Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis

Nogimori,Kenichi; Hori,Tomoko; Kawaguchi,Koji; Fukui,Takayuki; Mii,Shinji; Nakada,Hiroshi; Matsumoto,Yasuyuki; Yamauchi,Yoshio; Takahashi,Masahide; Furukawa,Keiko; Tetsuya,Okajima; Yokoi,Kohei; Hasegawa,Yoshinori; Furukawa,Koichi

doi:10.3892/ijo.2016.3638

Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis

Authors:
- Kenichi Nogimori
- Tomoko Hori
- Koji Kawaguchi
- Takayuki Fukui
- Shinji Mii
- Hiroshi Nakada
- Yasuyuki Matsumoto
- Yoshio Yamauchi
- Masahide Takahashi
- Keiko Furukawa
- Okajima Tetsuya
- Kohei Yokoi
- Yoshinori Hasegawa
- Koichi Furukawa
View Affiliations

Affiliations: Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya, Japan, Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan, Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan, Department of Molecular Bioscience, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan, Faculty of Life and Health Sciences, Chubu University, Kasugai, Japan, Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
Published online on: July 29, 2016 https://doi.org/10.3892/ijo.2016.3638
Pages: 1369-1376

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

ppGalNAc-T13 is upregulated along with reduced expression of GM1 in high metastatic sublines of the murine Lewis lung cancer cell line, but little is known about the implication of ppGalNAc-T13 expression in human cancers. Since lung cancer cell lines showed high expression levels of ppGalNAc-T13, we analyzed ppGalNAc-T13 expression in surgical lung cancer specimens to examine whether ppGalNAc-T13 can be used as a prognostic marker or a therapeutic target. We analyzed mRNA expression levels of GALNT13 and its variant exon usages in surgical specimens by real-time RT-PCR, and the results were evaluated by correlating with clinical data. Ninety-one surgical specimens were analyzed. Consequently, recurrence-free survival was significantly shorter (P=0.045) in high expression group of GALNT13 mRNA. In the analysis of tumor specific exon usage in GALNT13 RNA sequence, one variant exon was significantly associated with worse prognosis. By contrast, in another variant exon, positive variant expression group showed better prognosis than negative group. We also tried to detect GALNT13 mRNA in 63 serum samples from patients with lung cancers to examine whether GALNT13 mRNA can be measured in body fluids, detecting significant levels in 4 samples. Finally, expression of GM1, ppGalNAc-T13 and trimeric Tn antigen was examined by immunohistochemistry in order to evaluate them as a prognostic factor. It was demonstrated that ppGalNAc-T13 and trimeric Tn antigen had a relationship with worse prognosis in 35 investigated lung cancer patients. In conclusion, our results suggest that ppGalNAc-T13 might be a useful prognostic factor of lung cancers.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, et al: Spanish Lung Cancer Group: Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 361:958–967. 2009. View Article : Google Scholar : PubMed/NCBI
3	Solomon B, Varella-Garcia M and Camidge DR: ALK gene rearrangements: A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 4:1450–1454. 2009. View Article : Google Scholar : PubMed/NCBI
4	Hakomori S: Cancer-associated glycosphingolipid antigens: Their structure, organization, and function. Acta Anat (Basel). 161:79–90. 1998. View Article : Google Scholar
5	Kasahara K and Sanai Y: Possible roles of glycosphingolipids in lipid rafts. Biophys Chem. 82:121–127. 1999. View Article : Google Scholar
6	Fuster MM and Esko JD: The sweet and sour of cancer: Glycans as novel therapeutic targets. Nat Rev Cancer. 5:526–542. 2005. View Article : Google Scholar : PubMed/NCBI
7	Li M, Song L and Qin X: Glycan changes: Cancer metastasis and anti-cancer vaccines. J Biosci. 35:665–673. 2010. View Article : Google Scholar
8	Wiegandt H: Gangliosides. Glycolipids. 10. Wiegandt H: Elsevier Science Publishers; Amsterdam: pp. 199–260. 1985, View Article : Google Scholar
9	Cheresh DA, Rosenberg J, Mujoo K, Hirschowitz L and Reisfeld RA: Biosynthesis and expression of the disialoganglioside GD2, a relevant target antigen on small cell lung carcinoma for monoclonal antibody-mediated cytolysis. Cancer Res. 46:5112–5118. 1986.PubMed/NCBI
10	Yoshida S, Fukumoto S, Kawaguchi H, Sato S, Ueda R and Furukawa K: Ganglioside G_D2 in small cell lung cancer cell lines: Enhancement of cell proliferation and mediation of apoptosis. Cancer Res. 61:4244–4252. 2001.PubMed/NCBI
