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Hyperglycemia and microRNAs in prostate cancer

Prostate Cancer and Prostatic Diseases (2024)Cite this article

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Abstract

Background

Hyperglycemia can promote the development of prostate cancer (PCa). Differential expression levels of miRNAs between PCa patients and controls were also reported. Therefore, we examined the relationship between hyperglycemia and miRNA levels in PCa.

Methods

Relative expression of urinary miR-574-3p, miR-375, miR-205-5p, miR-200b-3p, miR-187-3p, miR-182-5p, and miR-100-5p were investigated in 105 PCa patients and 138 noncancer controls by Real-Time quantitative PCR. Fasting plasma glucose measurements were retrieved from clinical records. The differential miRNA expressions among groups were compared using non-parametric tests. Correlations with glucose and prostate-specific antigen (PSA) were tested using Pearson correlation coefficient.

Results

When we analyzed miRNA expression according to glycemic state, significant down-regulations were found for miR-200b-3p, miR-187-3p, miR-182-5p, and miR-100-5p in noncancer controls with high glucose. The lowest down-regulations were observed for miR-187-3p, miR-182-5p, and miR-100-5p. Subsequently, when hyperglycemia was considered in PCa, significant dysregulations of selected miRNAs were found in hyperglycemic PCa patients than in controls with high glucose. In particular, miR-375 and miR-182-5p showed a 3-FC in hyperglycemic PCa patients than controls who left hyperglycemia untreated. Conversely, only a down-regulation of miR-574-3p was observed in PCa patients regardless of glycemic status and only modest down-regulation of miR-574-3p, miR-200b-3p, miR-187-3p and miR-182-5p were found in normoglycemic PCa patients. Next, significant correlations between miRNAs and glucose (miR-200b-3p, miR-100-5p) and PSA (miR-205-5p and miR-187-3p) were detected in controls. Similarly, miR-205-5p and miR-187-3p were correlated with glucose in PCa patients, while miR-574-3p and miR-375 showed inverse relationships.

Conclusions

miRNA dysregulations can occur in hyperglycemic PCa patients as compared to noncancer controls who left hyperglycemia untreated. Hyperglycemia can consistently promote the expression of miR-375 and miR-182-5p. Uncontrolled hyperglycemic state could contribute to the creation of a suitable microenvironment for later PCa development by promoting gene expression.

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Fig. 1: Relative expression levels of miR-574-3p, miR-375, miR-205-5p, miR-200b-3p, miR-187-3p, miR-182-5p, and miR-100-5p according to prostate cancer and glycemic state.
Fig. 2: Heatmap showing correlations between the expression levels of miR-574-3p, miR-375, miR-205-5p, miR-200b-3p, miR-187-3p, miR-182-5p, miR-100-5p, and the concentrations of fasting plasma glucose and serum prostate-specific antigen (PSA) among noncancer controls and prostate cancer (PCa) patients.

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Data availability

The dataset used during the current study is available from the corresponding author upon reasonable request.

References

  1. 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 

  2. Auvinen A, Moss SM, Tammela TLJ, Taari K, Roobol MJ, Schrader FH, et al. Absolute effect of prostate cancer screening: balance of benefits and harms by center within the European randomized study of prostate cancer screening. Clin Cancer Res. 2015;22:243–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ahdoot M, Wilbur AR, Reese SE, Lebastchi AH, Mehralivand S, Gomella PT, et al. MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. N. Engl J Med. 2020;382:917–28.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nair VS, Pritchard CC, Tewari M, Ioannidis JPA. Design and analysis for studying microRNAs in human disease: a primer on -omic technologies. Am J Epidemiol. 2014;180:140–52.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  7. Ardekani AM, Naeini MM. The role of MicroRNAs in human diseases. Avicenna J Med Biotechnol. 2010;2:161–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fabris L, Ceder Y, Chinnaiyan AM, Jenster GW, Sorensen KD, Tomlins S, et al. The potential of MicroRNAs as prostate cancer biomarkers. Eur Urol. 2016;70:312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Aveta A, Cilio S, Contieri R, Spena G, Napolitano L, Manfredi C, et al. Urinary MicroRNAs as biomarkers of urological cancers: a systematic review. Int J Mol Sci. 2023;24:10846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Marrone MT, Selvin E, Barber JR, Platz EA, Joshu CE. Hyperglycemia, classified with multiple biomarkers simultaneously in men without diabetes, and risk of fatal prostate cancer. Cancer Prev Res. 2019;12:103.

