Advances in nano research

  • 제12권6호
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  • Pages.639-652
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  • 2022
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  • 2287-237X(pISSN)
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  • 2287-2388(eISSN)
테크노프레스 (Techno-Press)
권호 표지
DOI QR코드

DOI QR Code

P3H4 promotes renal cell carcinoma progression and suppresses antitumor immunity via regulating GDF15-MMP9-PD-L1 axis

  • Tian, Shuo (Chinese PLA Medical School) ;
  • Huang, Yan (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Lai, Dong (Chinese PLA Medical School) ;
  • Wang, Hanfeng (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Du, Songliang (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Shen, Donglai (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Chen, Weihao (Chinese PLA Medical School) ;
  • Xuan, Yundong (Chinese PLA Medical School) ;
  • Lu, Yongliang (Chinese PLA Medical School) ;
  • Feng, Huayi (Chinese PLA Medical School) ;
  • Zhang, Xiangyi (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Zhao, Wenlei (Chinese PLA Medical School) ;
  • Wang, Chenfeng (Chinese PLA Medical School) ;
  • Wang, Tao (Chinese PLA Medical School) ;
  • Wu, Shengpan (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Huang, Qingbo (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Niu, Shaoxi (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Wang, Baojun (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Ma, Xin (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital) ;
  • Zhang, Xu (Department of Urology, The Third Medical Centre, Chinese PLA General Hospital)
  • 투고 : 2021.01.18
  • 심사 : 2022.03.21
  • 발행 : 2022.06.25
⟨ 이전 논문 다음 논문 ⟩

초록

The prolyl 3-hydroxylase family member 4 (P3H4), is associated with post-translational modification of fibrillar collagens and aberrantly activated in cancer leading to tumor progression. However, its role in clear cell renal cell carcinoma (ccRCC) is still unknown. Here we reported that P3H4 was highly expressed in renal cancer tissues and significantly positive correlated with poor prognosis. Knockdown of P3H4 inhibited the proliferation, migration and metastasis of renal cancer cells in vitro and in vivo, and also, overexpression of it enhanced the oncogenic process. Mechanistically, P3H4 depletion decreased the levels of GDF15-MMP9 axis and repressed its downstream signaling. Further functional studies revealed that inhibition of GDF15 suppressed renal cancer cell growth and GDF15 recombinant human protein (rhGDF15) supplementation effectively rescued the inhibitory effect induced by P3H4 knockdown. Moreover, decreased levels of MMP9 caused by inhibition of P3H4-GDF15 signaling constrained the expression of PD-L1 and suppression of P3H4 accordingly promoted anti-tumor immunity via stimulating the infiltration of CD4+ and CD8+ T cells in syngeneic mice model. Taken together, our findings firstly demonstrated that P3H4 promotes ccRCC progression by activating GDF15-MMP9-PD-L1 axis and targeting P3H4-GDF15-MMP9 signaling pathway can be a novel strategy of controlling ccRCC malignancy.

키워드

과제정보

This work was supported by National Natural Science Foundation of China (Grand No. 81972389 and 81770790), and Distinguished Young Scholar Project of PLA General Hospital (Grand No. 2020-JQPY-002).

