Статья
Рак предстательной железы (РПЖ) остается одним из самых распространенных злокачественных новообразований у мужчин и одной из ведущих причин онкологической смертности, особенно на стадиях кастрационно-резистентного и метастатического течения заболевания. Накопленные данные свидетельствуют о ключевой роли популяции опухолевых стволовых клеток в инициации опухолевого роста, прогрессии, формировании внутриопухолевой гетерогенности, лекарственной и радиорезистентности РПЖ. В обзоре суммированы сведения и детально рассмотрены четыре перспективных регулятора стволовости и пластичности опухолевых клеток: онкобелок MUC1-C, трансмембранная сериновая протеаза TMPRSS4, орфанный ядерный рецептор TLX и адаптерный PDZ-белок MDA-9/Syntenin. Для каждого из этих молекулярных факторов обсуждаются структура, особенности экспрессии в ткани простаты, участие в ключевых сигнальных путях (Wnt/β-catenin, PI3K/AKT, MAPK, STAT3, NOTCH, TGF-β и др.), а также их вклад в эпителиально-мезенхимальный переход, поддержание ОСК-фенотипа, андроген-независимый рост и резистентность к стандартным видам терапии. Особое внимание уделено данным in vitro и in vivo, подтверждающим значимость MUC1-C, TMPRSS4, TLX и MDA-9/Syntenin как потенциальных биомаркеров неблагоприятного течения РПЖ и мишеней для таргетной и иммунотерапии.
1. Каприн А.Д., Старинский В.В., Петрова Г.В. (ред.) Злокачественные новообразования в России в 2017 году (заболеваемость и смертность). М., 2018.
2. Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. DOI: 10.3322/caac.21834
3. Zhou K., Lu H., Zhang J., Shen Q., Liu P., Xu Q., et al. Prostate cancer stem cells: an updated mini-review. J Cancer. 2024;15(20):6570–6. DOI: 10.7150/jca.100604
4. Омельчук Е.П., Кутилин Д.С., Димитриадис С.Н., Гусарева М.А., Тимошкина Н.Н. Молекулярные и генетические аспекты радиорезистентности рака простаты. Бюллетень Сибирской медицины. 2021;20(3):182–92. DOI: 10.20538/1682-0363-20213-182-192
5. Penning T.M. Dehydroepiandrosterone (DHEA)-SO4 depot and castration-resistant prostate cancer. Vitam Horm. 2018;108:309–31. DOI: 10.1016/bs.vh.2018.01.007
6. Nyquist M.D., Corella A., Coleman I., De Sarkar N., Kaipainen A., Ha G., et al. Combined TP53 and RB1 loss promotes prostate cancer resistance to a spectrum of therapeutics and confers vul-nerability to replication stress. Cell Rep. 2020;31(8):107669. DOI: 10.1016/j.celrep.2020.107669
7. Lumahan L.E.V., Arif M., Whitener A.E., Yi P. Regulating androgen receptor function in prostate cancer: exploring the diversity of post-translational modifications. Cells. 2024;13(2):191. DOI: 10.3390/cells13020191
8. Pan Y., Yuan C., Zeng C., Sun C., Xia L., Wang G., et al. Cancer stem cells and niches: challenges in immunotherapy resistance. Mol Cancer. 2025;24(1):52. DOI: 10.1186/s12943-025-02265-2
9. Lee H., Kim B., Park J., Park S., Yoo G., Yum S., et al. Cancer stem cells: landscape, challenges and emerging therapeutic innovations. Signal Transduct Target Ther. 2025;10(1):248. DOI: 10.1038/s41392-025-02360-2
10. Yuan H., Qiu Y., Mei Z., Liu J., Wang L., Zhang K., et al. Cancer stem cells and tumor-associated macrophages: Interactions and therapeutic opportunities. Cancer Lett. 2025;624:217737. DOI: 10.1016/j.canlet.2025.217737
11. Wang H., Li J., Du F., Deng H. Cancer stem cells: Bridging microenvironmental interactions and clinical therapy. Clin Transl Med. 2025;15(7):e70406. DOI: 10.1002/ctm2.70406
12. Haddadin L., Sun X. Stem cells in cancer: from mechanisms to therapeutic strategies. Cells. 2025;14(7):538. DOI: 10.3390/cells14070538
