Skip to main content

Advertisement

SpringerLink
Log in

Hypermethylation of MIR129-2 Regulates SOX4 Transcription and Associates with Metastasis in Patients with Colorectal Cancer

  • Original Research
  • Published:
Journal of Gastrointestinal Cancer Aims and scope Submit manuscript

Abstract

Background

MicroRNA-129–2 (miR-129–2), targeting SOX4, has been shown to be involved in the pathogenesis of different cancers. Here in this study, we examined the methylation levels of the promoter region of MIR19-2 gene as well as transcription of miR-129–2 and mRNA expression of SOX4 in the tumoral tissues from colorectal cancer (CRC) patients and compared those in the normal marginal tissues.

Methods

Fifty CRC patients with Iranian Azari ethnicity were recruited. Genomic DNAs were extracted from the tumoral and normal tissues and the methylation level of the promoter regions of the MIR129-2 gene was determined using methylation-specific PCR (MSP) by evaluating 100 CG sites. The RNA content of the samples was isolated and the transcript levels of miR-129–2 and SOX4 were measured using quantitative real-time PCR.

Results

Methylation level of the MIR192-2 promoter was significantly higher in the tumoral tissues compared to that in the normal marginal tissues (84% vs. 28%; P = 0.0041). The expression level of miR-192–2 was significantly downregulated (fold change = 0.34, P = 0.028) but SOX4 mRNA expression was upregulated (fold change = 2.7, P = 0.019) in the tumoral tissues compared to that in the normal marginal tissues. There was a significant correlation between the methylation level of the MIR192-2 promoter and the expression levels of miR-192–2 and SOX4 in the tumoral tissues. Associations were observed between the methylation of the MIR192-2 promoter and lymph node and liver metastasis.

Conclusions

It seems that MIR192-2 promoter hypermethylation might regulate the expression of SOX4 and therefore modulate metastasis in CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–64.

    Article  Google Scholar 

  2. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669–85.

    Article  CAS  Google Scholar 

  3. Asadi M, Shanehbandi D, Zarintan A, Pedram N, Baradaran B, Zafari V, Shirmohamadi M, Hashemzadeh S. TP53Gene Pro72Arg (rs1042522) single nucleotide polymorphism as not a risk factor for colorectal cancer in the Iranian Azari population. Asian Pacific journal of cancer prevention: APJCP. 2017;18(12):3423.

    PubMed  PubMed Central  Google Scholar 

  4. Kamran S, Seyedrezazadeh E, Shanehbandi D, Asadi M, Zafari V, Shekari N, Namvar L, Zarredar H. Combination therapy with KRAS and P38α siRNA suppresses colorectal cancer growth and development in SW480 cell line. J Gastrointest Cancer. 2021. https://doi.org/10.1007/s12029-021-00667-1.

    Article  PubMed  Google Scholar 

  5. Shanehbandi D, Zarredar H, Asadi M, Zafari V, Esmaeili S, Seyedrezazadeh E, Soleimani Z, Sabagh Jadid H, Eyvazi S, Feyziniya S, Moghadam SB, Khalili M. Anticancer impacts of Terminalia catappa extract on SW480 colorectal neoplasm cell line. J Gastrointest Cancer. 2021;52(1):99–105. https://doi.org/10.1007/s12029-019-00349-z.

    Article  CAS  PubMed  Google Scholar 

  6. Ahagh MH, Dehghan G, Mehdipour M, Teimuri-Mofrad R, Payami E, Sheibani N, Ghaffari M, Asadi M. Synthesis, characterization, anti-proliferative properties and DNA binding of benzochromene derivatives: increased Bax/Bcl-2 ratio and caspase-dependent apoptosis in colorectal cancer cell line. Bioorg Chem. 2019;93.

  7. Akbari M, Shomali N, Faraji A, Shanehbandi D, Asadi M, Mokhtarzadeh A, Shabani A, Baradaran B. CD133: an emerging prognostic factor and therapeutic target in colorectal cancer. Cell Biol Int. 2020;44(2):368–80.

    Article  Google Scholar 

  8. Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, Sahebkar A. PD-1/PD-L1 pathway: basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824–37.

    Article  CAS  Google Scholar 

  9. Low EE, Demb J, Liu L, Earles A, Bustamante R, Williams CD, Provenzale D, Kaltenbach T, Gawron AJ, Martinez ME. Risk factors for early-onset colorectal cancer. Gastroenterology. 2020;159(2):492-501.e497.

    Article  CAS  Google Scholar 

  10. Babaie F, Hosseinzadeh R, Ebrazeh M, Seyfizadeh N, Aslani S, Salimi S, Hemmatzadeh M, Azizi G, Jadidi-Niaragh F, Mohammadi H. The roles of ERAP1 and ERAP2 in autoimmunity and cancer immunity: new insights and perspective. Mol Immunol. 2020;121:7–19.

