Hypoxia-Related Tumor Acidosis Affects MicroRNA Expression Pattern in Prostate and Breast Tumor Cells

  • A. RiemannEmail author
  • S. Reime
  • O. Thews
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 977)


MicroRNAs (miRNAs) are small non-coding RNA sequences which are able to modulate the expression of many functional proteins. The expression level of miRNAs can be modulated by parameters of the tumor microenvironment like hypoxia, nutrient deprivation or oxidative stress. Since miRNAs can act either as oncogenes or tumor suppressors, this may affect malignant progression or therapy resistance. In the present study it was analyzed whether extracellular acidosis can impact on miRNA expression. Therefore, tumor cells (R3327-AT-1 prostate and Walker-256 mammary carcinoma cells) were incubated at pH 6.6 (acidosis) or pH 7.4 (control) for 24 h and changes in miRNA expression were analyzed by PCR array for 84 cancer-associated miRNAs and Next-Generation Sequencing (NGS) with a panel of 765 miRNAs.

In the cancer-related PCR array an acidosis-induced reduction of 5 miRNAs in AT-1 and 6 miRNAs in Walker-256 cells was seen. The miR-203a was consensually down-regulated in both cell lines. Using NGS, 19 miRNAs were found to be upregulated and 14 miRNAS were downregulated in AT-1 prostate cancer cells. In Walker-256 cells the expression of 21 miRNAs was increased and decreased for 17 miRNAs. Eleven miRNAs were regulated by acidosis in both tumor cell lines in the same direction.

Acidosis induced changes in the miRNA expression of prostate and breast carcinoma cells. However, miRNA profiles differed strongly between the tumor cell lines (and between the experimental methods used), indicating that cells can react individually to microenvironmental stress. However, some miRNAs were consensually regulated in both cell lines and thus might represent a general cellular response to an extracellular acidosis.


Acidosis Tumor MicroRNA Next Generation Sequencing (NGS) Tumor microenvironment 



The study was supported by the Wilhelm-Roux program of the medical faculty, University of Halle (FKZ 29/12).


  1. 1.
    Eulalio A, Huntzinger E, Izaurralde E (2008) Getting to the root of miRNA-mediated gene silencing. Cell 132:9–14CrossRefPubMedGoogle Scholar
  2. 2.
    Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6:259–269CrossRefPubMedGoogle Scholar
  3. 3.
    Lujambio A, Lowe SW (2012) The microcosmos of cancer. Nature 482:347–355CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Zaravinos A (2015) The regulatory role of microRNAs in EMT and cancer. J Oncol 2015:865–816CrossRefGoogle Scholar
  5. 5.
    Leung AK, Sharp PA (2007) microRNAs: a safeguard against turmoil? Cell 130:581–585CrossRefPubMedGoogle Scholar
  6. 6.
    Gottlieb RA, Pourpirali S (2016) Lost in translation: miRNAs and mRNAs in ischemic preconditioning and ischemia/reperfusion injury. J Mol Cell Cardiol 95:70–77CrossRefPubMedGoogle Scholar
  7. 7.
    Wentz-Hunter KK, Potashkin JA (2011) The role of miRNAs as key regulators in the neoplastic microenvironment. Mol Biol Int 2011:839–872CrossRefGoogle Scholar
  8. 8.
    Vaupel P, Kallinowski F, Okunieff P (1989) Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49:6449–6465PubMedGoogle Scholar
  9. 9.
    Estrella V, Chen T, Lloyd M et al (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–1535CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Riemann A, Schneider B, Gündel D et al (2014) Acidic priming enhances metastatic potential of cancer cells. Pflugers Arch 466:2127–2138CrossRefPubMedGoogle Scholar
  11. 11.
    Taylor S, Spugnini EP, Assaraf YG et al (2015) Microenvironment acidity as a major determinant of tumor chemoresistance: proton pump inhibitors (PPIs) as a novel therapeutic approach. Drug Resist Updat 23:69–78CrossRefPubMedGoogle Scholar
  12. 12.
    Gerweck LE, Seetharaman K (1996) Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res 56:1194–1198PubMedGoogle Scholar
  13. 13.
    Thews O, Gassner B, Kelleher DK et al (2006) Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 8:143–152CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lohcharoenkal W, Harada M, Loven J et al (2016) MicroRNA-203 inversely correlates with differentiation grade, targets c-MYC and functions as a tumor suppressor in cSCC. J Invest Dermatol 136:2485–2494CrossRefPubMedGoogle Scholar
  15. 15.
    Nassirpour R, Mathur S, Gosink MM et al (2014) Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms. BMC Genomics 15:485CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vinall RL, Tepper CG, Ripoll AA et al (2016) Decreased expression of let-7c is associated with non-response of muscle-invasive bladder cancer patients to neoadjuvant chemotherapy. Genes Cancer 7:86–97PubMedPubMedCentralGoogle Scholar
  17. 17.
    Ge J, Chen Z, Li R et al (2014) Upregulation of microRNA-196a and microRNA-196b cooperatively correlate with aggressive progression and unfavorable prognosis in patients with colorectal cancer. Cancer Cell Int 14:128CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Julius-Bernstein-Institute of PhysiologyUniversity of HalleHalleGermany

Personalised recommendations