Acidic extracellular environment affects miRNA expression in tumors in vitro and in vivo. Issue 7 (18th December 2018)

• Record Type: Journal Article
• Authors: Riemann, Anne; Reime, Sarah; Thews, Oliver
• Is Part Of: International journal of cancer. Volume 144:Issue 7(2019)
• Page Start: 1609
• Page End: 1618
• Publication Date: 2018-12-18
• Subjects: miRNA expression -- acidosis -- hypoxia -- mammary carcinoma -- prostate carcinoma; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31790
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Hypoxia can control the expression of miRNAs in tumors which play an important role for the control of the malignant behavior. The aim of the study was to analyze whether extracellular acidosis, a common feature of tumors, also has an impact on the miRNA expression in isolated cells as well as in solid tumors. MiRNA expression was analyzed in two rat tumor cell lines (AT1 prostate and Walker‐256 mammary carcinomas) by NGS and qPCR. In vivo the same cell lines were implanted subcutaneously and the tumor pH was modulated by inspiratory hypoxia and inhibition of the respiratory chain. In addition, the expression of five genes (Brip1, Ercc6l, Ikbke, Per3, Tlr5) which are potential targets of the miRNAs were analyzed on mRNA level. Screening showed that 38 (AT1) resp. 41 (Walker‐256) miRNAs were pH‐dependent. Validation by qPCR revealed that only 4 miRNAs were consistently regulated in both cell lines: miR‐183, miR‐203a, miR‐215 and miR‐7a. The expression of miR‐7a was increased by low pH whereas all others were decreased. In the tumors in vivo all 4 miRNAs were down‐regulated. The potential targets showed pH dependency in both cell lines. In conclusion, extracellular acidosis regulates the expression of miRNAs in vitro and in vivo . The expression of targets of these miRNAs were also pH‐dependent. The pH may therefore affect the biological behavior of tumors via miRNAs. Abstract : What's new? MicroRNAs (miRNAs) serve critical roles in gene regulation and influence the malignant behavior of cells. Among the factors that influence miRNA expression are extracellular stimuli, though little is known about the impact of such stimuli in the tumor microenvironment. Here, in rat tumor cell lines, extracellular acidosis (pH = 6.6) was found to regulate the expression of multiple miRNAs, including miR‐7a, miR‐183, miR‐203a, and miR‐215. The pH‐dependency of miRNA expression was further detectable in solid tumors in rats in vivo, in which expression was downregulated for all miRNAs. The findings suggest that pH can influence tumor behavior via effects on miRNA function.