Skip to main content
Top
Published in: Annals of Surgical Oncology 4/2010

01-04-2010 | Colorectal Cancer

TGM2 Is a Novel Marker for Prognosis and Therapeutic Target in Colorectal Cancer

Authors: Norikatsu Miyoshi, MD, Hideshi Ishii, MD, Koshi Mimori, MD, Fumiaki Tanaka, MD, Toshiki Hitora, MD, Mitsuyoshi Tei, MD, Mitsugu Sekimoto, MD, Yuichiro Doki, MD, PhD, Masaki Mori, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Issue 4/2010

Login to get access

Abstract

Background

Transglutaminase 2 (TGM2) plays a role in cell growth and survival through the antiapoptosis signaling pathway.

Methods

We analyzed TGM2 gene expression in 91 paired cases of colorectal cancer (CRC) and noncancerous regions and seven CRC cell lines to demonstrate the importance of TGM2 expression for the prediction of prognosis of CRC. TGM2 expression was higher in CRC tissue than in corresponding normal tissue by real-time reverse transcriptase–polymerase chain reaction (P = .015).

Results

Patients in the high TGM2 expression group showed a poorer overall survival rate than those in the low expression group (P = .001), indicating that the increase in TGM2 expression was an independent prognostic factor. TGM2 was also expressed in the seven CRC cell lines. The in vitro proliferation assay showed that TGM2 expression is involved with tumor growth.

