LIF/LIFR 轴在癌症中的多效性作用、功能和靶向治疗：旧观念的新视角。
The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights.
机构信息
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
Evestra, Inc, San Antonio, TX 78245, USA.
出版信息
Biochim Biophys Acta Rev Cancer. 2022 Jul;1877(4):188737. doi: 10.1016/j.bbcan.2022.188737. Epub 2022 Jun 6.
Abstract
The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
摘要
白血病抑制因子 (LIF)及其同源受体 (LIFR) 的失调与多种癌症的发生、进展和转移有关。LIF 在癌症中发挥重要的促肿瘤作用，而 LIFR 则作为促肿瘤和抑肿瘤因子发挥作用。上皮细胞和基质细胞通过自分泌和旁分泌信号机制分泌 LIF，该机制与 LIFR 结合，随后与辅助受体糖蛋白 130 (gp130) 结合，激活 JAK/STAT1/3、PI3K/AKT、mTORC1/p70s6K、Hippo/YAP 和 MAPK 信号通路。临床上，激活 LIF/LIFR 轴与不良预后和抗癌治疗耐药有关。本文综述了 LIFR 的结构和配体、LIF/LIFR 信号在发育生物学、干细胞、癌症干细胞、LIFR 的遗传学和表观遗传学、长非编码 RNA 和 microRNA 对 LIFR 的调控以及 LIF/LIFR 信号在癌症中的作用。最后，讨论了在临床前和早期临床试验中优先阻断 LIF 与 LIFR 相互作用的中和抗体和小分子抑制剂，以及针对 LIFR 的拮抗剂。
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