Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion.
IQGAP1 is a multifunctional protein involved in actin cytoskeleton assembly and E-cadherin-mediated cell adhesion. We reported previously IQGAP1 overexpression in human colorectal carcinomas especially at the invasion front (IF) and that such overexpression tended to correlate with lymph node metastasis in advanced cases. Thus, in this study, we investigated the clinicopathological significance of IQGAP1 expression in 85 cases of pT2-3 colorectal carcinomas with special reference to its expression pattern and prognosis, followed by analysis of the role of IQGAP1 in cancer invasion in vitro. Quantitative reverse transcription-PCR showed significant upregulation of IQGAP1 in colorectal carcinomas compared with normal mucosa. Immunohistochemically, IQGAP1 expression pattern was classified into diffuse (20%), IF-associated (35.3%) and focal (44.7%). The diffuse pattern was associated with higher rates of distant metastasis. Patients with IQGAP1 overexpression and diffuse pattern had significantly shorter survival (p < 0.0001) than others, and the diffuse pattern was an independent predictor of poor survival by multivariate analysis. In vitro invasion assays using three human colon carcinoma cell lines showed that IQGAP1 siRNA significantly suppressed hepatocyte growth factor (HGF)-stimulated cell invasion. HGF reduced membranous localization of alpha-catenin, but did not alter localization of E-cadherin, beta-catenin and IQGAP1 in membranes. Suppression of IQGAP1 expression by siRNA did not alter membranous localization of alpha-catenin even in the presence of HGF. Our results indicate that IQGAP1 plays a critical role in colon cancer cell invasion, and therefore diffuse and high expression of IQGAP1 predicts poor prognosis in patients with colorectal carcinoma.
Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
Hiroyuki
H
Hayashi
Kazuki
K
Nabeshima
Mikiko
M
Aoki
Makoto
M
Hamasaki
Sotaro
S
Enatsu
Yasushi
Y
Yamauchi
Yuichi
Y
Yamashita
Hiroshi
H
Iwasaki
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D017931:DNA Primers; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
D017931:DNA Primers; C101203:IQ motif containing GTPase activating protein 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins