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Role of a Disease-associated ST3Gal-4 in Non-small Cell Lung Cancer

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Abstract

Sialylation promotes tumorigenesis by affecting various cancer-related events, including apoptosis inhibition, cell growth, invasion, migration, metastasis, chemo-resistance, and immunomodulation in favor of tumor progression. An altered expression of sialyltransferase enzymes is responsible for synthesizing various tumor-associated sialylated structures. In the present study, our findings have revealed a significant up-regulation of ST3Gal-4 transcript in the two major subtypes of NSCLC cell lines [squamous cell carcinoma cell line (NCI-H520) and adenocarcinoma cell line (A549)]. Thus, the role of the ST3Gal-4 gene was assessed on cancer-associated signal transduction pathways in these cells in view of proliferation, invasion, and migration. ST3Gal-4 was silenced by transfection of both the cell lines with esi-ST3Gal-4-RNA, which RT-PCR and western immunoblotting confirmed. Silencing of ST3Gal-4 resulted in a decreased expression of MAL-I interacting membrane-HSP60, identified earlier as an α2,3-sialylated glycoprotein, thus pointing towards the possible role of ST3Gal-4 in its sialylation. The proliferation, invasion, and migration of both types of NSCLC cells were reduced significantly in the ST3Gal-4 silenced cells. Our findings were substantiated by the down-regulation of β-catenin and E-cadherin, a reduced expression of activated AKT1, ERK1/2, and NF-ƙB in these cells. We propose that ST3Gal-4 may be the disease-associated sialyltransferase involved in α2,3 sialylation of the membrane proteins, including HSP60 of the NSCLC cells. This may lead to the conformational alteration of these proteins, required for the activation of E-cadherin/β-catenin, AKT, and ERK/NF-ƙB mediated signal transduction pathways in these cells, resulting in their proliferation, invasion, and migration.

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All data generated or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Dobie, C., & Skropeta, D. (2021). Insights into the role of sialylation in cancer progression and metastasis. British Journal of Cancer, 124(1), 76–90.

    Article  CAS  PubMed  Google Scholar 

  2. Li, F., & Ding, J. (2019). Sialylation is involved in cell fate decision during development, reprogramming, and cancer progression. Protein & Cell, 10(8), 550–565.

    Article  CAS  Google Scholar 

  3. Schultz, M. J., Swindall, A. F., & Bellis, S. L. (2012). Regulation of the metastatic cell phenotype by sialylated glycans. Cancer and Metastasis Reviews, 31, 501–518.

    Article  CAS  PubMed  Google Scholar 

  4. Wang, P.-H. (2005). Altered glycosylation in cancer: sialic acids and sialyltransferases. Journal of Molecular Cancer, 1, 73–81.

    CAS  Google Scholar 

  5. Pérez-Garay, M., Arteta, B., Pagès, L., De Llorens, R., De Bolòs, C., Vidal-Vanaclocha, F., & Peracaula, R. (2010). α2, 3-sialyltransferase ST3Gal III modulates pancreatic cancer cell motility and adhesion in vitro and enhances its metastatic potential in vivo. PloS One, 5, e12524.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pearce, O. M., & Läubli, H. (2015). Sialic acids in cancer biology and immunity. Glycobiology, 26, 111–128.

    Article  PubMed  Google Scholar 

  7. Garnham, R., Scott, E., Livermore, K. E. & Munkley, J. (2019). ST6GAL1: A key player in cancer. Oncology Letters, 18, 983–989.

  8. Venturi, G., Ferreira, I. G., Pucci, M., Ferracin, M., Malagolini, N., Chiricolo, M. & Dall’olio, F. (2019). Impact of sialyltransferase ST6GAL1 overexpression on different colon cancer cell types. Glycobiology, 29, 684–695.

  9. Wu, H., Shi, X. L., Zhang, H. J., Song, Q. J., Yang, X. B., Hu, W. D., Mei, G. L., Chen, X., Mao, Q. S., & Chen, Z. (2016). Overexpression of ST3Gal-I promotes migration and invasion of HCCLM3 in vitro and poor prognosis in human hepatocellular carcinoma. Oncology Targets Therapy, 9, 2227–2236.

    Article  CAS  Google Scholar 

  10. Yuan, Q., Chen, X., Han, Y., Lei, T., Wu, Q., Yu, X., Wang, L., Fan, Z., & Wang, S. (2018). Modification of α2, 6‐sialylation mediates the invasiveness and tumorigenicity of non‐small cell lung cancer cells in vitro and in vivo via Notch1/Hes1/MMPs pathway. International Journal of Cancer, 143, 2319–2330.