참고문헌

  1. Abd El-Aziz, S.H., Endo, Y., Miyamaori, H., Takino, T. and Sato, H. (2007), "Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth", Cancer Sci., 98(9), 1330-1335. https://doi.org/10.1111/j.1349-7006.2007.00547.x.
  2. Ahmed, D.S., Isnard, S., Lin, J., Routy, B. and Routy, J.P. (2021), "GDF15/GFRAL pathway as a metabolic signature for cachexia in patients with cancer", J. Cancer., 12(4), 1125-1132. https://doi.org/10.7150/jca.50376.
  3. Assadi, A., Zahabi, A. and Hart, R.A. (2020), "GDF15, an update of the physiological and pathological roles it plays: A review", Pflug. Arch. Eur, J, Phys., 472(11), 1535-1546. https://doi.org/10.1007/s00424-020-02459-1.
  4. Baek, S.J. and Eling, T. (2019), "Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases", Pharmacol. Ther., 198, 46-58. https://doi.org/10.1016/j.pharmthera.2019.02.008.
  5. Bucalo, M.L., Barbieri, C., Roca, S., Ion Titapiccolo, J., Ros Romero, M.S., Ramos, R., Albaladejo, M., Manzano, D., Mari, F. and Molina, M. (2018), "The anaemia control model: Does it help nephrologists in therapeutic decision-making in the management of anaemia?", Nefrologia, 38(5), 491-502. https://doi.org/10.1016/j.nefroe.2018.10.001.
  6. Buchholz, K., Antosik, P., Grzanka, D., Gagat, M., Smolinska, M., Grzanka, A., Gzil, A., Kasperska, A. and Klimaszewska-Wisniewska, A. (2021), "Expression of the body-weight signaling players: GDF15, GFRAL and RET and their clinical relevance in gastric cancer", J. Cancer, 12(15), 4698-4709. https://doi.org/10.7150/jca.55511.
  7. Chen, Q., Pearlman, R.E. and Moens, P.B. (1992), "Isolation and characterization of a cDNA encoding a synaptonemal complex protein", Biochem. Cell Biol., 70(10-11), 1030-1038. https://doi.org/10.1139/o92-147.
  8. Coll, A.P., Chen, M., Taskar, P., Rimmington, D., Patel, S., Tadross, J.A., Cimino, I., Yang, M., Welsh, P., Virtue, S., Goldspink, D.A., Miedzybrodzka, E.L., Konopka, A.R., Esponda, R.R., Huang, J.T., Tung, Y.C.L., Rodriguez-Cuenca, S., Tomaz, R.A., Harding, H.P., Melvin, A., Yeo, G.S.H., Preiss, D., Vidal-Puig, A., Vallier, L., Nair, K.S., Wareham, N.J., Ron, D., Gribble, F.M., Reimann, F., Sattar, N., Savage, D.B., Allan, B.B. and O'Rahilly, S. (2020), "GDF15 mediates the effects of metformin on body weight and energy balance", Nature, 578(7795), 444-448. https://doi.org/10.1038/s41586-019-1911-y.
  9. Coussens, L.M., Fingleton, B. and Matrisian, L.M. (2002), "Matrix metalloproteinase inhibitors and cancer: trials and tribulations", Science, 295(5564), 2387-2392. https://doi.org/10.1126/science.1067100.
  10. Day, E.A., Ford, R.J., Smith, B.K., Mohammadi-Shemirani, P., Morrow, M.R., Gutgesell, R.M., Lu, R., Raphenya, A.R., Kabiri, M., McArthur, A.G., McInnes, N., Hess, S., Pare, G., Gerstein, H.C. and Steinberg, G.R. (2019), "Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss", Nat. Metab., 1(12), 1202-1208. https://doi.org/10.1038/s42255-019-0146-4.
  11. Dorandish, S., Williams, A., Atali, S., Sendo, S., Price, D., Thompson, C., Guthrie, J., Heyl, D. and Evans, H.G. (2021), "Regulation of amyloid-beta levels by matrix metalloproteinase-2/9 (MMP2/9) in the media of lung cancer cells", Sci. Rep., 11(1), 9708. https://doi.org/10.1038/s41598-021-88574-0.
