Advertisement

Tumor Biology

, Volume 37, Issue 9, pp 12213–12221 | Cite as

Silencing of ST6GalNAc I suppresses the proliferation, migration and invasion of hepatocarcinoma cells through PI3K/AKT/NF-κB pathway

  • Xiao Yu
  • Qiang Wu
  • Liping Wang
  • Yujie Zhao
  • Qingqing Zhang
  • Qingtao Meng
  • Pawan
  • Shujing Wang
Original Article

Abstract

ST6GalNAc I is the major Sialyl-Tn antigen (STn) synthase that is highly correlated with tumor invasion and metastasis. However, the roles and molecular mechanisms by which ST6GalNAc I mediates the malignant phenotypes of hepatocarcinoma cells still remain poorly unknown. In this study, we investigated the expression of STn and ST6GalNAc I in mouse hepatocarcinoma cell lines Hca-F, Hca-P, and Hepa1-6, which have different metastatic potential, as compared with normal mouse liver cell line IAR-20. The results showed that the expression of ST6GalNAc I and STn in Hca-F and Hca-P cells was much higher than that in Hepa1-6 and IAR20 cells. Knockdown of ST6GalNAc I by shRNA in Hca-F cells significantly decreased the expression of STn and inhibited the growth of tumor cells in vitro and in vivo. This reduction of ST6GalNAc I expression also led to the decreased migration and invasion of Hca-F cells. Furthermore, we found that ST6GalNAc I knockdown inhibited the expression levels of PI3k, p-Akt473, p-Akt308, NF-κB, and their downstream molecules. Together, our results suggest a role of ST6GalNAc I in promoting the growth and invasion of hepatocarcinoma cells through regulating PI3K/AKT signaling, and ST6GalNAc I might be a promising marker for the prognosis and therapy of hepatocarcinoma.

Keywords

ST6GalNAc I STn Hepatocarcinoma Proliferation Migration Invasion 

Notes

Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (31470799) and the Natural Science Foundation of Liaoning Province (2014023032).

