LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation
LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen-Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation
复制标题
LIMS1 通过增强 HIF1A 蛋白翻译来促进缺氧葡萄糖条件下胰腺癌细胞的存活。
DOI：
10.1158/1078-0432.ccr-18-3533
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发表时间：
2019-07-01
影响因子：
11.5
通讯作者：
Ren, He
中科院分区：
文献类型：
--
作者：
Huang, Chongbiao;Li, Yang;Ren, He
目的：氧糖剥夺是实体瘤的共同特征。癌细胞适应恶劣微环境的调控网络仍不清楚。我们确定了LIM和衰老细胞抗原样结构域蛋白1（LIMS 1）在氧-葡萄糖剥夺conditions.Experimental Design癌细胞存活中的机制作用：通过免疫组化染色和分析三种人类实体瘤的癌症基因组图谱中的mRNA表达谱来确定LIMS 1的表达水平。通过分子生物学和细胞生物学方法研究LIMS 1在肿瘤细胞代谢和生长中的作用。结果：LIMS 1在胰腺导管腺癌（PDAC）中的表达显著升高。LIMS 1高表达与肿瘤TNM分期及预后有关。LIMS 1表达增加是肿瘤细胞在氧糖剥夺条件下存活的关键。从机制上讲，LIMS 1增强了GLUT 1表达和膜转位，这有助于肿瘤细胞适应葡萄糖剥夺应激。此外，LIMS 1通过激活AKT/mTOR信号促进HIF 1A蛋白翻译，而低氧诱导因子1（HIF 1）反式激活LIMS 1转录，从而在PDAC细胞适应缺氧应激中形成正反馈环。用jetPEI纳米载体递送的抗LIMS 1 siRNA抑制LIMS 1显著增加了细胞死亡并抑制了肿瘤生长。结论：LIMS 1通过激活AKT/mTOR信号传导和增强HIF 1A蛋白翻译促进胰腺癌细胞在氧-葡萄糖剥夺条件下的存活。LIMS 1对于肿瘤适应氧葡萄糖剥夺条件至关重要，并且是癌症治疗的有希望的治疗靶点。
Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions.Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics.Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expression was pivotal for tumor cells to survive in the oxygenglucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth.Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygenglucose deprivation conditions and is a promising therapeutic target for cancer treatment.