PMID- 16778186
OWN - NLM
STAT- MEDLINE
DCOM- 20060810
LR  - 20181201
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 12
DP  - 2006 Jun 15
TI  - Amphiregulin contributes to the transformed phenotype of human hepatocellular 
      carcinoma cells.
PG  - 6129-38
AB  - Hepatocellular carcinoma is a major cause of cancer-related deaths. Current 
      treatments are not effective, and the identification of relevant pathways and 
      novel therapeutic targets are much needed. Increasing evidences point to the 
      activation of the epidermal growth factor receptor (EGFR) as an important 
      mechanism in the development of hepatocarcinoma. We previously described that 
      amphiregulin (AR), a ligand of the EGFR, is not expressed in healthy liver but is 
      up-regulated during chronic liver injury, the background on which most liver 
      tumors develop. Now, we have studied the expression and role of AR in human 
      hepatocarcinoma. AR expression and function was studied in human liver tumors and 
      cell lines. AR is expressed in human hepatocellular carcinoma tissues and cell 
      lines and behaves as a mitogenic and antiapoptotic growth factor for 
      hepatocarcinoma cells. We provide several lines of evidence, including AR 
      silencing by small interfering RNAs and inhibition of amphiregulin by 
      neutralizing antibodies, showing the existence of an AR-mediated autocrine loop 
      that contributes to the transformed phenotype. Indeed, interference with 
      endogenous AR production resulted in reduced constitutive EGFR signaling, 
      inhibition of cell proliferation, anchorage-independent growth, and enhanced 
      apoptosis. Moreover, knockdown of AR potentiated transforming growth factor-beta 
      and doxorubicin-induced apoptosis. Conversely, overexpression of AR in SK-Hep1 
      cells enhanced their proliferation rate, anchorage-independent growth, drug 
      resistance, and in vivo tumorigenic potential. These observations suggest that AR 
      is involved in the acquisition of neoplastic traits in the liver and thus 
      constitutes a novel therapeutic target in human hepatocarcinoma.
FAU - Castillo, Josefa
AU  - Castillo J
AD  - Division of Hepatology and Gene Therapy, Center for Applied Medical Research, 
      University of Navarra, Pamplona, Spain.
FAU - Erroba, Elena
AU  - Erroba E
FAU - Perugorria, Maria J
AU  - Perugorria MJ
FAU - Santamaria, Monica
AU  - Santamaria M
FAU - Lee, David C
AU  - Lee DC
FAU - Prieto, Jesus
AU  - Prieto J
FAU - Avila, Matias A
AU  - Avila MA
FAU - Berasain, Carmen
AU  - Berasain C
LA  - eng
GR  - CA 43793/CA/NCI NIH HHS/United States
GR  - CA 49793/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Areg protein, mouse)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - TC62B68RSL (4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline)
SB  - IM
MH  - Aged
MH  - Amphiregulin
MH  - Animals
MH  - Apoptosis/physiology
MH  - Carcinoma, Hepatocellular/metabolism/*pathology
MH  - Cell Growth Processes/physiology
MH  - Cell Line, Tumor
MH  - Cell Transformation, Neoplastic/metabolism/*pathology
MH  - EGF Family of Proteins
MH  - ErbB Receptors/antagonists & inhibitors/metabolism
MH  - Glycoproteins/antagonists & inhibitors/*metabolism/pharmacology
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/*metabolism/pharmacology
MH  - Liver Neoplasms/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Middle Aged
MH  - Quinazolines/pharmacology
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction
MH  - Up-Regulation
EDAT- 2006/06/17 09:00
MHDA- 2006/08/11 09:00
CRDT- 2006/06/17 09:00
PHST- 2006/06/17 09:00 [pubmed]
PHST- 2006/08/11 09:00 [medline]
PHST- 2006/06/17 09:00 [entrez]
AID - 66/12/6129 [pii]
AID - 10.1158/0008-5472.CAN-06-0404 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jun 15;66(12):6129-38. doi: 10.1158/0008-5472.CAN-06-0404.