Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Glutamate acid decarboxylase 1 promotes metastasis of human oral cancer by β-catenin translocation and MMP7 activation

Authors: Ryota Kimura, Atsushi Kasamatsu, Tomoyoshi Koyama, Chonji Fukumoto, Yukinao Kouzu, Morihiro Higo, Yosuke Endo-Sakamoto, Katsunori Ogawara, Masashi Shiiba, Hideki Tanzawa, Katsuhiro Uzawa

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Glutamate decarboxylase 1 (GAD1), a rate-limiting enzyme in the production of γ-aminobutyric acid (GABA), is found in the GABAergic neurons of the central nervous system. Little is known about the relevance of GAD1 to oral squamous cell carcinoma (OSCC). We investigated the expression status of GAD1 and its functional mechanisms in OSCCs.

Methods

We evaluated GAD1 mRNA and protein expressions in OSCC-derived cells using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunoblotting analyses. To assess the critical functions of GAD1, i.e., cellular proliferation, invasiveness, and migration, OSCC-derived cells were treated with the shRNA and specific GAD1 inhibitor, 3-mercaptopropionic acid (3-MPA). GAD1 expression in 80 patients with primary OSCCs was analyzed and compared to the clinicopathological behaviors of OSCC.

Results

qRT-PCR and immunoblotting analyses detected frequent up-regulation of GAD1 in OSCC-derived cells compared to human normal oral keratinocytes. Suppression of nuclear localization of β-catenin and MMP7 secretion was observed in GAD1 knockdown and 3-MPA-treated cells. We also found low cellular invasiveness and migratory abilities in GAD1 knockdown and 3-MPA-treated cells. In the clinical samples, GAD1 expression in the primary OSCCs was significantly (P < 0.05) higher than in normal counterparts and was correlated significantly (P < 0.05) with regional lymph node metastasis.

