Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Environment-Sensitive Ectodomain Shedding of Epithin/PRSS14 Increases Metastatic Potential of Breast Cancer Cells by Producing CCL2

  • Received : 2021.09.29
  • Accepted : 2022.01.28
  • Published : 2022.08.31
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Abstract

Epithin/PRSS14 is a membrane serine protease that plays a key role in tumor progression. The protease exists on the cell surface until its ectodomain shedding, which releases most of the extracellular domain. Previously, we showed that the remaining portion on the membrane undergoes intramembrane proteolysis, which results in the liberation of the intracellular domain and the intracellular domain-mediated gene expression. In this study, we investigated how the intramembrane proteolysis for the nuclear function is initiated. We observed that ectodomain shedding of epithin/PRSS14 in mouse breast cancer 4T1 cells increased depending on environmental conditions and was positively correlated with invasiveness of the cells and their proinvasive cytokine production. We identified selenite as an environmental factor that can induce ectodomain shedding of the protease and increase C-C motif chemokine ligand 2 (CCL2) secretion in an epithin/PRSS14-dependent manner. Additionally, by demonstrating that the expression of the intracellular domain of epithin/PRSS14 is sufficient to induce CCL2 secretion, we established that epithin/PRSS14-dependent shedding and its subsequent intramembrane proteolysis are responsible for the metastatic conversion of 4T1 cells under these conditions. Consequently, we propose that epithin/PRSS14 can act as an environment-sensing receptor that promotes cancer metastasis by liberating the intracellular domain bearing transcriptional activity under conditions promoting ectodomain shedding.

Keywords

Acknowledgement

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2022R1A2B5B02001854) and a Korea University Grant.

