title: Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells.
abstract: The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the β2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial-mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that β2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as α-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and β-catenin. Isoprenaline stimulation of β2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting β2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression.
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China.|Department of General Surgery, The 266th hospital of Chinese PLA, Chengde, 067000, Hebei, People's Republic of China.|Department of Pathology, Cancer Research Laboratory, Chengde Medical College, Chengde, 067000, Hebei, People's Republic of China.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: 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, People's Republic of China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Geng
authors.affiliation: Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Sun
authors.affiliation: Department of Pathology, Cancer Research Laboratory, Chengde Medical College, Chengde, 067000, Hebei, People's Republic of China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: 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, People's Republic of China.|Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Science, Trauma Center of Postgraduate Medical School, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Fu
authors.affiliation: Department of General Surgery, The 266th hospital of Chinese PLA, Chengde, 067000, Hebei, People's Republic of China. youngcheer2003@foxmail.com.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Chinese PLA General Hospital, 28 Fu Xing Road, Beijing, 100853, People's Republic of China. weibo@vip.163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007545:Isoproterenol
keywords: Cancer stem cells; Epithelial–mesenchymal transition; Gastric cancer; Stress