胰岛素受体底物-1缺乏在KRAS突变型肺腺癌中驱动促炎表型。
Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma.
作者信息
Metz Heather E, Kargl Julia, Busch Stephanie E, Kim Kyoung-Hee, Kurland Brenda F, Abberbock Shira R, Randolph-Habecker Julie, Knoblaugh Sue E, Kolls Jay K, White Morris F, Houghton A McGarry
机构信息
Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Department of Pathology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Institute of Experimental and Clinical Pharmacology, Medical University of Graz, 8036 Graz, Austria;
出版信息
Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8795-800. doi: 10.1073/pnas.1601989113. Epub 2016 Jul 20.
Insulin receptor substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many pathways activated in lung cancer. It has been assumed that IRS-1 promotes tumor growth through its ability to activate PI3K signaling downstream of the insulin-like growth factor receptor. Surprisingly, tumors with reduced IRS-1 staining in a human lung adenocarcinoma tissue microarray displayed a significant survival disadvantage, especially within the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant subgroup. Accordingly, adenoviral Cre recombinase (AdCre)-treated LSL-Kras/Irs-1(fl/fl) (Kras/Irs-1(-/-)) mice displayed increased tumor burden and mortality compared with controls. Mechanistically, IRS-1 deficiency promotes Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling via the IL-22 receptor, resulting in enhanced tumor-promoting inflammation. Treatment of Kras/Irs-1(+/+) and Kras/Irs-1(-/-) mice with JAK inhibitors significantly reduced tumor burden, most notably in the IRS-1-deficient group.
胰岛素受体底物1（IRS-1）是一种信号衔接蛋白，可与肺癌中激活的多种信号通路相互作用。一直以来人们认为，IRS-1通过激活胰岛素样生长因子受体下游的PI3K信号传导来促进肿瘤生长。令人惊讶的是，在人肺腺癌组织芯片中IRS-1染色减少的肿瘤显示出明显的生存劣势，尤其是在 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）突变亚组中。因此，与对照组相比，经腺病毒 Cre 重组酶（AdCre）处理的 LSL-Kras/Irs-1(fl/fl)（Kras/Irs-1(-/-)）小鼠表现出肿瘤负担增加和死亡率上升。从机制上讲，IRS-1 缺陷通过白细胞介素-22 受体促进 Janus 激酶/信号转导和转录激活因子（JAK/STAT）信号传导，导致促肿瘤炎症增强。用 JAK 抑制剂治疗 Kras/Irs-1(+/+)和 Kras/Irs-1(-/-)小鼠可显著降低肿瘤负担，在 IRS-1 缺陷组中最为明显。
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