Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An integrated ceRNA network identifies miR-375 as an upregulated miRNA playing a tumor suppressive role in aggressive prostate cancer

Oncogene (2024)Cite this article

Subjects

Abstract

Prostate cancer (PCa) remains a significant cause of morbidity and mortality among men worldwide. A number of genes have been implicated in prostate tumorigenesis, but the mechanisms underlying their dysregulation are still incompletely understood. Evidence has established the competing endogenous RNA (ceRNA) theory as a novel regulatory mechanism for post-transcriptional alterations. Yet, a comprehensive characterization of ceRNA network in PCa lacks. Here we utilize stringent in-silico methods to construct a large ceRNA network across different PCa stages, and provide experimental demonstration for the competing regulation among protumorigenic SEC23A, PHTF2, and their corresponding ceRNA pairs. Using machine learning, we establish a ceRNA-based signature (ceRNA_sig) predictive of androgen receptor (AR) activity, tumor aggressiveness, and patient outcomes. Importantly, we identify miR-375 as a key node in PCa ceRNA network, which is upregulated in PCa relative to normal tissues. Forced expression of miR-375 significantly inhibits, while its inhibition promotes, aggressive behaviors of both AR+ and AR− PCa cells in vitro and in vivo. Mechanistically, we show that miR-375 predominantly targets genes possessing oncogenic roles (e.g., proliferation, DNA repair, and metastasis), and thus release targets with tumor suppressive functions. This action model well clarifies why an upregulated miRNA plays a tumor suppressive role in PCa. Together, our study provides new insights into understanding of transcriptomic aberrations during PCa evolution, and nominates miR-375 as a potential therapeutic target for combating aggressive PCa.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification and functional annotation of dysregulation genes during PCa progression.
Fig. 2: Construction and prognosis value of ceRNA network in PCa.
Fig. 3: Molecular characterization of ceRNA_sig high vs. low PCa patients.
Fig. 4: miR-375 inhibits PCa development in vitro and in vivo.
Fig. 5: RNA-seq analysis reveals global miR-375 targeted signaling molecules and pathways.
Fig. 6: miR-375-centered ceRNAs reciprocally regulate each other.
Fig. 7: SEC23A and PHTF2 play oncogenic roles in PCa.

Similar content being viewed by others

Data availability

The RNA-seq data have been deposited in GEO database under accession code GSE234110.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Zhang D, Zhao S, Li X, Kirk JS, Tang DG. Prostate luminal progenitor cells in development and cancer. Trends Cancer. 2018;4:769–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang D, Park D, Zhong Y, Lu Y, Rycaj K, Gong S, et al. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Commun. 2016;7:10798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang D, Hu Q, Liu X, Ji Y, Chao HP, Liu Y, et al. Intron retention is a hallmark and spliceosome represents a therapeutic vulnerability in aggressive prostate cancer. Nat. Commun. 2020;11:2089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zou C, He Q, Feng Y, Chen M, Zhang D. A m(6)Avalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response. NAR Cancer. 2022;4:zcac010.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  8. Cramer P. Organization and regulation of gene transcription. Nature. 2019;573:45–54.

    Article  CAS  PubMed  Google Scholar 

  9. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjostrom M, et al. The DNA methylation landscape of advanced prostate cancer. Nat. Genetics. 2020;52:778–89.

    Article  CAS  PubMed  Google Scholar 

  10. Li Q, Deng Q, Chao HP, Liu X, Lu Y, Lin K, et al. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun. 2018;9:3600.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ala U, Karreth FA, Bosia C, Pagnani A, Taulli R, Leopold V, et al. Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments. Proc Natl Acad Sci USA. 2013;110:7154–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, et al. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wei Y, Tang X, Ren Y, Yang Y, Song F, Fu J, et al. An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity. Signal Transduct Targeted Ther. 2021;6:421.

    Article  CAS  Google Scholar 

  14. Song YX, Sun JX, Zhao JH, Yang YC, Shi JX, Wu ZH, et al. Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. Nat Commun. 2017;8:289.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chan JJ, Kwok ZH, Chew XH, Zhang B, Liu C, Soong TW, et al. A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer. Nucleic Acids Res. 2018;46:1998–2011.

