Polypeptide N-acetylgalactosaminyltransferase 2 regulates cellular metastasis-associated behavior in gastric cancer

Hua,Dong; Shen,Li; Xu,Lan; Jiang,Zhi; Zhou,Yinghui; Yue,Aihuan; Zou,Shitao; Cheng,Zhihong; Wu,Shiliang

doi:10.3892/ijmm.2012.1130

Polypeptide N-acetylgalactosaminyltransferase 2 regulates cellular metastasis-associated behavior in gastric cancer

Authors:
- Dong Hua
- Li Shen
- Lan Xu
- Zhi Jiang
- Yinghui Zhou
- Aihuan Yue
- Shitao Zou
- Zhihong Cheng
- Shiliang Wu
View Affiliations

Affiliations: The Fourth Affiliated Hospital of Soochow University, Wuxi, Jiangsu 214062, P.R. China, Department of Biochemistry and Mollecular Biology, School of Medicine, Soochow University, Suzhou, Jiangsu 215123, P.R. China
Published online on: September 18, 2012 https://doi.org/10.3892/ijmm.2012.1130
Pages: 1267-1274
Copyright: © Hua et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aberrant glycosylation of cell surface glycoprotein due to specific alterations of glycosyltransferase activity is usually associated with invasion and metastasis of cancer, particularly of gastric carcinomas. Polypeptide N-acetylgalactosaminyltransferase 2 (ppGalNAc-T2), which catalyzes initiation of mucin-type O-glycosylation, is also involved in tumor migration and invasion. However, a comprehensive understanding of how ppGalNAc-T2 correlates with the metastasic potential of human gastric cancer is not currently available. In the present study, ppGalNAc-T2 was detected in a variety of human poorly differentiated tumor cells, and expression appeared to be higher in SGC7901 gastric cancer cells. In addition, we investigated the potential effects of ppGalNAc-T2 on growth and metastasis-associated behavior in SGC7901 cells after stable transfection with ppGalNAc-T2 sense and antisense vectors. We found that cell proliferation, adhesion and invasion were decreased in ppGalNAc-T2 overexpressed cells but increased in ppGalNAc-T2 downregulated cells. Therefore, we attempted to clarify the mechanisms underlying the anti-metastatic activities of ppGalNAc-T2. Further investigation indicated that overexpression of ppGalNAc-T2 is involved in the inhibition of matrix metalloproteinase (MMP)-2 expression at both the protein and mRNA levels, which may be associated with ppGalNAc-T2 suppressing the expression of transforming growth factor (TGF)-β1. However, it did not exhibit any apparent correlation with MMP-14 expression levels. Our data show the effect of ppGalNAc-T2 on proliferation, adhesion or invasion of SGC7901 gastric cancer cells, suggesting that ppGalNAc-T2 may exert anti-proliferative and anti-metastatic activity through the decrease of MMP-2 and TGF-β1. These results indicate that ppGalNAc‑T2 may be used as a novel therapeutic target for human gastric cancer treatment.