    Article  CAS  Google Scholar 

  11. Murtola TJ, Vihervuori VJY, Lahtela J, Talala K, Taari K, Tammela TLJ, et al. Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Br J cancer. 2018;118:1248–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Murtola TJ, Salli SM, Talala K, Taari K, Tammela TLJ, Auvinen A. Blood glucose, glucose balance, and disease-specific survival after prostate cancer diagnosis in the Finnish Randomized Study of Screening for Prostate Cancer. Prostate Cancer Prostatic Dis. 2019;22:453–60.

    Article  CAS  PubMed  Google Scholar 

  13. Arthur R, Muller H, Garmo H, Holmberg L, Stattin P, Malmstrom H, et al. Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories. Cancer Med. 2016;5:1307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Paiva RM, Zauli DAG, Neto BS, Brum IS. Urinary microRNAs expression in prostate cancer diagnosis: a systematic review. Clin Transl Oncol. 2020;22:2061–73.

    Article  CAS  PubMed  Google Scholar 

  15. Al-Mahayni S, Ali M, Khan M, Jamsheer F, Moin ASM, Butler AE. Glycemia-induced miRNA changes: a review. Int J Mol Sci. 2023;24:7488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu Z, Dong J, Wang L-E, Ma H, Liu J, Zhao Y, et al. Serum microRNA profiling and breast cancer risk: the use of miR-484/191 as endogenous controls. Carcinogenesis. 2012;33:828–34.

    Article  CAS  PubMed  Google Scholar 

  17. Echouffo-Tcheugui JB, Selvin E. Prediabetes and what it means: the epidemiological evidence. Annu Rev Public Health. 2021;42:59–77.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Oger F, Gheeraert C, Mogilenko D, Benomar Y, Molendi-Coste O, Bouchaert E, et al. Cell-specific dysregulation of microrna expression in obese white adipose tissue. J Clin Endocrinol Metab. 2014;99:2821–33.

    Article  CAS  PubMed  Google Scholar 

  19. Weale CJ, Matshazi DM, Davids SFG, Raghubeer S, Erasmus RT, Kengne AP, et al. Circulating miR-30a-5p and miR-182-5p in prediabetes and screen-detected diabetes mellitus. Diabetes Metab Syndr Obes. 2020;13:5037–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pek SLT, Sum CF, Lin MX, Cheng AKS, Wong MTK, Lim SC, et al. Circulating and visceral adipose miR-100 is down-regulated in patients with obesity and Type 2 diabetes. Mol Cell Endocrinol. 2016;427:112–23.

    Article  CAS  PubMed  Google Scholar 

  21. Li X, Li J, Cai Y, Peng S, Wang J, Xiao Z, et al. Hyperglycaemia-induced miR-301a promotes cell proliferation by repressing p21 and Smad4 in prostate cancer. Cancer Lett. 2018;418:211–20.

    Article  CAS  PubMed  Google Scholar 

  22. Gajeton J, Krukovets I, Muppala S, Verbovetskiy D, Zhang J, Stenina-Adognravi O. Hyperglycemia-induced miR-467 drives tumor inflammation and growth in breast cancer. Cancers. 2021;13:1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hudson RS, Yi M, Esposito D, Watkins SK, Hurwitz AA, Yfantis HG, et al. MicroRNA-1 is a candidate tumor suppressor and prognostic marker in human prostate cancer. Nucleic Acids Res. 2012;40:3689–703.

    Article  CAS  PubMed  Google Scholar 

  24. Abramovic I, Vrhovec B, Skara L, Vrtaric A, Nikolac Gabaj N, Kulis T, et al. MiR-182-5p and miR-375-3p have higher performance than PSA in discriminating prostate cancer from Benign prostate hyperplasia. Cancers. 2021;13:2068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Szczyrba J, Loprich E, Wach S, Jung V, Unteregger G, Barth S, et al. The MicroRNA profile of prostate carcinoma obtained by deep sequencing. Mol Cancer Res. 2010;8:529–38.