Conclusions

Our data showed that up-regulation of GAD1 was a characteristic event in OSCCs and that GAD1 was correlated with cellular invasiveness and migration by regulating β-catenin translocation and MMP7 activation. GAD1 might play an important role in controlling tumoral invasiveness and metastasis in oral cancer.
Appendix
Available only for authorised users
Literature
1.
Erlander MG, Tobin AJ: The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem Res. 1991, 16: 215-226. 10.1007/BF00966084.CrossRefPubMed
2.
Young SZ, Bordey A: GABA’s control of stem and cancer cell proliferation in adult neural and peripheral niches. Physiology (Bethesda). 2009, 24: 171-185. 10.1152/physiol.00002.2009.CrossRef
3.
Rambrand T, Pociot F, Rønningen KS, Rønningen K, Nerup J, Michelsen BK: Genetic markers for glutamic acid decarboxylase do not predict insulin-dependent diabetes mellitus in pairs of affected siblings. The Danish Study Group of Diabetes in Childhood. Hum Genet. 1997, 99: 177-185. 10.1007/s004390050334.CrossRefPubMed
4.
Hijazi J, Bedat-Millet AL, Hannequin D: Stiff-person syndrome and other neurological disorders associated with anti-GAD antibodies. Rev Med Interne. 2010, 31: 23-28. 10.1016/j.revmed.2009.01.012.CrossRefPubMed
5.
Condie BG, Bain G, Gottlieb DI, Capecchi MR: Cleft palate in mice with a targeted mutation in the gamma-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67. Proc Natl Acad Sci U S A. 1997, 94: 11451-11455. 10.1073/pnas.94.21.11451.CrossRefPubMedPubMedCentral
6.
Li CM, Kim CE, Margolin AA, Guo M, Zhu J, Mason JM, Hensle TW, Murty VV, Grundy PE, Fearon ER, et al: CTNNB1 mutations and overexpression of Wnt/beta-catenin target genes in WT1-mutant Wilms’ tumors. Am J Pathol. 2004, 165: 1943-1953. 10.1016/S0002-9440(10)63246-4.CrossRefPubMedPubMedCentral
7.
Schwartz DR, Wu R, Kardia SL, Levin AM, Huang CC, Shedden KA, Kuick R, Misek DE, Hanash SM, Taylor JM, et al: Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas. Cancer Res. 2003, 63: 2913-2922.PubMed
8.
Orsulic S, Huber O, Aberle H, Arnold S, Kemler R: E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. J Cell Sci. 1999, 112 (Pt 8): 1237-1245.PubMed
9.
Huang J, Xiao D, Li G, Ma J, Chen P, Yuan W, Hou F, Ge J, Zhong M, Tang Y: EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells. Oncogene. 2013, 10: 1-11.
10.
Howard S, Deroo T, Fujita Y, Itasaki N: A positive role of cadherin in Wnt/β-catenin signalling during epithelial-mesenchymal transition. PLoS One. 2011, 6: e23899-10.1371/journal.pone.0023899.CrossRefPubMedPubMedCentral
11.
Li VS, Ng SS, Boersema PJ, Low TY, Karthaus WR, Gerlach JP, Mohammed S, Heck AJ, Maurice MM, Mahmoudi T, et al: Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell. 2012, 149: 1245-1256. 10.1016/j.cell.2012.05.002.CrossRefPubMed
12.
Valenta T, Hausmann G, Basler K: The many faces and functions of β-catenin. EMBO J. 2013, 31: 2714-2736.CrossRef
13.
Ougolkov AV, Yamashita K, Mai M, Minamoto T: Oncogenic beta-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer. Gastroenterology. 2002, 122: 60-71. 10.1053/gast.2002.30306.CrossRefPubMed
14.
Pajouh MS, Nagle RB, Breathnach R, Finch JS, Brawer MK, Bowden GT: Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol. 1991, 117: 144-150. 10.1007/BF01613138.CrossRefPubMed
15.
Yoshimoto M, Itoh F, Yamamoto H, Hinoda Y, Imai K, Yachi A: Expression of MMP-7 (PUMP-1) mRNA in human colorectal cancers. Int J Cancer. 1993, 54: 614-618. 10.1002/ijc.2910540415.CrossRefPubMed
16.
Adachi Y, Itoh F, Yamamoto H, Matsuno K, Arimura Y, Kusano M, Endoh T, Hinoda Y, Oohara M, Hosokawa M, et al: Matrix metalloproteinase matrilysin (MMP-7) participates in the progression of human gastric and esophageal cancers. Int J Oncol. 1998, 13: 1031-1035.PubMed
17.
Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH: Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol. 1996, 149: 273-282.PubMedPubMedCentral
18.
Samukange V, Yasukawa K, Inouye K: Interaction of 8-anilinonaphthalene 1-sulphonate (ANS) and human matrix metalloproteinase 7 (MMP-7) as examined by MMP-7 activity and ANS fluorescence. J Biochem. 2012, 151: 533-540. 10.1093/jb/mvs025.CrossRefPubMed
19.
Chuang HC, Su CY, Huang HY, Huang CC, Chien CY, Du YY, Chuang JH: Active matrix metalloproteinase-7 is associated with invasion in buccal squamous cell carcinoma. Mod Pathol. 2008, 21: 1444-1450. 10.1038/modpathol.2008.99.CrossRefPubMed
20.
