 处理原代和已建立的 EEC 细胞可增加 LIF 及其受体 LIFR 的表达，并增强 EEC 细胞的增殖。用 LIFR 抑制剂 EC359 处理 EEC 细胞，消除了 ADP-CM 诱导的集落形成和细胞活力，并减少了 EEC 类器官的生长。使用蛋白质印迹、RT-qPCR 和报告基因检测的机制研究证实，ADP-CM 激活 LIF/LIFR 下游信号传导，而添加 EC359 可以有效减弱这种信号传导。在异种移植试验中，脂肪细胞的共同植入显着增强了 EEC 异种移植肿瘤的生长。此外，用 EC359 治疗可显着减弱体内脂肪细胞诱导的 EEC 进展。总的来说，我们的数据支持这样的前提：LIF/LIFR 信号在肥胖驱动的 EEC 进展中发挥重要作用，而 LIFR 抑制剂 EC359 有潜力抑制脂肪细胞驱动的肿瘤进展。
In this study, we utilized global RNA-seq to elucidate the molecular mechanisms by which obese conditions promote progression of endometrioid endometrial cancer (EEC). Our results suggest that obese conditions upregulate LIF/LIFR signaling, and EEC tumors collected from obese patients have high levels of LIF. Mechanistic studies suggest that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor, EC359, has the potential to suppress the tumor progression driven by increased adiposity found in obese patients. Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM induced colony formation andcell viability and decreased growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.
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影响因子：
4.6
作者：
Nickel A;Blücher C;Kadri OA;Schwagarus N;Müller S;Schaab M;Thiery J;Burkhardt R;Stadler SC
通讯作者：
Stadler SC
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
白血病抑制因子可以通过PI3K/AKT依赖性MCL-1激活来保护胆管癌细胞免受药物诱导的凋亡。
影响因子：
--
作者：
Morton SD;Cadamuro M;Brivio S;Vismara M;Stecca T;Massani M;Bassi N;Furlanetto A;Joplin RE;Floreani A;Fabris L;Strazzabosco M
通讯作者：
Strazzabosco M
影响因子：
1.6
作者：
Celik, Engin;Kizildag Yirgin, Inci;Salihoglu, Mehmet Y.
通讯作者：
Salihoglu, Mehmet Y.
影响因子：
4.8
作者：
Gonzalez, RR;Rueda, BR;Leavis, PC
通讯作者：
Leavis, PC