    Article  CAS  PubMed  Google Scholar 

  16. Yang G, Chen X, Quan Z, Liu M, Guo Y, Tang Y, et al. Comprehensive analysis of the FOXA1-related ceRNA network and identification of the MAGI2-AS3/DUSP2 axis as a prognostic biomarker in prostate cancer. Front Oncol. 2023;13:1048521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang J, Huang J, Guo Y, Fu Y, Cao Y, Zhou K, et al. Identification and functional analysis of LncRNA-XIST ceRNA network in prostate cancer. BMC Cancer. 2022;22:935.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang Y, Lieberman R, Pan J, Zhang Q, Du M, Zhang P, et al. miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. Mol Cancer. 2016;15:70.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Selth LA, Das R, Townley SL, Coutinho I, Hanson AR, Centenera MM, et al. A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer. Oncogene. 2017;36:24–34.

    Article  CAS  PubMed  Google Scholar 

  20. Gan J, Liu S, Zhang Y, He L, Bai L, Liao R, et al. MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis. Exp Mol Med. 2022;54:1290–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Article  Google Scholar 

  22. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Macedo-Silva C, Benedetti R, Ciardiello F, Cappabianca S, Jeronimo C, Altucci L. Epigenetic mechanisms underlying prostate cancer radioresistance. Clin Epigenetics. 2021;13:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bushweller JH. Targeting transcription factors in cancer - from undruggable to reality. Nat Rev Cancer. 2019;19:611–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Han H, Cho JW, Lee S, Yun A, Kim H, Bae D, et al. TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018;46:D380–D386.

    Article  CAS  PubMed  Google Scholar 

  26. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomas-Jardin SE, Dahl H, Nawas AF, Bautista M, Delk NA. NF-kappaB signaling promotes castration-resistant prostate cancer initiation and progression. Pharmacol Ther. 2020;211:107538.

    Article  CAS  PubMed  Google Scholar 

  28. Chan JM, Zaidi S, Love JR, Zhao JL, Setty M, Wadosky KM, et al. Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. Science. 2022;377:1180–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Xiong J, Yan L, Zou C, Wang K, Chen M, Xu B, et al. Integrins regulate stemness in solid tumor: an emerging therapeutic target. J Hematol Oncol. 2021;14:177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Beltran H, Prandi D, Mosquera JM, Benelli M, Puca L, Cyrta J, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22:298–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18:248–62.

    Article  CAS  PubMed  Google Scholar 

  33. Liu C, Tang DG. MicroRNA regulation of cancer stem cells. Cancer Res. 2011;71:5950–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ouyang Y, Gao P, Zhu B, Chen X, Lin F, Wang X, et al. Downregulation of microRNA-429 inhibits cell proliferation by targeting p27Kip1 in human prostate cancer cells. Mol Med Rep. 2015;11:1435–41.

    Article  CAS  PubMed  Google Scholar 

  35. Sharma S, Pei X, Xing F, Wu SY, Wu K, Tyagi A, et al. Regucalcin promotes dormancy of prostate cancer. Oncogene. 2021;40:1012–26.

    Article  CAS  PubMed  Google Scholar 

  36. Bhagirath D, Liston M, Patel N, Akoto T, Lui B, Yang TL, et al. MicroRNA determinants of neuroendocrine differentiation in metastatic castration-resistant prostate cancer. Oncogene. 2020;39:7209–23.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Fu Y, Cao T, Zou X, Ye Y, Liu Y, Peng Y, et al. AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer. Oncogenesis. 2023;12:1.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zeng B, Zhao Q, Sun Z, Liu D, Chen H, Li X, et al. SEC23A is an independent prognostic biomarker in bladder cancer correlated With MAPK signaling. Front Genet. 2021;12:672832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chi Y, Wang H, Wang F, Ding M. PHTF2 regulates lipids metabolism in gastric cancer. Aging. 2020;12:6600–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lu X, Fong KW, Gritsina G, Wang F, Baca SC, Brea LT, et al. HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer. Nat Genetics. 2022;54:670–83.

    Article  CAS  PubMed  Google Scholar 

  41. Jing J, Wang B, Liu P. The functional role of SEC23 in vesicle transportation, autophagy and cancer. Int J Biol Sci. 2019;15:2419–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cheng Q, Liu K, Xiao J, Shen K, Wang Y, Zhou X, et al. SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop. J Exp Clin Cancer Res. 2023;42:232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;162:454.