    Article  CAS  PubMed  Google Scholar 

  11. Colomb, F., Krzewinski-Recchi, M.-A., Steenackers, A., Vincent, A., Harduin-Lepers, A., Delannoy, P., & Groux-Degroote, S. (2017). TNF upregulates ST3GAL4 and sialyl-Lewisx expression in lung epithelial cells through an intronic ATF2-responsive element. Biochemical Journal, 474, 65–78.

    Article  CAS  PubMed  Google Scholar 

  12. Chiang, C. H., Wang, C. H., Chang, H. C., More, S. V., Li, W. S., & Hung, W. C. (2010). A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin‐mediated signaling. Journal of Cellular Physiology, 223, 492–499.

    CAS  PubMed  Google Scholar 

  13. Sriuranpong, V., Borges, M. W., Ravi, R. K., Arnold, D. R., Nelkin, B. D., Baylin, S. B., & Ball, D. W. (2001). Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Research, 61, 3200–3205.

    CAS  PubMed  Google Scholar 

  14. Martin, T. A., & Jiang, W. G. (2009). Loss of tight junction barrier function and its role in cancer metastasis. Biochimica et Biophysica Acta, 1788(4), 872–891.

    Article  CAS  PubMed  Google Scholar 

  15. Awaya, H., Takeshima, Y., Amatya, V. J., Ishida, H., Yamasaki, M., Kohno, N., & Inai, K. (2005). Loss of expression of E‐cadherin and β‐catenin is associated with progression of pulmonary adenocarcinoma. Pathology International, 55, 14–18.

    Article  CAS  PubMed  Google Scholar 

  16. Wu, X., Zhao, J., Ruan, Y., Sun, L., Xu, C., & Jiang, H. (2018). Sialyltransferase ST3GAL1 promotes cell migration, invasion and TGF-beta1-induced EMT, and confers paclitaxel resistance in ovarian cancer. Cell Death Disease, 9, 1102.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Stewart, D. J. (2014). Wnt signaling pathway in non–small cell lung cancer. JNCI: Journal of the National Cancer Institute, 106, 1–11.

  18. Ma, H., Zhou, H., Song, X., Shi, S., Zhang, J., & Jia, L. (2015). Modification of sialylation is associated with multidrug resistance in human acute myeloid leukemia. Oncogene, 34, 726.

    Article  CAS  PubMed  Google Scholar 

  19. Dolcet, X., Llobet, D., Pallares, J., & Matias-Guiu, X. (2005). NF-kB in development and progression of human cancer. Virchows Archive, 446, 475–482.

    Article  CAS  Google Scholar 

  20. Britain, C. M., Dorsett, K. A., & Bellis, S. L. (2017). The glycosyltransferase ST6Gal-I protects tumor cells against serum growth factor withdrawal by enhancing survival signaling and proliferative potential. Journal of Biological Chemistry, 292, 4663–4673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lalli, R. C., Kaur, K., Chakraborti, A., Srinivasan, R., & Ghosh, S. (2019). Maackia amurensis agglutinin induces apoptosis in cultured drug resistant human non-small cell lung cancer cells. Glycoconjugate Journal, 36, 473–485.

    Article  Google Scholar 

  22. Mehta, S., Chhetra, R., Srinivasan, R., Sharma, S. C., Behera, D., & Ghosh, S. (2013). Potential importance of Maackia amurensis agglutinin in non-small cell lung cancer. Biological Chemistry, 394, 889–900.

    Article  CAS  PubMed  Google Scholar 

  23. Singh, P., Kumari, M., Bal, A., Srinivasan, R. & Ghosh, S. (2020). Heat shock protein 60 is a disease-associated sialoglycoprotein in human non-small cell lung cancer. Biological Chemistry, 401, 969–983.

  24. Strober, W. (2001). Trypan blue test of cell viability. Current Protocols in Immunology, 21, A-3B.

  25. Si, L.-L., Lv, L., Zhou, W.-H., & Hu, W.-D. (2015). Establishment and identification of human primary lung cancer cell culture in vitro. International Journal of Clinical and Experimental Pathology, 8(6), 6540–6546.

    PubMed  PubMed Central  Google Scholar 

  26. Chomczynski, P., & Sacchi, N. (2006). The single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nature Protocols, 1, 581–585.

    Article  CAS  PubMed  Google Scholar 

  27. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods, 25, 402–408.