11	Yoshida S, Kawaguchi H, Sato S, Ueda R and Furukawa K: An anti-GD2 monoclonal antibody enhances apoptotic effects of anti-cancer drugs against small cell lung cancer cells via JNK (c-Jun terminal kinase) activation. Jpn J Cancer Res. 93:816–824. 2002. View Article : Google Scholar : PubMed/NCBI
12	Alfonso S, Valdés-Zayas A, Santiesteban ER, Flores YI, Areces F, Hernández M, Viada CE, Mendoza IC, Guerra PP, García E, et al: A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 20:3660–3671. 2014. View Article : Google Scholar : PubMed/NCBI
13	Kannagi R: Molecular mechanism for cancer-associated induction of sialyl Lewis X and sialyl Lewis A expression-The Warburg effect revisited. Glycoconj J. 20:353–364. 2004. View Article : Google Scholar : PubMed/NCBI
14	Brockhausen I: Mucin-type O-glycans in human colon and breast cancer: Glycodynamics and functions. EMBO Rep. 7:599–604. 2006. View Article : Google Scholar : PubMed/NCBI
15	Cao Y, Stosiek P, Springer GF and Karsten U: Thomsen-Friedenreich-related carbohydrate antigens in normal adult human tissues: A systematic and comparative study. Histochem Cell Biol. 106:197–207. 1996. View Article : Google Scholar : PubMed/NCBI
16	Ju T, Otto VI and Cummings RD: The Tn antigen-structural simplicity and biological complexity. Angew Chem Int Ed Engl. 50:1770–1791. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhang Q and Furukawa K, Chen HH, Sakakibara T, Urano T and Furukawa K: Metastatic potential of mouse Lewis lung cancer cells is regulated via ganglioside GM1 by modulating the matrix metalloprotease-9 localization in lipid rafts. J Biol Chem. 281:18145–18155. 2006. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Iwasaki H, Wang H, Kudo T, Kalka TB, Hennet T, Kubota T, Cheng L, Inaba N, Gotoh M, et al: Cloning and characterization of a new human UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase, designated pp-GalNAc-T13, that is specifically expressed in neurons and synthesizes GalNAc α-serine/threonine antigen. J Biol Chem. 278:573–584. 2003. View Article : Google Scholar
19	Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tokuda N, Tsuchida A, Matsubara T, Hori T, Okajima T, et al: pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen. Biochem Biophys Res Commun. 419:7–13. 2012. View Article : Google Scholar : PubMed/NCBI
20	Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tsuchida A, Okajima T and Furukawa K, Urano T and Furukawa K: Trimeric Tn antigen on syndecan 1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin α5β1 and matrix metalloproteinase 9. J Biol Chem. 288:24264–24276. 2013. View Article : Google Scholar : PubMed/NCBI
21	Berois N, Blanc E, Ripoche H, Mergui X, Trajtenberg F, Cantais S, Barrois M, Dessen P, Kågedal B, Bénard J, et al: ppGalNAc-T13: A new molecular marker of bone marrow involvement in neuroblastoma. Clin Chem. 52:1701–1712. 2006. View Article : Google Scholar : PubMed/NCBI
22	Naruke T, Suemasu K and Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg. 76:832–839. 1978.PubMed/NCBI
23	Morita N, Yajima Y, Asanuma H, Nakada H and Fujita-Yamaguchi Y: Inhibition of cancer cell growth by anti-Tn monoclonal antibody MLS128. Biosci Trends. 3:32–37. 2009.
24	Zamri N, Masuda N, Oura F, Yajima Y, Nakada H and Fujita-Yamaguchi Y: Effects of two monoclonal antibodies, MLS128 against Tn-antigen and 1H7 against insulin-like growth factor-I receptor, on the growth of colon cancer cells. Biosci Trends. 6:303–312. 2012.
25	Zamri N, Masuda N, Oura F, Kabayama K, Yajima Y, Nakada H, Yamamoto K and Fujita-Yamaguchi Y: Characterization of anti-Tn-antigen MLS128 binding proteins involved in inhibiting the growth of human colorectal cancer cells. Biosci Trends. 7:221–229. 2013.PubMed/NCBI
26	Gerken TA, Revoredo L, Thome JJ, Tabak LA, Vester-Christensen MB, Clausen H, Gahlay GK, Jarvis DL, Johnson RW, Moniz HA, et al: The lectin domain of the polypeptide GalNAc transferase family of glycosyltransferases (ppGalNAc Ts) acts as a switch directing glycopeptide substrate glycosylation in an N- or C-terminal direction, further controlling mucin type O-glycosylation. J Biol Chem. 288:19900–19914. 2013. View Article : Google Scholar : PubMed/NCBI
27	Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB and Johnson DH: Eastern Cooperative Oncology Group: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med. 343:1217–1222. 2000. View Article : Google Scholar : PubMed/NCBI
28	Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, et al; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs observation in resected non-small-cell lung cancer. N Engl J Med. 352:2589–2597. 2005. View Article : Google Scholar : PubMed/NCBI