Conclusions

The present study suggests that TGM2 is useful as a predictive marker for patient prognosis and may be a novel therapeutic target for CRC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Kohno SI, Luo C, Nawa A, et al. Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus. Cancer Gene Ther. 2007;14:918–26.CrossRefPubMed Kohno SI, Luo C, Nawa A, et al. Oncolytic virotherapy with an HSV amplicon vector expressing granulocyte-macrophage colony-stimulating factor using the replication-competent HSV type 1 mutant HF10 as a helper virus. Cancer Gene Ther. 2007;14:918–26.CrossRefPubMed
3.
go back to reference Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4:140–56.CrossRefPubMed Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 2003;4:140–56.CrossRefPubMed
4.
go back to reference Antonyak MA, Singh US, Lee DA, et al. Effects of tissue transglutaminase on retinoic acid–induced cellular differentiation and protection against apoptosis. J Biol Chem. 2001;276:33582–7.CrossRefPubMed Antonyak MA, Singh US, Lee DA, et al. Effects of tissue transglutaminase on retinoic acid–induced cellular differentiation and protection against apoptosis. J Biol Chem. 2001;276:33582–7.CrossRefPubMed
5.
go back to reference Boehm JE, Singh U, Combs C, et al. Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb. J Biol Chem. 2002;277:20127–30.CrossRefPubMed Boehm JE, Singh U, Combs C, et al. Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb. J Biol Chem. 2002;277:20127–30.CrossRefPubMed
6.
go back to reference Antonyak MA, Miller AM, Jansen JM, et al. Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells. J Biol Chem. 2004;279:41461–7.CrossRefPubMed Antonyak MA, Miller AM, Jansen JM, et al. Augmentation of tissue transglutaminase expression and activation by epidermal growth factor inhibit doxorubicin-induced apoptosis in human breast cancer cells. J Biol Chem. 2004;279:41461–7.CrossRefPubMed
7.
go back to reference Mangala LS, Mehta K. Tissue transglutaminase (TG2) in cancer biology. Prog Exp Tumor Res. 2005;38:125–38.CrossRefPubMed Mangala LS, Mehta K. Tissue transglutaminase (TG2) in cancer biology. Prog Exp Tumor Res. 2005;38:125–38.CrossRefPubMed
8.
9.
go back to reference Mann AP, Verma A, Sethi G, et al. Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res. 2006;66:8788–95.CrossRefPubMed Mann AP, Verma A, Sethi G, et al. Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res. 2006;66:8788–95.CrossRefPubMed
10.
go back to reference Sobin LH, Fleming ID. TNM classification of malignant tumors, 5th edn. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4. Sobin LH, Fleming ID. TNM classification of malignant tumors, 5th edn. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer. 1997;80:1803–4.
11.
go back to reference Mimori K, Mori M, Shiraishi T, et al. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer. 1997;76:531–6.PubMed Mimori K, Mori M, Shiraishi T, et al. Clinical significance of tissue inhibitor of metalloproteinase expression in gastric carcinoma. Br J Cancer. 1997;76:531–6.PubMed
12.
go back to reference Mori M, Staniunas RJ, Barnard GF, et al. The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology. 1993;105:820–6.PubMed Mori M, Staniunas RJ, Barnard GF, et al. The significance of carbonic anhydrase expression in human colorectal cancer. Gastroenterology. 1993;105:820–6.PubMed
13.
go back to reference Fesus L, Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 2002;27:534–9.CrossRefPubMed Fesus L, Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci. 2002;27:534–9.CrossRefPubMed
14.
go back to reference Mehta K. High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells. Int J Cancer. 1994;58:400–6.CrossRefPubMed Mehta K. High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells. Int J Cancer. 1994;58:400–6.CrossRefPubMed
15.
go back to reference Chen JS, Konopleva M, Andreeff M, et al. Drug-resistant breast carcinoma (MCF-7) cells are paradoxically sensitive to apoptosis. J Cell Physiol. 2004;200:223–34.CrossRefPubMed Chen JS, Konopleva M, Andreeff M, et al. Drug-resistant breast carcinoma (MCF-7) cells are paradoxically sensitive to apoptosis. J Cell Physiol. 2004;200:223–34.CrossRefPubMed
16.
go back to reference Mehta K, Fok J, Miller FR, et al. Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res. 2004;10:8068–76.CrossRefPubMed Mehta K, Fok J, Miller FR, et al. Prognostic significance of tissue transglutaminase in drug resistant and metastatic breast cancer. Clin Cancer Res. 2004;10:8068–76.CrossRefPubMed
17.
go back to reference Herman JF, Mangala LS, Mehta K. Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells. Oncogene. 2006;25:3049–58.CrossRefPubMed Herman JF, Mangala LS, Mehta K. Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells. Oncogene. 2006;25:3049–58.CrossRefPubMed
18.
go back to reference Sarang Z, Molnar P, Nemeth T, et al. Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology. 2005;42:578–87.CrossRefPubMed Sarang Z, Molnar P, Nemeth T, et al. Tissue transglutaminase (TG2) acting as G protein protects hepatocytes against Fas-mediated cell death in mice. Hepatology. 2005;42:578–87.CrossRefPubMed
19.
go back to reference Aeschlimann D, Paulsson M. Transglutaminases: protein cross-linking enzymes in tissues and body fluids. Thromb Haemost. 1994;71:402–15.PubMed Aeschlimann D, Paulsson M. Transglutaminases: protein cross-linking enzymes in tissues and body fluids. Thromb Haemost. 1994;71:402–15.PubMed
