title: Expression of C4.4A at the invasive front is a novel prognostic marker for disease recurrence of colorectal cancer.
abstract: Metastasis-associated gene C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. The aim of this study was to explore the expression and clinical relevance of C4.4A in colorectal cancer. By quantitative RT-PCR, 154 colorectal cancer tissues were examined for C4.4A mRNA. We examined 132 colorectal cancer tissues by immunohistochemistry using a new polyclonal antibody that recognizes the C4.4A protein C-terminus containing the glycosylphosphatidyl-inositol anchor signaling sequence. A significant difference in 5-year overall survival was found between samples with high and low expression of C4.4A mRNA (P = 0.0005). Immunohistochemistry showed strong membranous staining of C4.4A at the invasive front of colorectal cancer tumors and at the frontier of metastatic lesions to lymph node and lung. The membranous staining with enhanced intensity at the invasive front of the primary colorectal cancer (Type A: 34/132, 25.6%) was associated with depth of invasion (P = 0.033) and venous invasion (P = 0.003), and was a significant independent prognostic factor (5-year overall survival in the entire series [n = 132; P = 0.004] and disease-free survival in stage II and III colorectal cancers [n = 82; P = 0.003]). Moreover, Type A C4.4A expression was linked to shorter liver metastasis-free survival rate, lung metastasis-free survival rate, or hematogenous metastasis-free survival (P = 0.0279, P = 0.0061, and P = 0.0006, respectively). Our data indicate that expression of the C4.4A protein at the invasive front acts as a novel prognostic marker in colorectal cancer, possibly through invasion-related mechanisms.
authors.affiliation: Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Konishi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.forename: Masataka
authors.initials: M
authors.lastname: Ikeda
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Sekimoto
authors.forename: Nariaki
authors.initials: N
authors.lastname: Matsuura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takao
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000032:analysis*; D015815:Cell Adhesion Molecules / Q000032:analysis* / Q000235:genetics; D003110:Colonic Neoplasms / Q000401:mortality* / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local / Q000401:mortality*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C472589:LYPD3 protein, human; D012333:RNA, Messenger
references.citation: J Biol Chem. 2003 Feb 21;278(8):6482-9
references.pmid: 12477722
references.citation: Cancer Res. 2003 May 1;63(9):2292-9
references.pmid: 12727852
references.citation: N Engl J Med. 2004 Jun 3;350(23):2335-42
references.pmid: 15175435
references.citation: Oncogene. 1998 Oct 15;17(15):1989-2002
references.pmid: 9788443
references.citation: Int J Cancer. 2005 Jul 10;115(5):724-33
references.pmid: 15729693
references.citation: Int J Cancer. 2008 Feb 15;122(4):734-41
references.pmid: 17849475
references.citation: Gene. 2001 Jan 10;262(1-2):35-41
references.pmid: 11179665
references.citation: Cancer Res. 2001 Feb 15;61(4):1678-85
references.pmid: 11245483
references.citation: N Engl J Med. 2009 Apr 2;360(14):1408-17
references.pmid: 19339720
references.citation: Cell Growth Differ. 1996 May;7(5):663-78
references.pmid: 8732676
references.citation: Hepatology. 2001 Oct;34(4 Pt 1):638-50
references.pmid: 11584358
references.citation: Clin Cancer Res. 2008 Feb 1;14(3):677-84
references.pmid: 18245526
references.citation: Exp Cell Res. 1995 Sep;220(1):47-54
references.pmid: 7664842
references.citation: Oncogene. 1999 Jan 7;18(1):103-15
references.pmid: 9926925
references.citation: Int J Cancer. 2007 May 15;120(10):2135-47
references.pmid: 17278103
references.citation: Gastroenterology. 2003 Aug;125(2):556-71
references.pmid: 12891558
references.citation: Lung Cancer. 2007 Nov;58(2):260-6
references.pmid: 17706320
references.citation: Cancer Res. 1989 Mar 1;49(5):1294-9
references.pmid: 2917359
references.citation: Cancer Res. 2000 Jun 1;60(11):3043-50
references.pmid: 10850455
references.citation: Br J Cancer. 2007 Oct 22;97(8):1146-56
references.pmid: 17912244
references.citation: Biochem J. 2004 Jun 15;380(Pt 3):845-57
references.pmid: 15012588
references.citation: Cell Mol Life Sci. 2005 Apr;62(7-8):870-80
references.pmid: 15868410
references.citation: J Invest Dermatol. 2001 Feb;116(2):344-7
references.pmid: 11180013
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2082-90
references.pmid: 17404090
references.citation: Expert Rev Anticancer Ther. 2009 Jan;9(1):125-34
references.pmid: 19105712
references.citation: Nat Rev Cancer. 2007 May;7(5):370-80
references.pmid: 17457303
references.citation: Cancer Res. 1988 Dec 1;48(23):6863-71
references.pmid: 2846163
references.citation: Br J Cancer. 2006 Oct 9;95(7):889-95
references.pmid: 16969348
references.citation: J Surg Oncol. 2007 Jun 15;95(8):652-62
references.pmid: 17443723
references.citation: Br J Cancer. 2003 Feb 24;88(4):579-85
references.pmid: 12592373
references.citation: J Clin Oncol. 2002 Oct 15;20(20):4232-41
references.pmid: 12377967