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Fitzmaurice C, Dicker D, Pain A, Hamavid H, Moradi-Lakeh M, MacIntyre MF, et al. The Global Burden of Cancer 2013. JAMA Oncol. 2015;1:505–27.CrossRefPubMedGoogle Scholar
  2. 2.
    Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang J, Sun MZ, Li RK, Liu SQ, Mao J, Huang YH, et al. Ech1 is a potent suppressor of lymphatic metastasis in hepatocarcinoma. Biomed Pharmacother. 2013;67:557–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang J, Song MY, Wang JW, Sun MZ, Li RK, Huang YH, et al. Enoyl coenzyme A hydratase 1 is an important factor in the lymphatic metastasis of tumors. Biomed Pharmacother. 2011;65:157–62.CrossRefPubMedGoogle Scholar
  5. 5.
    Schneider F, Kemmner W, Haensch W, Franke G, Gretschel S, Karsten U, et al. Overexpression of sialyltransferase CMP-sialic acid: Galbeta1, 3GalNAc-R alpha6-Sialyltransferase is related to poor patient survival in human colorectal carcinomas. Cancer Res. 2001;61:4605–11.PubMedGoogle Scholar
  6. 6.
    Campos D, Freitas D, Gomes J, Magalhães A, Steentoft C, Gomes C, et al. Probing the O-glycoproteome of gastric cancer cell lines for biomarker discovery. Mol Cell Proteomics. 2015;14(6):1616–29.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ricardo S, Marcos-Silva L, Pereira D, Pinto R, Almeida R, Söderberg O, et al. Detection of glyco-mucin profiles improves specificity of MUC16 and MUC1 biomarkers in ovarian serous tumours. Mol Oncol. 2015;9(2):503–12.CrossRefPubMedGoogle Scholar
  8. 8.
    Leivonen M, Nordling S, Lundin J, von Boguslawski K, Haglund C. STn and prognosis in breast cancer. Oncology. 2001;61:299–305.CrossRefPubMedGoogle Scholar
  9. 9.
    Ferreira JA, Videira PA, Lima L, Pereira S, Silva M, Carrascal M, et al. Overexpression of tumour-associated carbohydrate antigen sialyl-Tn in advanced bladder tumours. Mol Oncol. 2013;7:719–31.CrossRefPubMedGoogle Scholar
  10. 10.
    Carrascal MA, Severino PF, Guadalupe Cabral M, Silva M, Ferreira JA, Calais F, et al. Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells. Mol Oncol. 2014;8:753–65.CrossRefPubMedGoogle Scholar
  11. 11.
    Ozaki H, Matsuzaki H, Ando H, Kaji H, Nakanishi H, Ikehara Y, et al. Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model. Clin Exp Metastasis. 2012;29:229–38.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Loureiro LR, Carrascal MA, Barbas A, Ramalho JS, Novo C, Delannoy P, et al. Challenges in antibody development against Tn and Sialyl-Tn antigens. Biomolecules. 2015;5:1783–809.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Munkley J, Oltean S, Vodák D, Wilson BT, Livermore KE, Zhou Y, et al. The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer. Oncotarget. 2015;6:34358–74.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kurosawa N, Takashima S, Kono M, Ikehara Y, Inoue M, Tachida Y, et al. Molecular cloning and genomic analysis of mouse GalNAc alpha2, 6-sialyltransferase (ST6GalNAc I). J Biochem. 2000;127:845–54.CrossRefPubMedGoogle Scholar
  15. 15.
    Vandermeersch S, Vanbeselaere J, Delannoy CP, Drolez A, Mysiorek C, Guérardel Y, et al. Accumulation of GD1α ganglioside in MDA-MB-231 breast cancer cells expressing ST6GalNAc V. Molecules. 2015;20:6913–24.CrossRefPubMedGoogle Scholar
  16. 16.
    Senda M, Ito A, Tsuchida A, Hagiwara T, Kaneda T, Nakamura Y, et al. Identification and expression of a sialyltransferase responsible for the synthesis of disialylgalactosylgloboside in normal and malignant kidney cells: downregulation of ST6GalNAc VI in renal cancers. Biochem J. 2007;402:459–70.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ren D, Jia L, Li Y, Gong Y, Liu C, Zhang X, et al. ST6GalNAcII mediates the invasive properties of breast carcinoma through PI3K/Akt/NF-kB signaling pathway. IUBMB Life. 2014;66:300–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Marcos NT, Bennett EP, Gomes J, Magalhaes A, Gomes C, David L, et al. ST6GalNAc-I controls expression of sialyl-Tn antigen in gastrointestinal tissues. Front Biosci (Elite Ed). 2011;3:1443–55.Google Scholar
  19. 19.
    Marcos NT, Pinho S, Grandela C, Cruz A, Samyn-Petit B, Harduin-Lepers A, et al. Role of the human ST6GalNAc-I and ST6GalNAc-II in the synthesis of the cancer-associated sialy-Tnantigen. Cancer Res. 2004;64:7050–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Chu H, Zhou H, Liu Y, Liu X, Hu Y, Zhang J. Functional expression of CXC chemokine recepter-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability. Int J Biochem Cell Biol. 2007;39:197–205.CrossRefPubMedGoogle Scholar
  21. 21.
    Tamura F, Sato Y, Hirakawa M, Yoshida M, Ono M, Osuga T, et al. RNAi-mediated gene silencing of ST6GalNAc I suppresses the metastatic potential ingastric cancer cells. Gastric Cancer. 2016;19:85–97.CrossRefPubMedGoogle Scholar
  22. 22.
    Yu S, Zhang L, Li N, Fan J, Liu L, Zhang J, et al. Caveolin-1 up-regulates ST6Gal-I to promote the adhesive capability of mouse hepatocarcinoma cells to fibronectin via FAK-mediated adhesion signaling. Biochem Biophys Res Commun. 2012;427:506–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang S, Chen X, Wei A, Yu X, Niang J. α2, 6-linked sialic acids on N-glycansnodulate the adhesion of hepatocarcinoma cells to lymph no des. Tumor Biol. 2015;36:885–92.CrossRefGoogle Scholar
  24. 24.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86.CrossRefPubMedGoogle Scholar
  25. 25.
    Li Y, Chen X. Sialic acid metabolism and sialyltransferases: natural functions and applications. Appl Microbiol Biotechnol. 2012;94:887–905.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Julien S, Adriaenssens E, Ottenberg K, Furlan A, Courtand G, Vercoutter-Edouart AS, et al. ST6GalNAc I expression in MDA-MB-231 breast cancer cells greatly modifies their O-glycosylation pattern and enhances their tumourigenicity. Glycobiology. 2006;16:54–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Dimitroff CJ. Galectin-binding O-glycosylations as regulators of malignancy. Cancer Res. 2015;75:3195–202.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Xu F, Fan C, Fan S, Liu F, Wen T, An G, et al. Expression profile of mucin-associated sialyl-Tn antigen in Chinese patients with different colorectal lesions (adenomas, carcinomas). Int J Clin Exp Pathol. 2015;8:11549–54.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Lo CY, Antonopoulos A, Gupta R, Qu J, Dell A, Haslam SM, et al. Competition between core-2 GlcNAc-transferase and ST6GalNAc-transferase regulates the synthesis of the leukocyte selectin ligand on human P-selectin glycoprotein ligand-1. J Biol Chem. 2013;288:13974–87.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Koch A, et al. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010;30:4951–8.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D. Anania FA concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67:2497–507.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Costa C, Pereira S, Lima L, Peixoto A, Fernandes E, Neves D, et al. Abnormal protein glycosylation and activated PI3K/Akt/mTOR pathway: role in bladder cancer prognosis and targeted therapeutics. PLoS One. 2015;16(10):e0141253.CrossRefGoogle Scholar
  33. 33.
    Jin J, Shen X, Chen L, Bao LW, Zhu LM. TMPRSS4 promotes invasiveness of human gastric cancer cells through activation of NF-kB/MMP-9 signaling. Biomed Pharmacother. 2016;77:30–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Li C, Li F, Zhao K, Yao J, Cheng Y, Zhao L, et al. LFG-500 inhibits the invasion of cancer cells via down-regulation of PI3K/AKT/NF-kB signaling pathway. PLoS One. 2014;9(3):e91332.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Xiao Yu
    • 1
  • Qiang Wu
    • 2
  • Liping Wang
    • 2
  • Yujie Zhao
    • 2
  • Qingqing Zhang
    • 1
  • Qingtao Meng
    • 3
  • Pawan
    • 1
  • Shujing Wang
    • 2
  1. 1.Department of PathologyDalian Medical UniversityDalianChina
  2. 2.Department of Biochemistry and Molecular Biology, Institute of GlycobiologyDalian Medical UniversityDalianChina
  3. 3.Department of Surgery, The Third People’s Hospital of DalianAffiliated Hospital of Dalian Medical UniversityDalianChina

Personalised recommendations