  12. Du, W., Zhang, L., Brett-Morris, A., Aguila, B., Kerner, J., Hoppel, C.L., Puchowicz, M., Serra, D., Herrero, L., Rini, B.I., Campbell, S. and Welford, S.M. (2017), "HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism", Nat. Commun., 8(1), 1769. https://doi.org/10.1038/s41467-017-01965-8.
  13. Egeblad, M. and Werb, Z. (2002), "New functions for the matrix metalloproteinases in cancer progression", Nat. Rev. Cancer., 2(3), 161-174. https://doi.org/10.1038/nrc745.
  14. Escudier, B., Porta, C., Schmidinger, M., Rioux-Leclercq, N., Bex, A., Khoo, V., Grunwald, V., Gillessen, S. and Horwich, A. (2019), "Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger", Ann. Oncol., 30(5), 706-720. https://doi.org/10.1093/annonc/mdz056.
  15. Fields, G.B. (1991), "A model for interstitial collagen catabolism by mammalian collagenases", J. Theor. Biol., 153(4), 585-602. https://doi.org/10.1016/s0022-5193(05)80157-2.
  16. Fields, G.B. (2013), "Interstitial collagen catabolism", J. Biol. Chem., 288(13), 8785-8793. https://doi.org/10.1074/jbc.R113.451211.
  17. Griner, S.E., Joshi, J.P. and Nahta, R. (2013), "Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion", Biochem. Pharmacol., 85(1), 46-58. https://doi.org/10.1016/j.bcp.2012.10.007.
  18. Gruenwald, K., Castagnola, P., Besio, R., Dimori, M., Chen, Y., Akel, N.S., Swain, F.L., Skinner, R.A., Eyre, D.R., Gaddy, D., Suva, L.J. and Morello, R. (2014), "Sc65 is a novel endoplasmic reticulum protein that regulates bone mass homeostasis", J. Bone Miner. Res., 29(3), 666-675. https://doi.org/10.1002/jbmr.2075.
  19. Guo, F., Zhou, Y., Guo, H., Ren, D., Jin, X. and Wu, H. (2021), "NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15", Cell Death Discov., 7(1), 78. https://doi.org/10.1038/s41420-021-00462-8.
  20. Hao, L., Pang, K., Pang, H., Zhang, J., Zhang, Z., He, H., Zhou, R., Shi, Z. and Han, C. (2020), "Knockdown of P3H4 inhibits proliferation and invasion of bladder cancer", Aging, 12(3), 2156-2168. https://doi.org/10.18632/aging.102732.
  21. Huang, L.L., Wang, Z., Cao, C.J., Ke, Z.F., Wang, F., Wang, R., Luo, C.Q., Lu, X. and Wang, L.T. (2017), "AEG-1 associates with metastasis in papillary thyroid cancer through upregulation of MMP2/9", Int. J. Oncol., 51(3), 812-822. https://doi.org/10.3892/ijo.2017.4074.
  22. Hudson, D.M. and Eyre, D.R. (2013), "Collagen prolyl 3-hydroxylation: A major role for a minor post-translational modification?", Connect. Tissue Res., 54(4-5), 245-251. https://doi.org/10.3109/03008207.2013.800867.
  23. Imai, K. and Takaoka, A. (2006), "Comparing antibody and small-molecule therapies for cancer", Nat. Rev. Cancer., 6(9), 714-727. https://doi.org/10.1038/nrc1913.
  24. Jin, X., Zhou, H., Song, J., Cui, H., Luo, Y. and Jiang, H. (2021), "P3H4 overexpression serves as a prognostic factor in lung adenocarcinoma", Comput. Math. Methods Med., 2021, 9971353. https://doi.org/10.1155/2021/9971353.
  25. Jonasch, E., Walker, C.L. and Rathmell, W.K. (2021), "Clear cell renal cell carcinoma ontogeny and mechanisms of lethality", Nat. Rev. Nephrol., 17(4), 245-261. https://doi.org/10.1038/s41581-020-00359-2.