View Figures

View References

1	Brooks SA, Carter TM, Bennett EP, Clausen H and Mandel U: Immunolocalisation of members of the polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T) family is consistent with biologically relevant altered cell surface glycosylation in breast cancer. Acta Histochem. 109:273–284. 2007. View Article : Google Scholar
2	Zhang H, Meng F, Wu S, et al: Engagement of I-branching {beta}-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-{beta} signaling. Cancer Res. 71:4846–4856. 2011.PubMed/NCBI
3	Christie DR, Shaikh FM, Lucas JA IV, Lucas JA III and Bellis SL: ST6Gal-I expression in ovarian cancer cells promotes an invasive phenotype by altering integrin glycosylation and function. J Ovarian Res. 1:32008. View Article : Google Scholar : PubMed/NCBI
4	Meany DL and Chan DW: Aberrant glycosylation associated with enzymes as cancer biomarkers. Clin Proteomics. 8:72011. View Article : Google Scholar : PubMed/NCBI
5	Petretti T, Schulze B, Schlag PM and Kemmner W: Altered mRNA expression of glycosyltransferases in human gastric carcinomas. Biochim Biophys Acta. 1428:209–218. 1999. View Article : Google Scholar : PubMed/NCBI
6	Chandrasekaran EV, Xue J, Piskorz C, et al: Potential tumor markers for human gastric cancer: an elevation of glycan:sulfotransferases and a concomitant loss of alpha1,2-fucosyltransferase activities. J Cancer Res Clin Oncol. 133:599–611. 2007. View Article : Google Scholar
7	Shimizu F, Nakayama J, Ishizone S, et al: Usefulness of the real-time reverse transcription-polymerase chain reaction assay targeted to alpha1,4-N-acetylglucosaminyltransferase for the detection of gastric cancer. Lab Invest. 83:187–197. 2003. View Article : Google Scholar
8	Liu Z, Shen L, Xu L, Sun X, Zhou J and Wu S: Downregulation of β-1,3-N-acetylglucosaminyltransferase-8 by siRNA inhibits the growth of human gastric cancer. Mol Med Rep. 4:497–503. 2011.
9	Zlocowski N, Sendra VG, Lorenz V, et al: Catalytic and glycan-binding abilities of ppGalNAc-T2 are regulated by acetylation. Biochem Biophys Res Commun. 410:140–145. 2011. View Article : Google Scholar : PubMed/NCBI
10	Li X, Wang J, Li W, et al: Characterization of ppGalNAc-T18, a member of the vertebrate-specific Y subfamily of UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferases. Glycobiology. 22:602–615. 2012. View Article : Google Scholar : PubMed/NCBI
11	Peng C, Togayachi A, Kwon YD, et al: Identification of a novel human UDP-GalNAc transferase with unique catalytic activity and expression profile. Biochem Biophys Res Commun. 402:680–686. 2010. View Article : Google Scholar : PubMed/NCBI
12	Mandel U, Hassan H, Therkildsen MH, et al: Expression of polypeptide GalNAc-transferases in stratified epithelia and squamous cell carcinomas: immunohistological evaluation using monoclonal antibodies to three members of the GalNAc-transferase family. Glycobiology. 9:43–52. 1999. View Article : Google Scholar
13	Gao Y, Tu YB, Guo Y, et al: PpGalNacT2 participating in vanadium-induced HL-60 cell differentiation. Mol Biol Rep. 38:1483–1489. 2011. View Article : Google Scholar : PubMed/NCBI
14	Liu C, Lin D, Xu L, Jiang Z, Zhou Y and Wu S: An anti-human ppGalNAcT-2 monoclonal antibody. Hybridoma. 30:549–554. 2011. View Article : Google Scholar : PubMed/NCBI
15	Liu J, Yang L, Jin M, Xu L and Wu S: regulation of the invasion and metastasis of human glioma cells by polypeptide N-acetylgalactosaminyltransferase 2. Mol Med Rep. 4:1299–1305. 2011.PubMed/NCBI
16	Shen L, Liu Z, Tu Y, Xu L, Sun X and Wu S: Regulation of MMP-2 expression and activity by beta-1,3-N-acetylglucosaminyltransferase-8 in AGS gastric cancer cells. Mol Biol Rep. 38:1541–1550. 2011. View Article : Google Scholar : PubMed/NCBI
17	Milac AL, Buchete NV, Fritz TA, Hummer G and Tabak LA: Substrate-induced conformational changes and dynamics of UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase-2. J Mol Biol. 373:439–451. 2007. View Article : Google Scholar : PubMed/NCBI
18	Ten Hagen KG, Fritz TA and Tabak LA: All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiology. 13:1R–16R. 2003.PubMed/NCBI
19	Wei M, Wang Z, Yao H, et al: P27(Kip1), regulated by glycogen synthase kinase-3beta, results in HMBA-induced differentiation of human gastric cancer cells. BMC Cancer. 11:1092011. View Article : Google Scholar : PubMed/NCBI
20	Zeng Y, Yang Z, Xu JG, Yang MS, Zeng ZX and You C: Differentially expressed genes from the glioblastoma cell line SHG-44 treated with all-trans retinoic acid in vitro. J Clin Neurosci. 16:285–294. 2009. View Article : Google Scholar : PubMed/NCBI
21	Qiu H, Guo XH, Mo JH, Jin MF, Wu SL and Chen HL: Expressions of polypeptide: N-acetylgalactosaminyltransferase in leukemia cell lines during 1,25-dihydroxyvitamin D3 induced differentiation. Glycoconj J. 23:575–584. 2006. View Article : Google Scholar : PubMed/NCBI
22	Jia HP, Look DC, Shi L, et al: ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol. 79:14614–14621. 2005. View Article : Google Scholar
23	Xu S, Mou H, Lu G, et al: Gene expression profile differences in high and low metastatic human ovarian cancer cell lines by gene chip. Chin Med J (Engl). 115:36–41. 2002.PubMed/NCBI
24	Langley RR and Fidler IJ: Tumor cell-organ microenvironment interactions in the pathogenesis of cancer metastasis. Endocr Rev. 28:297–321. 2007. View Article : Google Scholar : PubMed/NCBI
25	Fidler IJ: The organ microenvironment and cancer metastasis. Differentiation. 70:498–505. 2002. View Article : Google Scholar : PubMed/NCBI
26	Li Y, Li B, Xiang CP, Zhang Y, Li YY and Wu XL: Characterization of gastric cancer models from different cell lines orthotopically constructed using improved implantation techniques. World J Gastroenterol. 18:136–143. 2012. View Article : Google Scholar
27	Li HZ, Wang Y, Gao Y, et al: Effects of raf kinase inhibitor protein expression on metastasis and progression of human epithelial ovarian cancer. Mol Cancer Res. 6:917–928. 2008. View Article : Google Scholar : PubMed/NCBI
28	Li HZ, Gao Y, Zhao XL, et al: Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer. Mol Cancer Res. 7:832–840. 2009. View Article : Google Scholar : PubMed/NCBI
29	Gao M, Zhang JH, Zhou FX, et al: Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1. Oncol Rep. 27:585–593. 2012.
30	Sato H, Takino T, Okada Y, et al: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature. 370:61–65. 1994. View Article : Google Scholar : PubMed/NCBI
31	Zucker S, Drews M, Conner C, et al: Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP). J Biol Chem. 273:1216–1222. 1998. View Article : Google Scholar : PubMed/NCBI
32	Taipale J, Miyazono K, Heldin CH and Keski-Oja J: Latent transforming growth factor-beta 1 associates to fibroblast extra-cellular matrix via latent TGF-beta binding protein. J Cell Biol. 124:171–181. 1994. View Article : Google Scholar : PubMed/NCBI