    Article  CAS  PubMed  Google Scholar 

  28. Towbin, H., Staehelin, T., & Gordon, J. (1979). Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proceedings of the National Academy of Sciences, 76, 4350–4354.

    Article  CAS  Google Scholar 

  29. Smith, P. E., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M., Fujimoto, E. K., Goeke, N. M., Olson, B. J., & Klenk, D. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry, 150, 76–85.

    Article  CAS  PubMed  Google Scholar 

  30. Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680.

    Article  CAS  PubMed  Google Scholar 

  31. Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2), 55–63.

    Article  CAS  PubMed  Google Scholar 

  32. Mikami, S., Katsube, K., Oya, M., Ishida, M., Kosaka, T., Mizuno, R., Mukai, M., & Okada, Y. (2011). Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis. Laboratory Investigation; a Journal of Technical Methods and Pathology, 91(10), 1443–1458.

    Article  CAS  PubMed  Google Scholar 

  33. Cai, Z., Wang, Q., Zhou, Y., Zheng, L., Chiu, J. F., & He, Q. Y. (2010). Epidermal growth factor-induced epithelial-mesenchymal transition in human esophageal carcinoma cells–a model for the study of metastasis. Cancer Letters, 296(1), 88–95.

    Article  CAS  PubMed  Google Scholar 

  34. Trinchera, M., Aronica, A., & Dall’olio, F. (2017). Selectin ligands sialyl-Lewis a and sialyl-Lewis x in gastrointestinal cancers. Biology, 6, 16.

    Article  PubMed Central  Google Scholar 

  35. Pinho, S. S., & Reis, C. A. (2015). Glycosylation in cancer: mechanisms and clinical implications. Nature Reviews Cancer, 15, 540.

    Article  CAS  PubMed  Google Scholar 

  36. Bai, Q., Liu, L., Xia, Y., Long, Q., Wang, J., Xu, J., & Guo, J. (2015). Prognostic significance of ST3GAL-1 expression in patients with clear cell renal cell carcinoma. BMC Cancer, 15, 880.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chen, J. Y., Tang, Y. A., Huang, S. M., Juan, H. F., Wu, L. W., Sun, Y. C., Wang, S. C., Wu, K. W., Balraj, G., Chang, T. T., Li, W. S., Cheng, H. C., & Wang, Y. C. (2011a). A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Research, 71, 473–483.

    Article  CAS  PubMed  Google Scholar 

  38. Kono, M., Ohyama, Y., Lee, Y.-C., Hamamoto, T., Kojima, N., & Tsuji, S. (1997). Mouse β-galactoside α2, 3-sialyltransferases: comparison of in vitro substrate specificities and tissue specific expression. Glycobiology, 7, 469–479.

    Article  CAS  PubMed  Google Scholar 

  39. Chisada, S.-I., Yoshimura, Y., Sakaguchi, K., Uemura, S., Go, S., Ikeda, K., Uchima, H., Matsunaga, N., Ogura, K., & Tai, T. (2009). Zebrafish and mouse α2, 3-sialyltransferases responsible for synthesizing GM4 ganglioside. Journal of Biological Chemistry, 284, 30534–30546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gomes, C., Almeida, A., Barreira, A., Calheiros, J., Pinto, F., Abrantes, R., Costa, A., Polonia, A., Campos, D., Osório, H., Sousa, H., Pinto-de-Sousa, J., Kolarich, D., & Reis, C. A. (2019). Carcinoembryonic antigen carrying SLe(X) as a new biomarker of more aggressive gastric carcinomas. Theranostics, 9(24), 7431–7446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Perez-Garay, M., Arteta, B., Llop, E., Cobler, L., Pages, L., Ortiz, R., Ferri, M. J., de Bolos, C., Figueras, J., de Llorens, R., Vidal-Vanaclocha, F., & Peracaula, R. (2013). alpha2,3-Sialyltransferase ST3Gal IV promotes migration and metastasis in pancreatic adenocarcinoma cells and tends to be highly expressed in pancreatic adenocarcinoma tissues. The International Journal of Biochemistry & Cell Biology, 45(8), 1748–1757.

    Article  CAS  Google Scholar 

  42. Shen, L., Luo, Z., Wu, J., Qiu, L., Luo, M., Ke, Q., & Dong, X. (2017). Enhanced expression of alpha2,3-linked sialic acids promotes gastric cancer cell metastasis and correlates with poor prognosis. International Journal of Oncology, 50(4), 1201–1210.