20.
go back to reference Aeschlimann D, Koeller MK, Allen-Hoffmann BL, Mosher DF. Isolation of a cDNA encoding a novel member of the transglutaminase gene family from human keratinocytes. Detection and identification of transglutaminase gene products based on reverse transcription–polymerase chain reaction with degenerate primers. J Biol Chem. 1998;273:3452–60.CrossRefPubMed Aeschlimann D, Koeller MK, Allen-Hoffmann BL, Mosher DF. Isolation of a cDNA encoding a novel member of the transglutaminase gene family from human keratinocytes. Detection and identification of transglutaminase gene products based on reverse transcription–polymerase chain reaction with degenerate primers. J Biol Chem. 1998;273:3452–60.CrossRefPubMed
21.
go back to reference Chen JS, Mehta K. Tissue transglutaminase: an enzyme with a split personality. Int J Biochem Cell Biol. 1999;31:817–36.CrossRefPubMed Chen JS, Mehta K. Tissue transglutaminase: an enzyme with a split personality. Int J Biochem Cell Biol. 1999;31:817–36.CrossRefPubMed
22.
go back to reference Greenberg CS, Birckbichler PJ, Rice RH. Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 1991;5:3071–7.PubMed Greenberg CS, Birckbichler PJ, Rice RH. Transglutaminases: multifunctional cross-linking enzymes that stabilize tissues. FASEB J. 1991;5:3071–7.PubMed
23.
go back to reference Ai L, Kim WJ, Demircan B, et al. The transglutaminase 2 gene (TGM2.), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis. 2008;29:510–8.CrossRefPubMed Ai L, Kim WJ, Demircan B, et al. The transglutaminase 2 gene (TGM2.), a potential molecular marker for chemotherapeutic drug sensitivity, is epigenetically silenced in breast cancer. Carcinogenesis. 2008;29:510–8.CrossRefPubMed
24.
go back to reference Andre T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007;25:3732–8.CrossRefPubMed Andre T, Quinaux E, Louvet C, et al. Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1. J Clin Oncol. 2007;25:3732–8.CrossRefPubMed
25.
go back to reference Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134:1296–10.CrossRefPubMed Wolpin BM, Mayer RJ. Systemic treatment of colorectal cancer. Gastroenterology. 2008;134:1296–10.CrossRefPubMed
26.
go back to reference Kornmann M, Formentini A, Ette C, et al. Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment. Eur J Surg Oncol. 2008;34:1316–21.PubMed Kornmann M, Formentini A, Ette C, et al. Prognostic factors influencing the survival of patients with colon cancer receiving adjuvant 5-FU treatment. Eur J Surg Oncol. 2008;34:1316–21.PubMed
27.
go back to reference Bathe OF, Dowden S, Sutherland F, et al. 2004 Phase II study of neoadjuvant 5-FU + leucovorin + CPT-11 in patients with resectable liver metastases from colorectal adenocarcinoma. BMC Cancer. 4:32.CrossRefPubMed Bathe OF, Dowden S, Sutherland F, et al. 2004 Phase II study of neoadjuvant 5-FU + leucovorin + CPT-11 in patients with resectable liver metastases from colorectal adenocarcinoma. BMC Cancer. 4:32.CrossRefPubMed
28.
go back to reference Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet. 2002;359:2224–9.CrossRefPubMed Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet. 2002;359:2224–9.CrossRefPubMed
29.
go back to reference Weeks JC, Nelson H, Gelber S, et al. Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA. 2002;287:321–8.CrossRefPubMed Weeks JC, Nelson H, Gelber S, et al. Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial. JAMA. 2002;287:321–8.CrossRefPubMed
30.
go back to reference Group COoSTS. 2004 A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 350:2050–9.CrossRef Group COoSTS. 2004 A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 350:2050–9.CrossRef
31.
go back to reference Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol. 2007;25:3061–8.CrossRefPubMed Jayne DG, Guillou PJ, Thorpe H, et al. Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol. 2007;25:3061–8.CrossRefPubMed
32.
go back to reference Han JA, Park SC. Reduction of transglutaminase 2 expression is associated with an induction of drug sensitivity in the PC-14 human lung cancer cell line. J Cancer Res Clin Oncol. 1999;125:89–95.CrossRefPubMed Han JA, Park SC. Reduction of transglutaminase 2 expression is associated with an induction of drug sensitivity in the PC-14 human lung cancer cell line. J Cancer Res Clin Oncol. 1999;125:89–95.CrossRefPubMed
33.
go back to reference Devarajan E, Chen J, Multani AS, et al. Human breast cancer MCF-7 cell line contains inherently drug-resistant subclones with distinct genotypic and phenotypic features. Int J Oncol. 2002;20:913–20.PubMed Devarajan E, Chen J, Multani AS, et al. Human breast cancer MCF-7 cell line contains inherently drug-resistant subclones with distinct genotypic and phenotypic features. Int J Oncol. 2002;20:913–20.PubMed
Metadata
Title
TGM2 Is a Novel Marker for Prognosis and Therapeutic Target in Colorectal Cancer
Authors
Norikatsu Miyoshi, MD
Hideshi Ishii, MD
Koshi Mimori, MD
Fumiaki Tanaka, MD
Toshiki Hitora, MD
Mitsuyoshi Tei, MD
Mitsugu Sekimoto, MD
Yuichiro Doki, MD, PhD
Masaki Mori, MD, PhD, FACS
Publication date
01-04-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 4/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0865-y

Other articles of this Issue 4/2010

Annals of Surgical Oncology 4/2010 Go to the issue