  26. Kessenbrock, K., Plaks, V. and Werb, Z. (2010), "Matrix metalloproteinases: Regulators of the tumor microenvironment", Cell, 141(1), 52-67. https://doi.org/10.1016/j.cell.2010.03.015.
  27. Lai, Y., Tang, F., Huang, Y., He, C., Chen, C., Zhao, J., Wu, W. and He, Z. (2021), "The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy", J. Cell Physiol., 236(3), 1616-1627. https://doi.org/10.1002/jcp.29969.
  28. Lee, H.J., Cho, H.E. and Park, H.J. (2021), "Germinated black soybean fermented with Lactobacillus pentosus SC65 alleviates DNFB-induced delayed-type hypersensitivity in C57BL/6N mice", J. Ethnopharmacol., 265, 113236. https://doi.org/10.1016/j.jep.2020.113236.
  29. Lee, Y.M., Kim, J.M., Lee, H.J., Seong, I.O. and Kim, K.H. (2019), "Immunohistochemical expression of CD44, matrix metalloproteinase2 and matrix metalloproteinase9 in renal cell carcinomas", Urol. Oncol., 37(10), 742-748. https://doi.org/10.1016/j.urolonc.2019.04.017.
  30. Lerner, L., Hayes, T.G., Tao, N., Krieger, B., Feng, B., Wu, Z., Nicoletti, R., Chiu, M.I., Gyuris, J. and Garcia, J.M. (2015), "Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients", J. Cachexia Sarcopenia Muscle, 6(4), 317-324. https://doi.org/10.1002/jcsm.12033.
  31. Lerner, L., Tao, J., Liu, Q., Nicoletti, R., Feng, B., Krieger, B., Mazsa, E., Siddiquee, Z., Wang, R., Huang, L., Shen, L., Lin, J., Vigano, A., Chiu, M.I., Weng, Z., Winston, W., Weiler, S. and Gyuris, J. (2016), "MAP3K11/GDF15 axis is a critical driver of cancer cachexia", J. Cachexia Sarcopenia Muscle, 7(4), 467-482. https://doi.org/10.1002/jcsm.12077.
  32. Li, C., Wang, J., Kong, J., Tang, J., Wu, Y., Xu, E., Zhang, H. and Lai, M. (2016), "GDF15 promotes EMT and metastasis in colorectal cancer", Oncotarget, 7(1), 860-872. https://doi.org/10.18632/oncotarget.6205.
  33. Li, L., Zhang, R., Yang, H., Zhang, D., Liu, J., Li, J. and Guo, B. (2020), "GDF15 knockdown suppresses cervical cancer cell migration in vitro through the TGF-beta/Smad2/3/Snail1 pathway", FEBS Open Bio, 10(12), 2750-2760. https://doi.org/10.1002/2211-5463.13013.
  34. Li, S., Ma, Y.M., Zheng, P.S. and Zhang, P. (2018a), "GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2", J. Exp. Clin. Cancer Res., 37(1), 80. https://doi.org/10.1186/s13046-018-0744-0.
  35. Li, W., Ye, L., Chen, Y. and Chen, P. (2018b), "P3H4 is correlated with clinicopathological features and prognosis in bladder cancer", World J. Surg. Oncol., 16(1), 206. https://doi.org/10.1186/s12957-018-1507-2.
  36. Lodi, R.S., Yu, B., Xia, L. and Liu, F. (2021), "Roles and Regulation of Growth differentiation factor-15 in the Immune and tumor microenvironment", Hum. Immunol., 82(12), 937-944. https://doi.org/10.1016/j.humimm.2021.06.007.
  37. Lu, X., He, X., Su, J., Wang, J., Liu, X., Xu, K., De, W., Zhang, E., Guo, R. and Shi, Y.E. (2018), "EZH2-mediated epigenetic suppression of gdf15 predicts a poor prognosis and regulates cell proliferation in non-small-cell lung cancer", Mol. Ther. Nucleic. Acids., 12, 309-318. https://doi.org/10.1016/j.omtn.2018.05.016.
  38. Ma, J.J., Kong, L.M., Liao, C.G., Jiang, X., Wang, Y. and Bao, T.Y. (2012), "Suppression of MMP-9 activity by NDRG2 expression inhibits clear cell renal cell carcinoma invasion", Med Oncol. 29(5), 3306-3313. https://doi.org/10.1007/s12032-012-0265-1.