    Article  CAS  PubMed  Google Scholar 

  44. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  45. Yang XZ, Cheng TT, He QJ, Lei ZY, Chi J, Tang Z, et al. LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/beta-catenin pathway. Mol Cancer. 2018;17:126.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wu W, Li Q, Zhu Z, Li C, Lu P, Zhou X, et al. HTR1D functions as a key target of HOXA10-AS/miR-340-3p axis to promote the malignant outcome of pancreatic cancer via PI3K-AKT signaling pathway. Int J Biol Sci. 2022;18:3777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zheng ZQ, Li ZX, Zhou GQ, Lin L, Zhang LL, Lv JW, et al. Long noncoding RNA FAM225A promotes nasopharyngeal carcinoma tumorigenesis and metastasis by acting as ceRNA to sponge miR-590-3p/miR-1275 and upregulate ITGB3. Cancer Res. 2019;79:4612–26.

    Article  CAS  PubMed  Google Scholar 

  48. Yao B, Zhu S, Wei X, Chen MK, Feng Y, Li Z, et al. The circSPON2/miR-331-3p axis regulates PRMT5, an epigenetic regulator of CAMK2N1 transcription and prostate cancer progression. Mol Cancer. 2022;21:119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell. 2013;23:35–47.

    Article  CAS  PubMed  Google Scholar 

  50. Wu Y, Sun X, Song B, Qiu X, Zhao J. MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion. Cancer Med. 2017;6:1686–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. He Z, Li W, Zheng T, Liu D, Zhao S. Human umbilical cord mesenchymal stem cells-derived exosomes deliver microRNA-375 to downregulate ENAH and thus retard esophageal squamous cell carcinoma progression. J Exp Clin Cancer Res. 2020;39:140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu X, Liu Y, Li Y, Chen H, Zhang Y, Liu J, et al. Selective exosome exclusion of miR-375 by glioma cells promotes glioma progression by activating the CTGF-EGFR pathway. J Exp Clin Cancer Res. 2021;40:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li Q, Liu B, Chao HP, Ji Y, Lu Y, Mehmood R, et al. LRIG1 is a pleiotropic androgen receptor-regulated feedback tumor suppressor in prostate cancer. Nat Commun. 2019;10:5494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26:909–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lauss M, Donia M, Harbst K, Andersen R, Mitra S, Rosengren F, et al. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat Commun. 2017;8:1738.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell. 2017;171:934–49.e916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  58. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  59. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7.

    Article  Google Scholar 

  63. Huang HY, Lin YC, Cui S, Huang Y, Tang Y, Xu J, et al. miRTarBase update 2022: an informative resource for experimentally validated miRNA-target interactions. Nucleic Acids Res. 2022;50:D222–D230.

    Article  CAS  PubMed  Google Scholar 

  64. Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42:D92–97.

    Article  CAS  PubMed  Google Scholar 

  65. Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2015;43:D146–152.

    Article  CAS  PubMed  Google Scholar 

  66. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015;4:e05005.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Funding

This work was supported by grants from the Excellent Youth Foundation of Hunan Province (2021JJ10028), the National Natural Science Foundation of China (81972418), the Shenzhen Natural Science Foundation (JCYJ20220530160410024), and the Fundamental Research Funds for the Central Universities. CZ was supported, in part, by the Hunan Province Natural Science Foundation (2022JJ40111) and the Changsha Natural Science Foundation (kq2202182).

Author information

Author notes

  1. These authors contributed equally: Mengjie Chen, Cheng Zou, Yu Tian, Wenchao Li.

Authors and Affiliations

  1. Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, School of BioMedical Sciences, Hunan University, Changsha, China

    Mengjie Chen, Cheng Zou, Yu Tian, Yingying Li & Dingxiao Zhang

  2. Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China

    Wenchao Li

  3. Shenzhen Research Institute, Hunan University, Shenzhen, China

    Dingxiao Zhang

Authors
  1. Mengjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheng Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenchao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dingxiao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CZ and DZ conceived and designed the study, analyzed, and interpreted data, and finalized the manuscript. MC and YT performed most experiments with help from YL Specifically, WL provided the clinical samples and performed IHC analysis. CZ conducted Bioinformatic analysis with input from MC MC and CZ initially drafted the manuscript. All authors read and approved the manuscript. We apologize to the colleagues whose work was not cited due to space constraint.

Corresponding authors

Correspondence to Cheng Zou or Dingxiao Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, M., Zou, C., Tian, Y. et al. An integrated ceRNA network identifies miR-375 as an upregulated miRNA playing a tumor suppressive role in aggressive prostate cancer. Oncogene (2024). https://doi.org/10.1038/s41388-024-03011-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-024-03011-6

Search

Advanced search

Quick links