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信号转导和转录激活因子3作为醛脱氢酶阳性及CD44+/CD24+干细胞样胰腺癌细胞中的潜在治疗靶点。

STAT3 as a potential therapeutic target in ALDH+ and CD44+/CD24+ stem cell-like pancreatic cancer cells.

作者信息

Lin Li, Jou David, Wang Yina, Ma Haiyan, Liu Tianshu, Fuchs James, Li Pui-Kai, Lü Jiagao, Li Chenglong, Lin Jiayuh

机构信息

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43205, USA.

出版信息

Int J Oncol. 2016 Dec;49(6):2265-2274. doi: 10.3892/ijo.2016.3728. Epub 2016 Oct 12.

DOI:10.3892/ijo.2016.3728
PMID:27748818
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5118001/
Abstract

Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer including pancreatic cancer. Whether STAT3 is activated in stem cell-like pancreatic cancer cells and the effect of STAT3 inhibition, is still unknown. Flow cytometry was used to isolate pancreatic cancer stem-like cells which are identified by both aldehyde dehydrogenase (ALDH)-positive (ALDH+) as well as cluster of differentiation (CD) 44-positive/CD24-positive subpopulations (CD44+/CD24+). STAT3 activation and the effects of STAT3 inhibition by STAT3 inhibitors, LLL12, FLLL32, and Stattic in ALDH+ and CD44+/CD24+ cells were examined. Our results showed that ALDH+ and CD44+/CD24+ pancreatic cancer stem-like cells expressed higher levels of phosphorylated STAT3, an active form of STAT3, compared to ALDH-negative (ALDH-) and CD44-negative/CD24-negative (CD44-/CD24-) pancreatic cancer cells, suggesting that STAT3 is activated in pancreatic cancer stem-like cells. Small molecular STAT3 inhibitors inhibited STAT3 phosphorylation, STAT3 downstream target gene expression, cell viability, and tumorsphere formation in ALDH+ and CD44+/CD24+ cells. Our results indicate that STAT3 is a novel therapeutic target in pancreatic cancer stem-like cells and inhibition of activated STAT3 in these cells by STAT3 inhibitors may offer an effective treatment for pancreatic cancer.

摘要

信号转导子和转录激活子3（STAT3）的持续激活在包括胰腺癌在内的多种癌症中普遍存在。STAT3在胰腺癌细胞干性样细胞中是否被激活以及STAT3抑制的效果仍不清楚。采用流式细胞术分离胰腺癌干性样细胞，这些细胞通过醛脱氢酶（ALDH）阳性（ALDH+）以及分化簇（CD）44阳性/CD24阳性亚群（CD44+/CD24+）来鉴定。检测了ALDH+和CD44+/CD24+细胞中STAT3的激活情况以及STAT3抑制剂LLL12、FLLL32和Stattic对STAT3的抑制作用。我们的结果显示，与ALDH阴性（ALDH-）和CD44阴性/CD24阴性（CD44-/CD24-）胰腺癌细胞相比，ALDH+和CD44+/CD24+胰腺癌干性样细胞表达更高水平的磷酸化STAT3（STAT3的活性形式），这表明STAT3在胰腺癌干性样细胞中被激活。小分子STAT3抑制剂抑制了ALDH+和CD44+/CD24+细胞中STAT3的磷酸化、STAT3下游靶基因表达、细胞活力以及肿瘤球形成。我们的结果表明，STAT3是胰腺癌干性样细胞中的一个新的治疗靶点，STAT3抑制剂抑制这些细胞中激活的STAT3可能为胰腺癌提供有效的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/d719e2aec9d5/IJO-49-06-2265-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/79bf57edb542/IJO-49-06-2265-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/2769122571d4/IJO-49-06-2265-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/dca045aa8d39/IJO-49-06-2265-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/1866b041b8e6/IJO-49-06-2265-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/b7bdef47eae2/IJO-49-06-2265-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/d719e2aec9d5/IJO-49-06-2265-g05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/79bf57edb542/IJO-49-06-2265-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/2769122571d4/IJO-49-06-2265-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/dca045aa8d39/IJO-49-06-2265-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/1866b041b8e6/IJO-49-06-2265-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/b7bdef47eae2/IJO-49-06-2265-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a145/5118001/d719e2aec9d5/IJO-49-06-2265-g05.jpg

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