  39. Marshall, D.C., Lyman, S.K., McCauley, S., Kovalenko, M., Spangler, R., Liu, C., Lee, M., O'Sullivan, C., Barry-Hamilton, V., Ghermazien, H., Mikels-Vigdal, A., Garcia, C.A., Jorgensen, B., Velayo, A.C., Wang, R., Adamkewicz, J.I. and Smith, V. (2015), "Selective allosteric inhibition of mmp9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer", PLoS One, 10(5), e0127063. https://doi.org/10.1371/journal.pone.0127063.
  40. Motzer, R.J., Jonasch, E., Agarwal, N., Bhayani, S., Bro, W.P., Chang, S.S., Choueiri, T.K., Costello, B.A., Derweesh, I.H., Fishman, M., Gallagher, T.H., Gore, J.L., Hancock, S.L., Harrison, M.R., Kim, W., Kyriakopoulos, C., LaGrange, C., Lam, E.T., Lau, C., Michaelson, M.D., Olencki, T., Pierorazio, P.M., Plimack, E.R., Redman, B.G., Shuch, B., Somer, B., Sonpavde, G., Sosman, J., Dwyer, M. and Kumar, R. (2017), "Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology", J. Natl. Compr. Cancer Netw., 15(6), 804-834. https://doi.org/10.6004/jnccn.2017.0100.
  41. Nakayasu, E.S., Syed, F., Tersey, S.A., Gritsenko, M.A., Mitchell, H.D., Chan, C.Y., Dirice, E., Turatsinze, J.V., Cui, Y., Kulkarni, R.N., Eizirik, D.L., Qian, W.J., Webb-Robertson, B.M., Evans-Molina, C., Mirmira, R.G. and Metz, T.O. (2020), "Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention", Cell. Metab. 31(2), 363-374 e366. https://doi.org/10.1016/j.cmet.2019.12.005.
  42. Ochs, R.L., Stein Jr, T.W., Chan, E.K., Ruutu, M. and Tan, E.M. (2017), "cDNA cloning and characterization of a novel nucleolar protein", Mol. Biol. Cell., 7(7), 1015-1024. https://doi.org/10.1091/mbc.7.7.1015.
  43. Qian, H., Li, X., Zhang, W., Ma, L., Sun, J., Tang, X., Chen, Y., Teng, L., Wang, W., Li, D., Xu, Y., Li, C. and Cao, Y. (2018), "Caspase-10, matrix metalloproteinase-9 and total laminin are correlated with the tumor malignancy of clear cell renal cell carcinoma", Oncol. Lett., 16(2), 2039-2045. https://doi.org/10.3892/ol.2018.8845.
  44. Roy, R., Yang, J. and Moses, M.A. (2009), "Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer", J. Clin. Oncol., 27(31), 5287-5297. https://doi.org/10.1200/JCO.2009.23.5556.
  45. Smith, W.M., Purvis, I.J., Bomstad, C.N., Labak, C.M., Velpula, K.K., Tsung, A.J., Regan, J.N., Venkataraman, S., Vibhakar, R. and Asuthkar, S. (2019), "Therapeutic targeting of immune checkpoints with small molecule inhibitors", Am. J. Transl. Res., 11(2), 529-541.
  46. Spanopoulou, A. and Gkretsi, V. (2020), "Growth differentiation factor 15 (GDF15) in cancer cell metastasis: from the cells to the patients", Clin. Exp. Metastas., 37(4), 451-464. https://doi.org/10.1007/s10585-020-10041-3.
  47. Suriben, R., Chen, M., Higbee, J., Oeffinger, J., Ventura, R., Li, B., Mondal, K., Gao, Z., Ayupova, D., Taskar, P., Li, D., Starck, S.R., Chen, H.H., McEntee, M., Katewa, S.D., Phung, V., Wang, M., Kekatpure, A., Lakshminarasimhan, D., White, A., Olland, A., Haldankar, R., Solloway, M.J., Hsu, J.Y., Wang, Y., Tang, J., Lindhout, D.A. and Allan, B.B. (2020), "Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice", Nat Med. 26(8), 1264-1270. https://doi.org/10.1038/s41591-020-0945-x.