    Article  CAS  Google Scholar 

  11. Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 2010;11(4):252–63.

    Article  CAS  Google Scholar 

  12. Asadi M, Shanehbandi D, Zafari V, Khaze V, Somi MH, Hashemzadeh S. Transcript level of MicroRNA processing elements in gastric cancer. J Gastrointest Cancer. 2019;50(4):855–9.

    Article  CAS  Google Scholar 

  13. Wai Hon K, Zainal Abidin SA, Othman I, Naidu R. Insights into the role of microRNAs in colorectal cancer (CRC) metabolism. Cancers. 2020;12(9):2462.

    Article  Google Scholar 

  14. Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer. Int Immunopharmacol. 2020;84.

  15. Chen X, Hu H, Guan X, Xiong G, Wang Y, Wang K, Li J, Xu X, Yang K, Bai Y. CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer. 2012;130(7):1607–13.

    Article  CAS  Google Scholar 

  16. Gao Y, Feng B, Han S, Lu L, Chen Y, Chu X, Wang R, Chen L. MicroRNA-129 in human cancers: from tumorigenesis to clinical treatment. Cell Physiol Biochem. 2016;39(6):2186–202.

    Article  CAS  Google Scholar 

  17. Vervoort SJ, van Boxtel R, Coffer PJ. The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? Oncogene. 2013;32(29):3397–409.

    Article  CAS  Google Scholar 

  18. Kim MS, Lee J, Sidransky D. DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010;29(1):181–206.

    Article  CAS  Google Scholar 

  19. Shen R, Pan S, Qi S, Lin X, Cheng S. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem Biophys Res Commun. 2010;394(4):1047–52.

    Article  CAS  Google Scholar 

  20. Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J, Prosper F, Garcia-Foncillas J. Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer. 2009;125(11):2737–43.

    Article  CAS  Google Scholar 

  21. Alizadeh N, Asadi M, Shanehbandi D, Zafari V, Shomali N, Asvadi T, Sepehri B. Evaluation of the methylation of MIR129-2 gene in gastric cancer. J Gastrointest Cancer. 2020;51(1):267–70.

    Article  Google Scholar 

  22. Weiser MR. AJCC 8th edition: colorectal cancer. Ann Surg Oncol. 2018;25(6):1454–5.

    Article  Google Scholar 

  23. Aaboe M, Birkenkamp-Demtroder K, Wiuf C, Sørensen FB, Thykjaer T, Sauter G, Jensen KM-E, Dyrskjøt L, Ørntoft T. SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization. Can Res. 2006;66(7):3434–42.

    Article  CAS  Google Scholar 

  24. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative CT method. Nat Protoc. 2008;3(6):1101–8.

    Article  CAS  Google Scholar 

  25. Karimi L, Zeinali T, Hosseinahli N, Mansoori B, Mohammadi A, Yousefi M, Asadi M, Sadreddini S, Baradaran B, Shanehbandi D. miRNA-143 replacement therapy harnesses the proliferation and migration of colorectal cancer cells in vitro. J Cell Physiol. 2019;234(11):21359–68.

    Article  CAS  Google Scholar 

  26. Katada T, Ishiguro H, Kuwabara Y, Kimura M, Mitui A, Mori Y, Ogawa R, Harata K, Fujii Y. microRNA expression profile in undifferentiated gastric cancer. Int J Oncol. 2009;34(2):537–42.

    CAS  PubMed  Google Scholar 

  27. Wu Q, Yang Z, Xia L, Nie Y, Wu K, Shi Y, Fan D. Methylation of miR-129-5p CpG island modulates multi-drug resistance in gastric cancer by targeting ABC transporters. Oncotarget. 2014;5(22):11552.

    Article  Google Scholar 

  28. Døssing KB, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O, Federspiel B, Knigge U, Kjær A, Friis-Hansen L. Down-regulation of miR-129-5p and the let-7 family in neuroendocrine tumors and metastases leads to up-regulation of their targets Egr 1, G3bp1, Hmga2 and Bach1. Genes. 2015;6(1):1–21.

    Article  Google Scholar 

  29. Tan G, Cao X, Dai Q, Zhang B, Huang J, Xiong S, yu Zhang Y, Chen W, Yang J, Li H, . A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ. Oncotarget. 2015;6(11):8676.

    Article  Google Scholar 

  30. Duan L, Hao X, Liu Z, Zhang Y, Zhang G. MiR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. FEBS Lett. 2014;588(9):1644–51.

    Article  CAS  Google Scholar 

  31. Tian X-Y, Zhang L, Sun L-G, Li M. Epigenetic regulation of miR-129-2 leads to overexpression of PDGFRa and FoxP1 in glioma cells. Asian Pac J Cancer Prev. 2015;16(14):6129–33.

    Article  Google Scholar 

  32. Xiao Y, Li X, Wang H, Wen R, He J, Tang J. Epigenetic regulation of miR-129-2 and its effects on the proliferation and invasion in lung cancer cells. J Cell Mol Med. 2015;19(9):2172–80.