Endo Y, Uzawa K, Mochida Y, Shiiba M, Bukawa H, Yokoe H, Tanzawa H: Sarcoendoplasmic reticulum Ca(2+) ATPase type 2 downregulated in human oral squamous cell carcinoma. Int J Cancer. 2004, 110: 225-231. 10.1002/ijc.20118.CrossRefPubMed
21.
Kasamatsu A, Uzawa K, Nakashima D, Koike H, Shiiba M, Bukawa H, Yokoe H, Tanzawa H: Galectin-9 as a regulator of cellular adhesion in human oral squamous cell carcinoma cell lines. Int J Mol Med. 2005, 16: 269-273.PubMed
22.
Iyoda M, Kasamatsu A, Ishigami T, Nakashima D, Endo-Sakamoto Y, Ogawara K, Shiiba M, Tanzawa H, Uzawa K: Epithelial cell transforming sequence 2 in human oral cancer. PLoS One. 2010, 5: e14082-10.1371/journal.pone.0014082.CrossRefPubMedPubMedCentral
23.
Kouzu Y, Uzawa K, Koike H, Saito K, Nakashima D, Higo M, Endo Y, Kasamatsu A, Shiiba M, Bukawa H, et al: Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis. Br J Cancer. 2006, 94: 717-723.PubMedPubMedCentral
24.
Ogoshi K, Kasamatsu A, Iyoda M, Sakuma K, Yamatoji M, Sakamoto Y, Ogawara K, Shiiba M, Tanzawa H, Uzawa K: Dickkopf-1 in human oral cancer. Int J Oncol. 2011, 39: 329-336.PubMed
25.
Crick EW, Osorio I, Bhavaraju NC, Linz TH, Lunte CE: An investigation into the pharmacokinetics of 3-mercaptopropionic acid and development of a steady-state chemical seizure model using in vivo microdialysis and electrophysiological monitoring. Epilepsy Res. 2007, 74: 116-125. 10.1016/j.eplepsyres.2007.02.003.CrossRefPubMedPubMedCentral
26.
Netopilová M, Drsata J, Kubová H, Mares P: Differences between immature and adult rats in brain glutamate decarboxylase inhibition by 3-mercaptopropionic acid. Epilepsy Res. 1995, 20: 179-184. 10.1016/0920-1211(94)00068-8.CrossRefPubMed
27.
Tunnicliff G: Action of inhibitors on brain glutamate decarboxylase. Int J Biochem. 1990, 22: 1235-1241. 10.1016/0020-711X(90)90304-L.CrossRefPubMed
28.
Erdö SL: Postmortem increase of GABA levels in peripheral rat tissues: prevention by 3-mercapto-propionic acid. J Neural Transm. 1984, 60: 303-314. 10.1007/BF01249102.CrossRefPubMed
29.
Yamamoto A, Kasamatsu A, Ishige S, Koike K, Saito K, Kouzu Y, Koike H, Sakamoto Y, Ogawara K, Shiiba M, et al: Exocyst complex component Sec8: a presumed component in the progression of human oral squamous-cell carcinoma by secretion of matrix metalloproteinases. J Cancer Res Clin Oncol. 2013, 139: 533-542. 10.1007/s00432-012-1356-2.CrossRefPubMed
30.
Ho BY, Wu YM, Chang KJ, Pan TM: Dimerumic acid inhibits SW620 cell invasion by attenuating H2O2-mediated MMP-7 expression via JNK/C-Jun and ERK/C-Fos activation in an AP-1-dependent manner. Int J Biol Sci. 2011, 7: 869-880.CrossRefPubMedPubMedCentral
31.
Snoek-van Beurden PA, Von den Hoff JW: Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques. 2005, 38: 73-83. 10.2144/05381RV01.CrossRefPubMed
32.
Kim HJ, Park SY, Park OJ, Kim YM: Curcumin suppresses migration and proliferation of Hep3B hepatocarcinoma cells through inhibition of the Wnt signaling pathway. Mol Med Rep. 2013, 8: 282-286.PubMed
33.
Kobayashi T, Shimura T, Yajima T, Kubo N, Araki K: Transient gene silencing of galectin-3 suppresses pancreatic cancer cell migration and invasion through degradation of β-catenin. Int J Cancer. 2011, 129: 2775-2786. 10.1002/ijc.25946.CrossRefPubMed
34.
Zik M, Arazi T, Snedden WA, Fromm H: Two isoforms of glutamate decarboxylase in Arabidopsis are regulated by calcium/calmodulin and differ in organ distribution. Plant Mol Biol. 1998, 37: 967-975. 10.1023/A:1006047623263.CrossRefPubMed
35.
Meyre D, Boutin P, Tounian A, Deweirder M, Aout M, Jouret B, Heude B, Weill J, Tauber M, Tounian P, et al: Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children?. J Clin Endocrinol Metab. 2005, 90: 2384-2390. 10.1210/jc.2004-1468.CrossRefPubMed
36.
Maddox DM, Condie BG: Dynamic expression of a glutamate decarboxylase gene in multiple non-neural tissues during mouse development. BMC Dev Biol. 2001, 1: 1-10.1186/1471-213X-1-1.CrossRefPubMedPubMedCentral
37.
Maemura K, Shiraishi N, Sakagami K, Kawakami K, Inoue T, Murano M, Watanabe M, Otsuki Y: Proliferative effects of gamma-aminobutyric acid on the gastric cancer cell line are associated with extracellular signal-regulated kinase 1/2 activation. J Gastroenterol Hepatol. 2009, 24: 688-696. 10.1111/j.1440-1746.2008.05687.x.CrossRefPubMed
38.
Yamano Y, Uzawa K, Shinozuka K, Fushimi K, Ishigami T, Nomura H, Ogawara K, Shiiba M, Yokoe H, Tanzawa H: Hyaluronan-mediated motility: a target in oral squamous cell carcinoma. Int J Oncol. 2008, 32: 1001-1009.PubMed
