Document Detail


Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation.
MedLine Citation:
PMID:  21515913     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Uddalak Bharadwaj; Christian Marin-Muller; Min Li; Changyi Chen; Qizhi Yao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-23
Journal Detail:
Title:  Carcinogenesis     Volume:  32     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-04     Completed Date:  2011-09-15     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  1013-24     Citation Subset:  IM    
Affiliation:
Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
CA140828/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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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