References

  1. Aggarwal, V., Tuli, H.S., Varol, A., Thakral, F., Yerer, M.B., Sak, K., Varol, M., Jain, A., Khan, M.A., and Sethi, G. (2019). Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules 9, 735.
  2. Antalis, T.M., Buzza, M.S., Hodge, K.M., Hooper, J.D., and Netzel-Arnett, S. (2010). The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem. J. 428, 325-346. https://doi.org/10.1042/BJ20100046
  3. Aslakson, C.J. and Miller, F.R. (1992). Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 52, 1399-1405.
  4. Benaud, C., Dickson, R.B., and Lin, C.Y. (2001). Regulation of the activity of matriptase on epithelial cell surfaces by a blood-derived factor. Eur. J. Biochem. 268, 1439-1447. https://doi.org/10.1046/j.1432-1327.2001.02016.x
  5. Benaud, C., Oberst, M., Hobson, J.P., Spiegel, S., Dickson, R.B., and Lin, C.Y. (2002). Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase. J. Biol. Chem. 277, 10539-10546. https://doi.org/10.1074/jbc.M109064200
  6. Bonapace, L., Coissieux, M.M., Wyckoff, J., Mertz, K.D., Varga, Z., Junt, T., and Bentires-Alj, M. (2014). Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature 515, 130-133. https://doi.org/10.1038/nature13862
  7. Brill, A., Chauhan, A.K., Canault, M., Walsh, M.T., Bergmeier, W., and Wagner, D.D. (2009). Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion. Cardiovasc. Res. 84, 137-144. https://doi.org/10.1093/cvr/cvp176
  8. Chae, D.S., Han, S., Lee, M.K., and Kim, S.W. (2021). Genome edited Sirt1-Overexpressing human mesenchymal stem cells exhibit therapeutic effects in treating collagen-induced arthritis. Mol. Cells 44, 245-253. https://doi.org/10.14348/molcells.2021.0037
  9. Cho, E.G., Kim, M.G., Kim, C., Kim, S.R., Seong, I.S., Chung, C., Schwartz, R.H., and Park, D. (2001). N-terminal processing is essential for release of epithin, a mouse type II membrane serine protease. J. Biol. Chem. 276, 44581-44589. https://doi.org/10.1074/jbc.M107059200
  10. Cho, E.G., Schwartz, R.H., and Kim, M.G. (2005). Shedding of membrane epithin is blocked without LDLRA4 and its protease activation site. Biochem. Biophys. Res. Commun. 327, 328-334. https://doi.org/10.1016/j.bbrc.2004.12.014
  11. Cho, Y., Kim, S.B., Kim, J., Pham, A.V.Q., Yoon, M.J., Park, J.H., Hwang, K.T., Park, D., Cho, Y., Kim, M.G., et al. (2020). Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function. BMC Biol. 18, 60.
  12. Cho, Y., Park, D., and Kim, C. (2017). Disruption of TACE-filamin interaction can inhibit TACE-mediated ectodomain shedding. Biochem. Biophys. Res. Commun. 490, 997-1003. https://doi.org/10.1016/j.bbrc.2017.06.153
  13. Ha, S.Y., Kim, K.Y., Lee, N.K., Kim, M.G., and Kim, S.H. (2014). Overexpression of matriptase correlates with poor prognosis in esophageal squamous cell carcinoma. Virchows Arch. 464, 19-27. https://doi.org/10.1007/s00428-013-1504-3
  14. Ihara, S., Miyoshi, E., Ko, J.H., Murata, K., Nakahara, S., Honke, K., Dickson, R.B., Lin, C.Y., and Taniguchi, N. (2002). Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding beta 1-6 GlcNAc branching. J. Biol. Chem. 277, 16960-16967. https://doi.org/10.1074/jbc.M200673200
  15. Jin, X., Yagi, M., Akiyama, N., Hirosaki, T., Higashi, S., Lin, C.Y., Dickson, R.B., Kitamura, H., and Miyazaki, K. (2006). Matriptase activates stromelysin (MMP-3) and promotes tumor growth and angiogenesis. Cancer Sci. 97, 1327-1334. https://doi.org/10.1111/j.1349-7006.2006.00328.x
  16. Kang, J.Y., Dolled-Filhart, M., Ocal, I.T., Singh, B., Lin, C.Y., Dickson, R.B., Rimm, D.L., and Camp, R.L. (2003). Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res. 63, 1101-1105.
  17. Kim, C., Cho, Y., Kang, C.H., Kim, M.G., Lee, H., Cho, E.G., and Park, D. (2005). Filamin is essential for shedding of the transmembrane serine protease, epithin. EMBO Rep. 6, 1045-1051. https://doi.org/10.1038/sj.embor.7400534
  18. Kim, C., Lee, H.S., Lee, D., Lee, S.D., Cho, E.G., Yang, S.J., Kim, S.B., Park, D., and Kim, M.G. (2011). Epithin/PRSS14 proteolytically regulates angiopoietin receptor Tie2 during transendothelial migration. Blood 117, 1415-1424. https://doi.org/10.1182/blood-2010-03-275289
  19. Kim, D., Pertea, G., Trapnell, C., Pimentel, H., Kelley, R., and Salzberg, S.L. (2013). TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36.
  20. Kim, K.Y., Lee, G., Yoon, M., Cho, E.H., Park, C.S., and Kim, M.G. (2015). Expression analyses revealed thymic stromal co-transporter/Slc46A2 is in stem cell populations and is a putative tumor suppressor. Mol. Cells 38, 548-561. https://doi.org/10.14348/molcells.2015.0044
  21. Kim, M.G., Chen, C., Lyu, M.S., Cho, E.G., Park, D., Kozak, C., and Schwartz, R.H. (1999). Cloning and chromosomal mapping of a gene isolated from thymic stromal cells encoding a new mouse type II membrane serine protease, epithin, containing four LDL receptor modules and two CUB domains. Immunogenetics 49, 420-428. https://doi.org/10.1007/s002510050515
  22. Kim, S., Yang, J.W., Kim, C., and Kim, M.G. (2016). Impact of suppression of tumorigenicity 14 (ST14)/serine protease 14 (Prss14) expression analysis on the prognosis and management of estrogen receptor negative breast cancer. Oncotarget 7, 34643-34663. https://doi.org/10.18632/oncotarget.9155
  23. Kim, S.B., Lee, D., Jeong, J.W., Kim, C., Park, D., and Kim, M.G. (2010). Soluble epithin/PRSS14 secreted from cancer cells contains active angiogenic potential. Mol. Cells 29, 617-623. https://doi.org/10.1007/s10059-010-0077-0