13. Tong X., Dong C., Liang S. Mucin1 as a potential molecule for cancer immunotherapy and targeted therapy. J Cancer. 2024;15(1):54–67. DOI: 10.7150/jca.88261
14. Radziejewska I. The role of MUC1 in gastric cancer development. Cancers (Basel). 2025;17(20):3331. DOI: 10.3390/cancers17203331
15. Hikita S.T., Kosik K.S., Clegg D.O., Bamdad C. MUC1* mediates the growth of human pluripotent stem cells. PLoS One. 2008;3(10):e3312. DOI: 10.1371/journal.pone.0003312
16. Park J.A., Park S., Park H.B., Han M.K., Lee Y. MUC1-C Contributes to the maintenance of human embryonic stem cells and promotes somatic cell reprogramming. Stem Cells Dev. 2021;30(21):1082–91. DOI: 10.1089/scd.2021.0185
17. Lapointe J., Li C., Higgins J.P., Van de Rijn M., Bair E., Montgomery K., et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci U S A. 2004;101(3):811–6. DOI: 10.1073/pnas.0304146101
18. Kufe D. Dependence on MUC1-C in progression of neuroendocrine prostate cancer. Int J Mol Sci. 2023;24(4):3719. DOI: 10.3390/ijms24043719
19. Shigeta K., Daimon T., Hongo H., Ku S.Y., Ozawa H., Haratake N., et al. MUC1-C dependence in treatment-resistant prostate cancer uncovers a target for antibody-drug conjugate therapy. JCI Insight. 2025;10(14):e190924. DOI: 10.1172/jci.insight.190924
20. Nath S., Mukherjee P. MUC1: a multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332–42. DOI: 10.1016/j.molmed.2014.02.007
21. Yamashita N., Long M., Fushimi A., Yamamoto M., Hata T., Hagiwara M., et al. MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer. J Immunother Cancer. 2021;9(1):e002115. DOI: 10.1136/jitc-2020-002115
22. Altschuler Y., Kinlough C.L., Poland P.A., Bruns J.B., Apodaca G., Weisz O.A., et al. Clathrin-mediated endocytosis of MUC1 is modulated by its glycosylation state. Mol Biol Cell. 2000;11(3):819–31. DOI: 10.1091/mbc.11.3.819
23. Караулов А.В., Гурина Н.Н., Новиков Д.В., Фомина С.Г., Новиков В.В. Роль экспрессии белка muc1 в прогрессии опухоли. Вестник РАМН. 2016;71(5):392–6. DOI: 10.15690/vramn736
24. Hagiwara M., Yasumizu Y., Yamashita N., Rajabi H., Fushimi A., Long M.D., et al. MUC1-C activates the BAF (mSWI/SNF) complex in prostate cancer stem cells. Cancer Res. 2021;81(4):1111–22. DOI: 10.1158/0008-5472.CAN-20-2588
25. Kufe D.W. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009;9(12):874–85. DOI: 10.1038/nrc2761
26. Wan X., Liu J., Lu J.F., Tzelepi V., Yang J., Starbuck M.W., et al. Activation of β-catenin signaling in androgen receptor-negative prostate cancer cells. Clin Cancer Res. 2012;18(3):726–36. DOI: 10.1158/1078-0432.CCR-11-2521
27. Kufe D.W. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene. 2013;32(9):1073–81. DOI: 10.1038/onc.2012.158
28. Kim S. TMPRSS4, a type II transmembrane serine protease, as a potential therapeutic target in cancer. Exp Mol Med. 2023;55(4):716–24. DOI: 10.1038/s12276-023-00975-5
29. Shi G., Yang X., Dai B., Zhang H., Shen Y., Zhu Y., et al. Clinical significance of TMPRSS4 in prostate cancer. Int J Clin Exp Pathol. 2014;7(11):8053–8. PMID: 25550850
30. Yang Y.S., Wen D., Zhao X.F. Transmembrane protease TMPRSS4 promotes the formation and development of mismatch repair deficient colon cancer liver metastasis. Bull Exp Biol Med. 2021 May;171(2):242–6. DOI: 10.1007/s10517-021-05203-6. Erratum in: Bull Exp Biol Med. 2021;172(1):112. DOI: 10.1007/s10517-021-05343-9