39.
Kruck S, Eyrich C, Scharpf M, Sievert KD, Fend F, Stenzl A, Bedke J: Impact of an altered Wnt1/β-catenin expression on clinicopathology and prognosis in clear cell renal cell carcinoma. Int J Mol Sci. 2013, 14: 10944-10957. 10.3390/ijms140610944.CrossRefPubMedPubMedCentral
40.
Sawada G, Ueo H, Matsumura T, Uchi R, Ishibashi M, Mima K, Kurashige J, Takahashi Y, Akiyoshi S, Sudo T, et al: CHD8 is an independent prognostic indicator that regulates Wnt/β-catenin signaling and the cell cycle in gastric cancer. Oncol Rep. 2013, 30: 1137-1142.PubMed
41.
Abd El-Rehim D, Ali MM: Aberrant expression of β-catenin in invasive ductal breast carcinomas. J Egypt Natl Canc Inst. 2009, 21: 185-195.PubMed
42.
Usongo M, Li X, Farookhi R: Activation of the canonical WNT signaling pathway promotes ovarian surface epithelial proliferation without inducing β-catenin/Tcf-mediated reporter expression. Dev Dyn. 2013, 242: 291-300. 10.1002/dvdy.23919.CrossRefPubMed
43.
Chen HJ, Hsu LS, Shia YT, Lin MW, Lin CM: The β-catenin/TCF complex as a novel target of resveratrol in the Wnt/β-catenin signaling pathway. Biochem Pharmacol. 2012, 84: 1143-1153. 10.1016/j.bcp.2012.08.011.CrossRefPubMed
44.
Wang K, Li N, Yeung CH, Li JY, Wang HY, Cooper TG: Oncogenic Wnt/β-catenin signalling pathways in the cancer-resistant epididymis have implications for cancer research. Mol Hum Reprod. 2013, 19: 57-71. 10.1093/molehr/gas051.CrossRefPubMed
45.
Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, et al: Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol. 2002, 22: 1184-1193. 10.1128/MCB.22.4.1184-1193.2002.CrossRefPubMedPubMedCentral
46.
Oshima T, Akaike M, Yoshihara K, Shiozawa M, Yamamoto N, Sato T, Yamada R, Fujii S, Rino Y, Kunisaki C, et al: Clinicopathological significance of the gene expression of matrix metalloproteinase-7, insulin-like growth factor-1, insulin-like growth factor-2 and insulin-like growth factor-1 receptor in patients with colorectal cancer: insulin-like growth factor-1 receptor gene expression is a useful predictor of liver metastasis from colorectal cancer. Oncol Rep. 2008, 20: 359-364.PubMed
47.
Yamamoto H, Adachi Y, Itoh F, Iku S, Matsuno K, Kusano M, Arimura Y, Endo T, Hinoda Y, Hosokawa M, et al: Association of matrilysin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Cancer Res. 1999, 59: 3313-3316.PubMed
48.
Mimori K, Yamashita K, Ohta M, Yoshinaga K, Ishikawa K, Ishii H, Utsunomiya T, Barnard GF, Inoue H, Mori M: Coexpression of matrix metalloproteinase-7 (MMP-7) and epidermal growth factor (EGF) receptor in colorectal cancer: an EGF receptor tyrosine kinase inhibitor is effective against MMP-7-expressing cancer cells. Clin Cancer Res. 2004, 10: 8243-8249. 10.1158/1078-0432.CCR-04-0849.CrossRefPubMed
49.
Fanelli MF, Chinen LT, Begnami MD: The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer. Histopathology. 2012, 61: 153-161. 10.1111/j.1365-2559.2011.04139.x.CrossRefPubMed
50.
Barros SS, Henriques Á, Pereira KM, de Medeiros AM, Galvão HC, Freitas RA: Immunohistochemical expression of matrix metalloproteinases in squamous cell carcinoma of the tongue and lower lip. Arch Oral Biol. 2011, 56: 752-760. 10.1016/j.archoralbio.2010.11.022.CrossRefPubMed
Metadata
Title
Glutamate acid decarboxylase 1 promotes metastasis of human oral cancer by β-catenin translocation and MMP7 activation
Authors
Ryota Kimura
Atsushi Kasamatsu
Tomoyoshi Koyama
Chonji Fukumoto
Yukinao Kouzu
Morihiro Higo
Yosuke Endo-Sakamoto
Katsunori Ogawara
Masashi Shiiba
Hideki Tanzawa
Katsuhiro Uzawa
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-555

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue

Research article

Common low-penetrance risk variants associated with breast cancer in Polish women

Research article

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

Research article

Targeting cell migration and the endoplasmic reticulum stress response with calmodulin antagonists: a clinically tested small molecule phenocopy of SEC62 gene silencing in human tumor cells

Research article

Cross-sectional study of self-reported physical activity, eating habits and use of complementary medicine in breast cancer survivors

Research article

Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer

Research article

Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits