| Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation. | |
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MedLine Citation:
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PMID: 21515913 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mesothelin (MSLN) overexpression in pancreatic cancer (PC) leads to enhanced cell survival/proliferation and tumor progression. After screening for a number of growth factors/cytokines, we found that the MSLN expression correlated closely with interleukin (IL)-6 in human PC specimens and cell lines. Stably overexpressing MSLN in different PC cell lines (MIA-MSLN and Panc1-MSLN) led to higher IL-6 production. Silencing MSLN by small interfering RNA (siRNA) significantly reduced IL-6 levels. Blocking the observed constitutive activation of nuclear factor-kappaB (NF-κB) with IKK inhibitor wedelolactone in MIA-MSLN cells also reduced IL-6. Silencing IL-6 by siRNA reduced cell proliferation, cell cycle progression and induced apoptosis with significant decrease of c-myc/bcl-2. Interestingly, recombinant IL-6-induced proliferation of MIA-MSLN cells but not MIA-V cells. Although messenger RNA/protein levels of IL-6R did not vary, soluble IL-6R (sIL-6R) was significantly elevated in MIA-MSLN and was reduced by treatment with the TACE/ADAM17 inhibitor TAPI-1, indicating intramembrane IL-6R cleavage and IL-6 trans-signaling may be operative in MIA-MSLN cells. Blocking the IL-6/sIL-6R axis using sIL-6R antibody abrogated basal proliferation/survival as well as recombinant human IL-6-induced cell proliferation. Our data suggest that MSLN-activated NF-κB induces elevated IL-6 expression, which acts as a growth factor to support PC cell survival/proliferation through a novel auto/paracrine IL-6/sIL-6R trans-signaling. In addition, using a panel of PC cells with varying MSLN/IL-6 expressions, we showed that MSLN/IL-6 axis is a major survival axis in PC supporting tumor cell growth under anchorage-dependent and independent conditions. The close correlation between MSLN and IL-6 provides a new rationale for combination therapy for effective control of MSLN-overexpressing PCs. |
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Authors:
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Uddalak Bharadwaj; Christian Marin-Muller; Min Li; Changyi Chen; Qizhi Yao |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-23 |
Journal Detail:
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Title: Carcinogenesis Volume: 32 ISSN: 1460-2180 ISO Abbreviation: Carcinogenesis Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-07-04 Completed Date: 2011-09-15 Revised Date: 2012-09-24 |
Medline Journal Info:
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Nlm Unique ID: 8008055 Medline TA: Carcinogenesis Country: England |
Other Details:
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Languages: eng Pagination: 1013-24 Citation Subset: IM |
Affiliation:
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Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Base Sequence Blotting, Western Cell Line, Tumor Cell Proliferation* Cell Survival DNA Primers GPI-Linked Proteins / genetics, metabolism, physiology* Humans Interleukin-6 / blood, metabolism* NF-kappa B / metabolism Pancreatic Neoplasms / metabolism*, pathology Receptors, Interleukin-6 / metabolism* Signal Transduction* |
| Grant Support | |
ID/Acronym/Agency:
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CA140828/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/GPI-Linked Proteins; 0/Interleukin-6; 0/NF-kappa B; 0/Receptors, Interleukin-6; 0/mesothelin |
| Comments/Corrections | |
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