    Article  CAS  PubMed  Google Scholar 

  43. Colomb, F., Krzewinski-Recchi, M.-A., El Machhour, F., Mensier, E., Jaillard, S., Steenackers, A., Harduin-Lepers, A., Lafitte, J.-J., Delannoy, P., & Groux-Degroote, S. (2012). TNF regulates sialyl-Lewisx and 6-sulfo-sialyl-Lewisx expression in human lung through up-regulation of ST3GAL4 transcript isoform BX. Biochimie, 94, 2045–2053.

    Article  CAS  PubMed  Google Scholar 

  44. Gomes, C., Osório, H., Pinto, M. T., Campos, D., Oliveira, M. J., & Reis, C. A. (2013). Expression of ST3GAL4 leads to SLex expression and induces c-Met activation and an invasive phenotype in gastric carcinoma cells. PloS One, 8, e66737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Natoni, A., Macauley, M. S., & O’dwyer, M. E. (2016). Targeting selectins and their ligands in cancer. Frontiers in Oncology, 6, 93.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wu Y., Chen X., Dong W., Xu Z., Jian Y., Xu C., Zhang L., Wei A., Yu X., Wang S., Wang Y., Liu G., Sun X., Wang S., (2021). ST3Gal IV Mediates the growth and proliferation of cervical cancer cells in vitro and in vivo via the Notch/p21/CDKs Pathway. Frontiers in Oncology. 10, 540332.

  47. Van Den Bossche, J., Malissen, B., Mantovani, A., De Baetselier, P., & Van Ginderachter, J. A. (2012). Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood, 119, 1623–1633.

    Article  PubMed  Google Scholar 

  48. Goretsky, T., Bradford, E. M., Ye, Q., Lamping, O. F., Vanagunas, T., Moyer, M. P., Keller, P. C., Sinh, P., Llovet, J. M., & Gao, T. (2018). Beta-catenin cleavage enhances transcriptional activation. Scientific Reports, 8, 671.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Pećina-Šlaus, N. (2003). Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer cell international, 3, 17.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kawauchi, K., Ogasawara, T., Yasuyama, M., Otsuka, K., & Yamada, O. (2009). The PI3K/Akt pathway as a target in the treatment of hematologic malignancies. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 9, 550–559.

    CAS  Google Scholar 

  51. Qiu, Z. X., Zhang, K., Qiu, X. S., Zhou, M., & Li, W. M. (2013). The prognostic value of phosphorylated AKT expression in non-small cell lung cancer: a meta-analysis. PLoS One, 8, e81451.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Brognard, J., & Dennis, P. A. (2002). Variable apoptotic response of NSCLC cells to inhibition of the MEK/ERK pathway by small molecules or dominant negative mutants. Cell Death and Differentiation, 9(9), 893–904.

    Article  CAS  PubMed  Google Scholar 

  53. Vicent, S., Lopez-Picazo, J. M., Toledo, G., Lozano, M. D., Torre, W., Garcia-Corchon, C., Quero, C., Soria, J. C., Martin-Algarra, S., Manzano, R. G., & Montuenga, L. M. (2004). ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. British Journal of Cancer, 90, 1047–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Karin, M. (2006). Nuclear factor-κB in cancer development and progression. Nature, 441, 431.

    Article  CAS  PubMed  Google Scholar 

  55. Chen, W., Li, Z., Bai, L., & Lin, Y. (2011b). NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Frontiers in Bioscience (Landmark edition), 16, 1172–1185.

    Article  CAS  Google Scholar 

  56. Stathopoulos, G. T., Sherrill, T. P., Cheng, D.-S., Scoggins, R. M., Han, W., Polosukhin, V. V., Connelly, L., Yull, F. E., Fingleton, B., & Blackwell, T. S. (2007). Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis. Proceedings of the National Academy of Sciences, 104, 18514–18519.

    Article  CAS  Google Scholar 

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Funding

The work was supported by the grant sanctioned via letter no. 71/6-Edu-13/3245; dated 28.10.14 from PGIMER, Chandigarh, India.

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  1. Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, 160012, India

    Praveen Singh, Archana Joon, Munmun Kumari, Tanya Singh, Pratibha Maan & Sujata Ghosh

  2. Department of Histopathology, PGIMER, Chandigarh, 160012, India

    Amanjit Bal

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Singh, P., Joon, A., Kumari, M. et al. Role of a Disease-associated ST3Gal-4 in Non-small Cell Lung Cancer. Cell Biochem Biophys 80, 781–793 (2022). https://doi.org/10.1007/s12013-022-01091-3

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