title: Cancer-related inflammation and Barrett's carcinogenesis: interleukin-6 and STAT3 mediate apoptotic resistance in transformed Barrett's cells.
abstract: Cancer-related inflammation recently has been proposed as a major physiological hallmark of malignancy. Some genetic alterations known to promote cellular proliferation and induce malignant transformation also may participate in an intrinsic inflammatory pathway that produces a cancer-promoting inflammatory microenvironment. Little is known about this intrinsic inflammatory pathway in Barrett's esophagus. We have used a series of nontransformed and transformed human Barrett's epithelial cell lines developed in our laboratory to explore the potential contribution of interleukin (IL)-6 and signal transducer and activator of transcription (STAT3) (key molecules in the intrinsic inflammatory pathway) to Barrett's carcinogenesis. We determined IL-6 mRNA expression and protein secretion and protein expression of activated phospho-STAT3 and its downstream target myeloid cell leukemia (mcl)-1 (Mcl-1). We used an IL-6 blocking antibody and two JAK kinase inhibitors (AG490 and JAK inhibitor I) to assess whether STAT3 activation is IL-6 dependent. We also used small interfering RNAs (siRNAs) to STAT3 and Mcl-1 to assess effects of STAT3 pathway inhibition on apoptosis. Phospho-STAT3 was expressed only by transformed Barrett's cells, which also exhibited higher levels of IL-6 mRNA and of IL-6 and Mcl-1 proteins than nontransformed Barrett's cells. STAT3 phosphorylation could be blocked by IL-6 blocking antibody and by AG490 and JAK inhibitor I. In transformed Barrett's cells, rates of apoptosis following exposure to deoxycholic acid were significantly increased by transfection with siRNAs for STAT3 and Mcl-1. We conclude that activation of the IL-6/STAT3 pathway in transformed Barrett's epithelial cells enables them to resist apoptosis. These findings demonstrate a possible contribution of the intrinsic inflammatory pathway to carcinogenesis in Barrett's esophagus.
authors.affiliation: Department of Medicine, Veterans Affairs North Texas Health Care System, Children’s Hospital, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: Hui Ying
authors.initials: HY
authors.lastname: Zhang
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Huo
authors.forename: Edaire
authors.initials: E
authors.lastname: Cheng
authors.forename: David H
authors.initials: DH
authors.lastname: Wang
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Spechler
authors.forename: Rhonda F
authors.initials: RF
authors.lastname: Souza
mesh_terms: D017209:Apoptosis; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics; D003840:Deoxycholic Acid / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004941:Esophagitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D014443:Tyrosine
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C508600:IL6 protein, human; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003840:Deoxycholic Acid; D014443:Tyrosine; D053612:Janus Kinases; D019098:Telomerase