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
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The study was supported by the Wilhelm-Roux program of the medical faculty, University of Halle (FKZ 29/12).
Eulalio A, Huntzinger E, Izaurralde E (2008) Getting to the root of miRNA-mediated gene silencing. Cell 132:9–14CrossRefPubMedGoogle Scholar
Riemann A, Schneider B, Gündel D et al (2014) Acidic priming enhances metastatic potential of cancer cells. Pflugers Arch 466:2127–2138CrossRefPubMedGoogle Scholar
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
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
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
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
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
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
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