  24. Ko, C.J., Lan, S.W., Lu, Y.C., Cheng, T.S., Lai, P.F., Tsai, C.H., Hsu, T.W., Lin, H.Y., Shyu, H.Y., Wu, S.R., et al. (2017). Inhibition of cyclooxygenase-2-mediated matriptase activation contributes to the suppression of prostate cancer cell motility and metastasis. Oncogene 36, 4597-4609. https://doi.org/10.1038/onc.2017.82
  25. Kuhnle, N., Dederer, V., and Lemberg, M.K. (2019). Intramembrane proteolysis at a glance: from signalling to protein degradation. J. Cell Sci. 132, jcs217745.
  26. Kursvietiene, L., Mongirdiene, A., Bernatoniene, J., Sulinskiene, J., and Staneviciene, I. (2020). Selenium anticancer properties and impact on cellular redox status. Antioxidants (Basel) 9, 80.
  27. Lal, M. and Caplan, M. (2011). Regulated intramembrane proteolysis: signaling pathways and biological functions. Physiology (Bethesda) 26, 34-44.
  28. Lee, H.S., Park, B.M., Cho, Y., Kim, S., Kim, C., Kim, M.G., and Park, D. (2014). Shedding of epithin/PRSS14 is induced by TGF-beta and mediated by tumor necrosis factor-alpha converting enzyme. Biochem. Biophys. Res. Commun. 452, 1084-1090. https://doi.org/10.1016/j.bbrc.2014.09.055
  29. Levitin, F., Stern, O., Weiss, M., Gil-Henn, C., Ziv, R., Prokocimer, Z., Smorodinsky, N.I., Rubinstein, D.B., and Wreschner, D.H. (2005). The MUC1 SEA module is a self-cleaving domain. J. Biol. Chem. 280, 33374-33386. https://doi.org/10.1074/jbc.M506047200
  30. Liao, Z., Chua, D., and Tan, N.S. (2019). Reactive oxygen species: a volatile driver of field cancerization and metastasis. Mol. Cancer 18, 65.
  31. List, K., Szabo, R., Molinolo, A., Sriuranpong, V., Redeye, V., Murdock, T., Burke, B., Nielsen, B.S., Gutkind, J.S., and Bugge, T.H. (2005). Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev. 19, 1934-1950. https://doi.org/10.1101/gad.1300705
  32. Mantovani, A., Barajon, I., and Garlanda, C. (2018). IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol. Rev. 281, 57-61. https://doi.org/10.1111/imr.12614
  33. Mao, Z., Zhang, J., Shi, Y., Li, W., Shi, H., Ji, R., Mao, F., Qian, H., Xu, W., and Zhang, X. (2020). CXCL5 promotes gastric cancer metastasis by inducing epithelial-mesenchymal transition and activating neutrophils. Oncogenesis 9, 63.
  34. Martin, C.E. and List, K. (2019). Cell surface-anchored serine proteases in cancer progression and metastasis. Cancer Metastasis Rev. 38, 357-387. https://doi.org/10.1007/s10555-019-09811-7
  35. Oberst, M., Anders, J., Xie, B., Singh, B., Ossandon, M., Johnson, M., Dickson, R.B., and Lin, C.Y. (2001). Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo. Am. J. Pathol. 158, 1301-1311. https://doi.org/10.1016/S0002-9440(10)64081-3
  36. Oberst, M.D., Johnson, M.D., Dickson, R.B., Lin, C.Y., Singh, B., Stewart, M., Williams, A., al-Nafussi, A., Smyth, J.F., Gabra, H., et al. (2002). Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters. Clin. Cancer Res. 8, 1101-1107.
  37. Pastushenko, I. and Blanpain, C. (2019). EMT transition states during tumor progression and metastasis. Trends Cell Biol. 29, 212-226. https://doi.org/10.1016/j.tcb.2018.12.001
  38. Rayman, M.P. (2000). The importance of selenium to human health. Lancet 356, 233-241. https://doi.org/10.1016/S0140-6736(00)02490-9
  39. Saleem, M., Adhami, V.M., Zhong, W., Longley, B.J., Lin, C.Y., Dickson, R.B., Reagan-Shaw, S., Jarrard, D.F., and Mukhtar, H. (2006). A novel biomarker for staging human prostate adenocarcinoma: overexpression of matriptase with concomitant loss of its inhibitor, hepatocyte growth factor activator inhibitor-1. Cancer Epidemiol. Biomarkers Prev. 15, 217-227. https://doi.org/10.1158/1055-9965.EPI-05-0737
  40. Sales, K.U., Friis, S., Konkel, J.E., Godiksen, S., Hatakeyama, M., Hansen, K.K., Rogatto, S.R., Szabo, R., Vogel, L.K., Chen, W., et al. (2015). Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis. Oncogene 34, 346-356. https://doi.org/10.1038/onc.2013.563
  41. Szatrowski, T.P. and Nathan, C.F. (1991). Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794-798.
  42. Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D.R., Pimentel, H., Salzberg, S.L., Rinn, J.L., and Pachter, L. (2012). Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562-578. https://doi.org/10.1038/nprot.2012.016
  43. Tsai, C.H., Teng, C.H., Tu, Y.T., Cheng, T.S., Wu, S.R., Ko, C.J., Shyu, H.Y., Lan, S.W., Huang, H.P., Tzeng, S.F., et al. (2014). HAI-2 suppresses the invasive growth and metastasis of prostate cancer through regulation of matriptase. Oncogene 33, 4643-4652. https://doi.org/10.1038/onc.2013.412
  44. Tseng, C.C., Jia, B., Barndt, R., Gu, Y., Chen, C.Y., Tseng, I.C., Su, S.F., Wang, J.K., Johnson, M.D., and Lin, C.Y. (2017). Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity. PLoS One 12, e0183507.
  45. Wang, J.K., Teng, I.J., Lo, T.J., Moore, S., Yeo, Y.H., Teng, Y.C., Kaul, M., Chen, C.C., Zuo, A.H., Chou, F.P., et al. (2014). Matriptase autoactivation is tightly regulated by the cellular chemical environments. PLoS One 9, e93899.
  46. Wei, T., Simk, V., Levy, M., Xie, Y., Jin, Y., and Zemla, J. (2017). R package "corrplot": Visualization of a Correlation Matrix (Version 0.84).
  47. Yoshimura, T., Howard, O.M., Ito, T., Kuwabara, M., Matsukawa, A., Chen, K., Liu, Y., Liu, M., Oppenheim, J.J., and Wang, J.M. (2013). Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells. PLoS One8 , e58791.
  48. Zoratti, G.L., Tanabe, L.M., Varela, F.A., Murray, A.S., Bergum, C., Colombo, E., Lang, J.E., Molinolo, A.A., Leduc, R., Marsault, E., et al. (2015). Targeting matriptase in breast cancer abrogates tumour progression via impairment of stromal-epithelial growth factor signalling. Nat. Commun. 6, 6776.