31. Min H.J., Lee Y., Zhao X.F., Park Y.K., Lee M.K., Lee J.W., et al. TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion. Cell Signal. 2014;26(2):398–408. DOI: 10.1016/j.cellsig.2013.08.002
32. Jung H., Lee K.P., Park S.J., Park J.H., Jang Y.S., Choi S.Y., et al. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene. 2008;27(18):2635–47. DOI: 10.1038/sj.onc.1210914
33. Lee Y., Ko D., Min H.J., Kim S.B., Ahn H.M., Lee Y., et al. TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1. Oncotarget. 2016;7(31):50315–32. DOI: 10.18632/oncotarget.10382
34. Lee Y., Yoon J., Ko D., Yu M., Lee S., Kim S. TMPRSS4 promotes cancer stem-like properties in prostate cancer cells through upregulation of SOX2 by SLUG and TWIST1. J Exp Clin Cancer Res. 2021;40(1):372. DOI: 10.1186/s13046-021-02147-7
35. Nelson A.T., Wang Y., Nelson E.R. TLX, an orphan nuclear receptor with emerging roles in physiology and disease. Endocrinology. 2021;162(11):bqab184. DOI: 10.1210/endocr/bqab184
36. Liu H.K., Wang Y., Belz T., Bock D., Takacs A., Radlwimmer B., et al. The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation. Genes Dev. 2010;24:683–95. DOI: 10.1101/gad.560310
37. Faudone G., Bischoff-Kont I., Rachor L., Willems S., Zhubi R., Kaiser A., et al. Propranolol activates the orphan nuclear receptor TLX to counteract proliferation and migration of glioblastoma cells. J Med Chem. 2021;64(12):8727–38. DOI: 10.1021/acs.jmedchem.1c00733
38. Lin M.L., Patel H., Remenyi J., Banerji C.R., Lai C.F., Periyasamy M., et al. Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer. Oncotarget. 2015;6(25):21685–703. DOI: 10.18632/oncotarget.3942
39. Jia L., Wu D., Wang Y., You W., Wang Z., Xiao L., et al. Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription. Oncogene. 2018;37(25):3340–55. DOI: 10.1038/s41388-018-0198-z
40. Chow S.T., Fan J., Zhang X., Wang Y., Li Y., Ng C.F. Nuclear receptor TLX functions to promote cancer stemness and EMT in prostate cancer via its direct transactivation of CD44 and stem cell-regulatory transcription factors. Br J Cancer. 2024;131(9):1450–62. DOI: 10.1038/s41416-024-02843-z
41. Pintor-Romero V. G., Hurtado-Ortega E., Nicolás-Morales M. L., Gutiérrez-Torres M., Vences-Velázquez A., Ortuño-Pineda C., et al. Biological role and aberrant overexpression of syntenin-1 in cancer: potential role as a biomarker and therapeutic target. Biomedicines. 2023;11(4):1034. DOI: 10.3390/biomedicines11041034
42. Das S.K., Maji S., Wechman S.L., Bhoopathi P., Pradhan A.K., Talukdar S., et al. MDA-9/Syntenin (SDCBP): Novel gene and therapeutic target for cancer metastasis. Pharmacol Res. 2020; 155:104695. DOI: 10.1016/j.phrs.2020.104695
43. Das S.K., Bhutia S.K., Kegelman T.P., Peachy L., Oyesanya R.A., Dasgupta S., et al. MDA-9/syntenin: a positive gatekeeper of melanoma metastasis. Front Biosci (Landmark Ed). 2012;17(1):1–15. DOI: 10.2741/3911
44. Das S.K., Bhutia S.K., Azab B., Kegelman T.P., Peachy L., Santhekadur P.K., et al. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res. 2013;73(2):844–54. DOI: 10.1158/0008-5472.CAN-12-1681
45. Boukerche H., Su Z.Z., Prévot C., Sarkar D., Fisher P.B. Mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src. Proc Natl Acad Sci U S A. 2008;105(41):15914–9. DOI: 10.1073/pnas.0808171105
46. Dasgupta S., Menezes M.E., Das S.K., Emdad L., Janjic A., Bhatia S. Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling. Clin Cancer Res. 2013;19(17):4621–33. DOI: 10.1158/1078-0432.CCR-13-0585