    Article  CAS  PubMed  Google Scholar 

  26. Konoshenko MY, Lekchnov EA, Bryzgunova OE, Zaporozhchenko IA, Yarmoschuk SV, Pashkovskaya OA, et al. The panel of 12 cell-free microRNAs as potential biomarkers in prostate neoplasms. Diagnostics. 2020;10:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang NL, Li Q, Cheng NH, Guan G, Wang ZL, Qin Y, et al. miR-205 is frequently downregulated in prostate cancer and acts as a tumor suppressor by inhibiting tumor growth. Asian J Androl. 2013;15:735–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nayak B, Khan N, Garg H, Rustagi Y, Singh P, Seth A, et al. Role of miRNA-182 and miRNA-187 as potential biomarkers in prostate cancer and its correlation with the staging of prostate cancer. Int Braz J Urol. 2020;46:614–23.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Li Y, Li J, Yu H, Liu Y, Song H, Tian X, et al. HOXA5-miR-574-5p axis promotes adipogenesis and alleviates insulin resistance. Mol Ther Nucleic Acids. 2022;27:200–10.

    Article  CAS  PubMed  Google Scholar 

  30. Raza ST, Rizvi S, Afreen S, Srivastava S, Siddiqui Z, Fatima N, et al. Association of the circulating micro-RNAs with susceptible and newly diagnosed type 2 diabetes mellitus cases. Adv Biomark Sci Technol. 2022;5:57–67.

    Article  Google Scholar 

  31. Lieb V, Weigelt K, Scheinost L, Fischer K, Greither T, Marcou M, et al. Serum levels of miR-320 family members are associated with clinical parameters and diagnosis in prostate cancer patients. Oncotarget. 2018;9:10402–10416.

  32. Singh PK, Preus L, Hu Q, Yan L, Long MD, Morrison CD, et al. Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients. Oncotarget. 2014;5:824–40.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ramteke P, Deb A, Shepal V, Bhat MK. Hyperglycemia associated metabolic and molecular alterations in cancer risk, progression, treatment, and mortality. Cancers. 2019;11:1402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yaribeygi H, Atkin SL, Sahebkar A. A review of the molecular mechanisms of hyperglycemia-induced free radical generation leading to oxidative stress. J Cell Physiol. 2018;234:1300–12.

    Article  PubMed  Google Scholar 

  35. He S, Shi J, Mao J, Luo X, Liu W, Liu R, et al. The expression of miR-375 in prostate cancer: a study based on GEO, TCGA data and bioinformatics analysis. Pathol Res Pract. 2019;215:152375.

    Article  CAS  PubMed  Google Scholar 

  36. Pickl JMA, Tichy D, Kuryshev VY, Tolstov Y, Falkenstein M, Schuler J, et al. Ago-RIP-Seq identifies Polycomb repressive complex I member CBX7 as a major target of miR-375 in prostate cancer progression. Oncotarget. 2016;7:59589–603.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu Y, Yang C, Chen S, Liu W, Liang J, He S, et al. Cancer-derived exosomal miR-375 targets DIP2C and promotes osteoblastic metastasis and prostate cancer progression by regulating the Wnt signaling pathway. Cancer Gene Ther. 2022;30:437–49.

    PubMed  Google Scholar 

  38. Wang D, Lu G, Shao Y, Xu D. MiR-182 promotes prostate cancer progression through activating Wnt/β-catenin signal pathway. Biomed Pharmacother. 2018;99:334–9.

    Article  CAS  PubMed  Google Scholar 

  39. Stafford MYC, McKenna DJ. MiR-182 is upregulated in prostate cancer and contributes to tumor progression by targeting MITF. Int J Mol Sci. 2023;24:1824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525:256–60.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  41. Gonzalez P, Lozano P, Ros G, Solano F. Hyperglycemia and oxidative stress: an integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023;24:9352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pellacani D, Droop AP, Frame FM, Simms MS, Mann VM, Collins AT, et al. Phenotype-independent DNA methylation changes in prostate cancer. Br J Cancer. 2018;119:1133–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. O’Hagan HeatherM, Wang W, Sen S, DeStefano Shields C, Lee Stella S, Zhang Yang W, et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG islands. Cancer Cell. 2011;20:606–19.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Peluso M, Srivatanakul P, Jedpiyawongse A, Sangrajrang S, Munnia A, Piro S, et al. Aromatic DNA adducts and number of lung cancer risk alleles in Map-Ta-Phut Industrial Estate workers and nearby residents. Mutagenesis. 2013;28:57–63.

