Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation (original) (raw)

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1Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery

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1Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery

2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA

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1Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery

3Present address: The Vivian L. Smith Department of Neurosurgery, The University of Texas Health Science Center at Houston, Medical School, 6431 Fannin Street, MSB 3.000 Houston, TX 77030, USA

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1Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery

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1Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery

2Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA

*To whom correspondence should be addressed. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Mail stop BCM 391, Houston, TX 77030, USA. Tel: +1 713 798 1765, Fax+1 713 798 6633; Email: qizhiyao@bcm.edu

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Received:

17 September 2010

Revision received:

20 March 2011

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Uddalak Bharadwaj, Christian Marin-Muller, Min Li, Changyi Chen, Qizhi Yao, Mesothelin overexpression promotes autocrine IL-6/sIL-6R trans-signaling to stimulate pancreatic cancer cell proliferation, Carcinogenesis, Volume 32, Issue 7, July 2011, Pages 1013–1024, https://doi.org/10.1093/carcin/bgr075
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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.

© The Author 2011. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Topic:

• signal transduction
• cell proliferation
• interleukin-6
• protein overexpression
• mesothelin
• squamous intraepithelial lesions
• pmel17

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