47. Koo T.H., Lee J.J., Kim E.M., Kim K.W., Kim H.D., Lee J.H. Syntenin is overexpressed and promotes cell migration in metastatic human breast and gastric cancer cell lines. Oncogene. 2002;21(26):4080–8. DOI: 10.1038/sj.onc.1205514
48. Qian X.L., Li Y.Q., Yu B., Gu F., Liu F.F., Li W.D., et al. Syndecan binding protein (SDCBP) is overexpressed in estrogen receptor negative breast cancers, and is a potential promoter for tumor proliferation. PLoS One. 2013;8(3):e60046. DOI: 10.1371/journal.pone.0060046
49. Menezes M.E., Shen X.N., Das S.K., Emdad L., Sarkar D., Fisher P.B. MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer. Oncotarget. 2016;7(49):80175–89. DOI: 10.18632/oncotarget.13373
50. Yu Y., Li S., Wang K., Wan X. A PDZ protein MDA-9/Syntenin: as a target for cancer therapy. Comput Struct Biotechnol J. 2019;17:136–41. DOI: 10.1016/j.csbj.2019.01.002
51. Wang L.K., Pan S.H., Chang Y.L., Hung P.F., Kao S.H., Wang W.L., et al. MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma. Oncotarget. 2016;7(1):386–401. DOI: 10.18632/oncotarget.6299
52. Talukdar S., Das S.K., Pradhan A.K., Emdad L., Shen X.N., Windle J.J., et al. Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells. Oncotarget. 2016;7(34):54102–19. DOI: 10.18632/oncotarget.10851
53. Talukdar S., Das S.K., Pradhan A.K., Emdad L., Windle J.J., Sarkar D., et al. MDA-9/Syntenin (SDCBP) is a critical regulator of chemoresistance, survival and stemness in prostate cancer stem cells. Cancers (Basel). 2019;12(1):53. DOI: 10.3390/cancers12010053
54. Maji S., Pradhan A.K., Kumar A., Bhoopathi P., Mannangatti P., Guo C., et al. MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis. Proc Natl Acad Sci U S A. 2023;120(45):e2307094120. DOI: 10.1073/pnas.2307094120
55. Das S.K., Pradhan A.K., Bhoopathi P., Talukdar S., Shen X.N., Sarkar D., et al. The MDA-9/Syntenin/IGF1R/STAT3 Axis directs prostate cancer invasion. Cancer Res. 2018;78(11):2852–63. DOI: 10.1158/0008-5472.CAN-17-2992
56. Atawia I.M., Kushwaha P.P., Verma S., Lin S., Shankar E., Abdel-Gawad O., et al. Inhibition of Wnt/β-catenin pathway overcomes therapeutic resistance to abiraterone in castration-resistant prostate cancer. Mol Carcinog. 2023;62(9):1312–24. DOI: 10.1002/mc.23565
57. Liu Y.M., Wu A.D., Chen Y., Ma T.F., Dong B.Z., She Z.G., et al. Gastrodin inhibits prostate cancer proliferation by targeting canonical Wnt/β-catenin signaling pathway. Med Oncol. 2023;41(1):32. DOI: 10.1007/s12032-023-02254-9
58. Saito S., Ando K., Sakamoto S., Xu M., Yamada Y., Rii J., et al. The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism. Cancer Sci. 2024;115(7):2461–72. DOI: 10.1111/cas.16191
59. Lee M.H., Kundu J.K., Keum Y.S., Cho Y.Y., Surh Y.J., Choi B.Y. Resveratrol inhibits IL-6-induced transcriptional activity of AR and STAT3 in human prostate cancer LNCaP-FGC cells. Biomol Ther (Seoul). 2014;22(5):426–30. DOI: 10.4062/biomolther.2014.061
60. Cao H., Feng Y., Sun P., Chen L., Wang D., Gao R. Zhoushi Qiling decoction inhibits proliferation of human prostate cancer cells through IL6/STAT3 pathway. J Cancer. 2023;14(12):2246–54. DOI: 10.7150/jca.84943
61. Cai F., Guo S., Huang S., Li J., Liu W. Rubimaillin suppresses proliferation, migration and invasion of prostate cancer cells via the Notch-1/MMP signaling pathway. Cell Mol Biol (Noisy-le-grand). 2020;66(2):130–4. PMID: 32415939
62. Cai M., Ge S., Hong Y., Chen Y., Ren Y.Z., Zhong D., et al. Tegaserod maleate exerts anti-tumor effects on prostate cancer via repressing sonic hedgehog signaling pathway. Mol Med. 2025;31(1):30. DOI: 10.1186/s10020-025-01080-1