  48. Tsai, V.W.W., Husaini, Y., Sainsbury, A., Brown, D.A. and Breit, S.N. (2018), "The MIC-1/GDF15-GFRAL pathway in energy homeostasis: Implications for obesity, cachexia, and other associated diseases", Cell. Metab., 28(3), 353-368. https://doi.org/10.1016/j.cmet.2018.07.018.
  49. Van Doren, S.R. (2015), "Matrix metalloproteinase interactions with collagen and elastin", Matrix Biol., 44-46, 224-231. https://doi.org/10.1016/j.matbio.2015.01.005.
  50. Wan, B., Zeng, Q., Tang, X.Z. and Tang, Y.X. (2018), "P3H4 affects renal carcinoma through up-regulating miR-1/133a", Eur. Rev. Med. Pharmacol. Sci., 22(16), 5180-5186. https://doi.org/10.26355/eurrev_201808_15714.
  51. Wei, M., Liu, X., Cao, C., Yang, J., Lv, Y., Huang, J., Wang, Y. and Qin, Y. (2018), "An engineered PD-1-based and MMP-2/9-oriented fusion protein exerts potent antitumor effects against melanoma", BMB Rep., 51(11), 572-577. https://doi.org/10.5483/BMBRep.2018.51.11.076.
  52. Weliky, N., Leaman, D.H., Jr. and Kallman, B.J. (1975), "Stability and dissociation of P3H4-1 Burkitt's lymphoma cell soluble complement-fixing antigen identified with human serum", Cancer Res. 35(6), 1580-1585.
  53. Yang, C., Yu, H., Chen, R., Tao, K., Jian, L., Peng, M., Li, X., Liu, M. and Liu, S. (2019), "CXCL1 stimulates migration and invasion in ERnegative breast cancer cells via activation of the ERK/MMP2/9 signaling axis", Int. J. Oncol., 55(3), 684-696. https://doi.org/10.3892/ijo.2019.4840.
  54. Ye, Y., Kuang, X., Xie, Z., Liang, L., Zhang, Z., Zhang, Y., Ma, F., Gao, Q., Chang, R., Lee, H.H., Zhao, S., Su, J., Li, H., Peng, J., Chen, H., Yin, M., Peng, C., Yang, N., Wang, J., Liu, J., Liu, H., Han, L. and Chen, X. (2020), "Small-molecule MMP2/MMP9 inhibitor SB-3CT modulates tumor immune surveillance by regulating PD-L1", Genome Med. 12(1), 83. https://doi.org/10.1186/s13073-020-00780-z.
  55. Yue, Y.C., Yang, B.Y., Lu, J., Zhang, S.W., Liu, L., Nassar, K., Xu, X.X., Pang, X.Y. and Lv, J.P. (2020), "Metabolite secretions of Lactobacillus plantarum YYC-3 may inhibit colon cancer cell metastasis by suppressing the VEGF-MMP2/9 signaling pathway", Microb. Cell Fact., 19(1), 213. https://doi.org/10.1186/s12934-020-01466-2.
  56. Zhang, W., Hu, C., Wang, X., Bai, S., Cao, S., Kobelski, M., Lambert, J.R., Gu, J. and Zhan, Y. (2019), "Role of GDF15 in methylseleninic acid-mediated inhibition of cell proliferation and induction of apoptosis in prostate cancer cells", PLoS One, 14(9), e0222812. https://doi.org/10.1371/journal.pone.0222812.
  57. Zhao, F., Evans, K., Xiao, C., DeVito, N., Theivanthiran, B., Holtzhausen, A., Siska, P.J., Blobe, G.C. and Hanks, B.A. (2018), "Stromal fibroblasts mediate anti-PD-1 resistance via MMP-9 and dictate TGFbeta inhibitor sequencing in melanoma", Cancer Immunol. Res., 6(12), 1459-1471. https://doi.org/10.1158/2326-6066.CIR-18-0086.
  58. Zhou, R., Xu, L., Ye, M., Liao, M., Du, H. and Chen, H. (2014), "Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways", Horm. Metab. Res., 46(11), 753-760. https://doi.org/10.1055/s-0034-1376977.
  59. Zhu, H.F. and Li, Y. (2018), "Small-Molecule Targets in Tumor Immunotherapy", Nat. Prod. Bioprospect., 8(4), 297-301. https://doi.org/10.1007/s13659-018-0177-7.