    Article  CAS  PubMed  Google Scholar 

  45. Kutwin P, Konecki T, Borkowska EM, Magdalena T-B, Jablonowski Z. Urine miRNA as a potential biomarker for bladder cancer detection - a meta-analysis. Cent Eur J Urol. 2018;71:177–85.

    CAS  Google Scholar 

  46. Abramovic I, Ulamec M, Katusic Bojanac A, Bulic-Jakus F, Jezek D, Sincic N. miRNA in prostate cancer: challenges toward translation. Epigenomics. 2020;12:543–58.

    Article  CAS  PubMed  Google Scholar 

  47. Li W, Zhang X, Sang H, Zhou Y, Shang C, Wang Y, et al. Effects of hyperglycemia on the progression of tumor diseases. J Exp Clin Cancer Res. 2019;38:327.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Brennan E, McClelland A, Hagiwara S, Godson C, Kantharidis P. miRNAs in the pathophysiology of diabetes and their value as biomarkers. In: Epigenetic biomarkers and diagnostics. Boston: Academic Press; 2016, p. 643–61.

  49. Chen J-Y, Wang P-Y, Liu M-Z, Lyu F, Ma M-W, Ren X-Y, et al. Biomarkers for prostate cancer: from diagnosis to treatment. Diagnostics. 2023;13:3350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pang KH, Rosario DJ, Morgan SL, Catto JWF. Evaluation of a short RNA within prostate cancer gene 3 in the predictive role for future cancer using non-malignant prostate biopsies. PloS One. 2017;12:e0175070.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was partially supported by AIRC (Project Code: 17763) and Tuscany Region, Italy.

Author information

Author notes

  1. These authors contributed equally: Valentina Russo, Lara Tamburrino, Simone Morselli.

  2. These authors jointly supervised this work: Marco Zappa, Francesca Carozzi, Marco Peluso.

Authors and Affiliations

  1. Regional Laboratory of Cancer Prevention, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139, Florence, Italy

    Valentina Russo, Cristina Sani, Alessandra Mongia, Valentina Carradori, Eleonora Lallo, Armelle Munnia, Simonetta Bisanzi & Marco Peluso

  2. Andrology, Women’s Endocrinology and Gender Incongruence Unit, Center for Prevention, Diagnosis and Treatment of Infertility, Careggi University Hospital, 50139, Florence, Italy

    Lara Tamburrino, Elisabetta Baldi & Sara Marchiani

  3. Department of Urology, Hesperia Hospital, 41125, Modena, Italy

    Simone Morselli

  4. Centro Urologico Europeo (CUrE), 41125, Modena, Italy

    Simone Morselli

  5. Unit of Urological Robotic Surgery and Renal Transplantation, Careggi University Hospital, 50139, Florence, Italy

    Simone Morselli, Arcangelo Sebastianelli & Sergio Serni

  6. Department of Experimental and Clinical Medicine, University of Florence, 50139, Florence, Italy

    Elisabetta Baldi, Arcangelo Sebastianelli, Maria Rosaria Raspollini & Sergio Serni

  7. Department of Histopathology and Molecular Diagnostics, Careggi University Hospital, 50139, Florence, Italy

    Maria Rosaria Raspollini

  8. Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, 50139, Florence, Italy

    Sara Marchiani

  9. Division of Epidemiology and Clinical Governance, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139, Florence, Italy

    Carmen Visioli

  10. Clinical Chemistry Laboratory Unit, S. Luca Hospital, USL Toscana Nord Ovest, 55100, Lucca, Italy

    Stefano Rapi

  11. Retired, formerly at Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139, Florence, Italy

    Marco Zappa & Francesca Carozzi

Authors
  1. Valentina Russo
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  2. Lara Tamburrino
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  3. Simone Morselli
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  4. Cristina Sani
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  17. Marco Zappa
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  18. Francesca Carozzi
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  19. Marco Peluso
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Contributions

Concept and design: [MZ, FC, EB, SS, MRR and MP]. Drafting of the manuscript: [MP]. Acquisition, analysis or interpretation of data, critical revisions to manuscript: [all authors]. Statistical analysis: [MP].

Corresponding author

Correspondence to Marco Peluso.

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Russo, V., Tamburrino, L., Morselli, S. et al. Hyperglycemia and microRNAs in prostate cancer. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00809-z

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