Cancer-related inflammation and Barrett's carcinogenesis: Interleukin-6 and STAT3 mediate apoptotic resistance in transformed Barrett's cells

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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 cancerpromoting 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.

Original languageEnglish (US)
Pages (from-to)454-460
Number of pages7
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 1 2011

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Keywords

  • Barrett's esophagus
  • Malignant transformation

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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