title: Isoproterenol regulates CD44 expression in gastric cancer cells through STAT3/MicroRNA373 cascade.
abstract: Gastric cancer is a heterogeneous disease, and stem cells are thought to be the cell of origin contributed to this malignancy. However, studies with breast and intestinal cancer models show non-stem cancer cells can change their surface phenotype and convert into tumor-initiating cells induced by the signals emanating from surrounding tumor microenvironment. Here, we show that CD44 was expressed at different levels in gastric metastases compared with primary tumors, and also negatively correlated with the expression of miR-373. By using a panel of human gastric cancer cell lines and analysis of archived data from The Cancer Genomics Altas (TCGA) database, we verified the inverse correlation between CD44 and miR-373. Furthermore, the stress-associated hormone, isoproterenol, could increase the expression levels of "stem"-related proteins, such as CD44, Nanog, and Rex-1, and induce chemoresistance in gastric cancer cells. Transfection with miR-373, however, reversed not only the effect of isoproterenol on phenotypic conversion but also its effect on drug sensitivity. Isoproterenol triggered downstream target STAT3 mainly through β2-adrenergic receptors (β2-ARs). Activated STAT3 functioned as a miR-373 suppressor by binding to its promoter, which forms a positive feedback circuit to maintain CD44 activity and direct the phenotypic conversion from CD44(low) to CD44(hi) expression. Our data suggest an important role of β2-AR/STAT3/miR-373 signaling on the transformation of gastric cancer cells. This study also suggests a potential therapeutic or preventive treatment for gastric cancer patients who are especially prone to psychosocial stress.
authors: Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, PR China.
authors: Bo
authors: B
authors: Wei
authors: Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, PR China.
authors: Xiaoyan
authors: X
authors: Sun
authors: Key Research Laboratory of Tissue Repair and Regeneration of PLA, and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, PR China.
authors: Zhijun
authors: Z
authors: Geng
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, PR China.
authors: Ming
authors: M
authors: Shi
authors: Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, PR China.
authors: Zhida
authors: Z
authors: Chen
authors: Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, PR China.
authors: Lin
authors: L
authors: Chen
authors: Institutes of Pharmacology and Toxicology, Academy of Military Medical Sciences, 27 Taiping Road, Beijing 100850, PR China. Electronic address: yonganw@126.com.
authors: Yongan
authors: Y
authors: Wang
authors: Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing 100853, PR China. Electronic address: fuxiaobing@vip.sina.com.
authors: Xiaobing
authors: X
authors: Fu
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000556:secondary*; D014407:Tumor Cells, Cultured
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C527114:MIRN373 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cancer stem cells; Gastric cancer; Metastasis; MicroRNA; Stress