    Article  CAS  Google Scholar 

  33. Huang ZM, Yang J, Shen XY, Zhang XY, Meng FS, Xu JT, Zhang BF, Gao HJ. MicroRNA expression profile in non-cancerous colonic tissue associated with lymph node metastasis of colon cancer. J Dig Dis. 2009;10(3):188–94.

    Article  CAS  Google Scholar 

  34. Li M, Tian L, Wang L, Yao H, Zhang J, Lu J, Sun Y, Gao X, Xiao H, Liu M. Down-regulation of miR-129–5p inhibits growth and induces apoptosis in laryngeal squamous cell carcinoma by targeting APC. PloS one. 2013;8(10).

  35. Ahn S-G, Cho G-H, Jeong S-Y, Rhim H, Choi J-Y, Kim I-K. Identification of cDNAs for Sox-4, an HMG-Box protein, and a novel human homolog of yeast splicing factor SSF-1 differentially regulated during apoptosis induced by prostaglandin A2/Δ12-PGJ2 in Hep3B cells. Biochem Biophys Res Commun. 1999;260(1):216–21.

    Article  CAS  Google Scholar 

  36. Frierson HF Jr, El-Naggar AK, Welsh JB, Sapinoso LM, Su AI, Cheng J, Saku T, Moskaluk CA, Hampton GM. Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am J Pathol. 2002;161(4):1315–23.

    Article  CAS  Google Scholar 

  37. Mavropoulos A, Devos N, Biemar F, Zecchin E, Argenton F, Edlund H, Motte P, Martial JA, Peers B. SOX4b is a key player of pancreatic α cell differentiation in zebrafish. Dev Biol. 2005;285(1):211–23.

    Article  CAS  Google Scholar 

  38. Andersen C, Christensen L, Thorsen K, Schepeler T, Sørensen FB, Verspaget H, Simon R, Kruhøffer M, Aaltonen L, Laurberg S. Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer. Br J Cancer. 2009;100(3):511–23.

    Article  CAS  Google Scholar 

  39. Shin MS, Fredrickson TN, Hartley JW, Suzuki T, Agaki K, Morse HC. High-throughput retroviral tagging for identification of genes involved in initiation and progression of mouse splenic marginal zone lymphomas. Can Res. 2004;64(13):4419–27.

    Article  CAS  Google Scholar 

  40. Schilham MW, Oosterwegel MA, Moerer P, Ya J, de Boer PA, van de Wetering M, Verbeek S, Lamers WH, Kruisbeek AM, Cumano A. Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature. 1996;380(6576):711–4.

    Article  CAS  Google Scholar 

  41. Cheung M, Abu-Elmagd M, Clevers H, Scotting PJ. Roles of Sox4 in central nervous system development. Mol Brain Res. 2000;79(1–2):180–91.

    Article  CAS  Google Scholar 

  42. van de Wetering M, Oosterwegel M, van Norren K, Clevers H. Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes. EMBO J. 1993;12(10):3847–54.

    Article  Google Scholar 

  43. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet. 2000;16(4):168–74.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients for their participation in the study.

Author information

Authors and Affiliations

  1. Tuberculosis and Lung Disease Research Center, Daneshgah St, Tabriz University of Medical Science, Tabriz, Iran

    Alireza Rezayi Soufiani, Payam Mohammadi & Abdolreza Mehdinavaz Aghdam

  2. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Roya Dolatkhah, Mortaza Raeisi & Hadi Chavoshi

Authors
  1. Alireza Rezayi Soufiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roya Dolatkhah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mortaza Raeisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hadi Chavoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Payam Mohammadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Abdolreza Mehdinavaz Aghdam
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Alireza Rezayi Soufiani: performed the experiments, participated in manuscript drafting, and read the manuscript critically. Roya Dolatkhah: performed the experiments and data analysis, wrote a draft of the manuscript, and read the manuscript critically. Mortaza Raeisi: participated in data interpretation, participated in manuscript drafting, and read the manuscript critically. Hadi Chavoshi: participated in data analysis, participated in manuscript drafting, and read the manuscript critically. Payam Mohammadi: performed patient examination, participated in manuscript drafting, and read the manuscript critically. Abdolreza Mehdinavaz Aghdam: developed the main idea, interpreted the data, manuscript drafting, and read the manuscript critically.

Corresponding author

Correspondence to Abdolreza Mehdinavaz Aghdam.

Ethics declarations

Conflict of Interest

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rezayi Soufiani, A., Dolatkhah, R., Raeisi, M. et al. Hypermethylation of MIR129-2 Regulates SOX4 Transcription and Associates with Metastasis in Patients with Colorectal Cancer. J Gastrointest Canc 53, 718–724 (2022). https://doi.org/10.1007/s12029-021-00708-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12029-021-00708-9

Keywords

Search

Navigation