PMID- 24520077
OWN - NLM
STAT- MEDLINE
DCOM- 20140607
LR  - 20211021
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 74
IP  - 7
DP  - 2014 Apr 1
TI  - Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin 
      and TGF-alpha: impact on gastrointestinal cancers driven by secondary bile acids.
PG  - 2062-72
LID - 10.1158/0008-5472.CAN-13-2329 [doi]
AB  - Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development 
      of several gastrointestinal malignancies, but how they mediate this effect is 
      unclear. In this study, we offer evidence of a mechanism involving ectodomain 
      shedding of the EGFR ligands amphiregulin (AREG) and TGF-alpha, which rely upon the 
      cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates 
      in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and 
      tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma 
      (PDAC). TACE and AREG, but not TGF-alpha, were overexpressed in both colorectal 
      cancer and PDAC tissues compared with normal tissues. Exposure of colorectal 
      cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the 
      cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated 
      protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient 
      to attenuate DCA-induced AREG, but not TGF-alpha shedding. We also examined a role 
      for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA 
      interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, 
      and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and 
      attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our 
      findings define an AREG-dependent signaling pathway that mediates the oncogenic 
      effects of secondary BAs in gastrointestinal cancers, the targeting of which may 
      enhance therapeutic responses in their treatment.
CI  - (c)2014 AACR.
FAU - Nagathihalli, Nagaraj S
AU  - Nagathihalli NS
AD  - Authors' Affiliations: Departments of Surgery, Cancer Biology, Pathology, and 
      Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee; 
      Department of Pharmaceutical Sciences, University of Kentucky, Lexington, 
      Kentucky; and Department of Medicine, Washington University School of Medicine, 
      St. Louis, Missouri.
FAU - Beesetty, Yugandhar
AU  - Beesetty Y
FAU - Lee, Wooin
AU  - Lee W
FAU - Washington, M Kay
AU  - Washington MK
FAU - Chen, Xi
AU  - Chen X
FAU - Lockhart, A Craig
AU  - Lockhart AC
FAU - Merchant, Nipun B
AU  - Merchant NB
LA  - eng
GR  - R01 CA161976/CA/NCI NIH HHS/United States
GR  - P50 CA095103/CA/NCI NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - CA161976/CA/NCI NIH HHS/United States
GR  - P50 95103/PHS HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - P30DK058404/DK/NIDDK NIH HHS/United States
GR  - 5P30DK058404-08/DK/NIDDK NIH HHS/United States
GR  - 5P30 CA068485-1/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140211
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Bile Acids and Salts)
RN  - 0 (CCND1 protein, human)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (GPBAR1 protein, human)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 005990WHZZ (Deoxycholic Acid)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
SB  - IM
MH  - ADAM Proteins/metabolism
MH  - ADAM17 Protein
MH  - Amphiregulin
MH  - Bile Acids and Salts/*toxicity
MH  - Cyclin D1/genetics
MH  - Deoxycholic Acid/toxicity
MH  - EGF Family of Proteins
MH  - ErbB Receptors/physiology
MH  - Gastrointestinal Neoplasms/*chemically induced
MH  - Glycoproteins/*physiology
MH  - HCT116 Cells
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*physiology
MH  - Pancreas/metabolism
MH  - Phosphorylation
MH  - Receptors, G-Protein-Coupled/physiology
MH  - STAT3 Transcription Factor/physiology
MH  - Transforming Growth Factor alpha/*physiology
MH  - src-Family Kinases/metabolism
PMC - PMC3975694
MID - NIHMS566974
EDAT- 2014/02/13 06:00
MHDA- 2014/06/08 06:00
PMCR- 2015/04/01
CRDT- 2014/02/13 06:00
PHST- 2014/02/13 06:00 [entrez]
PHST- 2014/02/13 06:00 [pubmed]
PHST- 2014/06/08 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - 0008-5472.CAN-13-2329 [pii]
AID - 10.1158/0008-5472.CAN-13-2329 [doi]
PST - ppublish
SO  - Cancer Res. 2014 Apr 1;74(7):2062-72. doi: 10.1158/0008-5472.CAN-13-2329. Epub 
      2014 Feb 11.