Abstract
miRNAs play a crucial role in cancer development and progression. However, results on the impact of miRNAs on drug sensitivity and tumor biology vary, and most studies to date focussed on either increasing or decreasing miRNA expression levels. Therefore, the current study investigated the role of different expression levels of miR-130a-3p and miR-148a-3p on drug resistance and tumor biology in four esophageal squamous cell carcinoma cell lines. Interestingly, up- and downregulation of both miRNAs significantly increased sensitivity towards chemotherapy. MiRNA modulation also reduced adherence and migration potential, and increased apoptosis rates. Target analyses showed that up- and downregulation of both miRNAs activated the apoptotic p53-pathway via increased expression of either BAX (miR-148a-3p) or Caspase 9 (miR-130a-3p). miR-148a-3p downregulation seemed to mediate its effects primarily via regulation of Bim rather than Bcl-2 levels, whereas we found the opposite scenario following miR-148a-3p upregulation. A similar effect was observed for miR-130a-3p regulating Bcl-2 and XIAP. Our data provide the first evidence that miRNA modulation in both directions may lead to similar effects on chemotherapy response and tumor biology in esophageal squamous cell carcinoma. Most interestingly, up- and downregulation seem to mediate their effects via modulating the balance of several validated or predicted targets.
Highlights
Esophageal cancer (EC) is characterised by poor 5-year survival rates of 15–34% due to, among other reasons, the development of chemotherapy resistance[1]
In our own most recent work, we demonstrated that several miRNAs including miR-130a-3p and miR148a-3p impact on response to chemotherapy and biological behaviour in esophageal squamous cell carcinoma[2,3,13]
We investigated the effect of up- and downregulation of miR-130a-3p and miR-148a-3p on response to chemotherapy treatment with Cisplatin and 5-FU in esophageal squamous cell carcinoma (ESCC) cell lines
Summary
Esophageal cancer (EC) is characterised by poor 5-year survival rates of 15–34% due to, among other reasons, the development of chemotherapy resistance[1]. MiRNAs, their function and their control of gene expression are believed to be tissue specific This might, at least in part, explain these contradictory results in different tumor types[33]. For both miRNAs conflicting results have been described even for the same tumour type, such as gastric cancer[14,29,31,34] Based on these incongruous findings in the literature, and the fact that most studies focussed on either increasing or decreasing miRNA expression levels in tumors but did not investigate effects of alteration of miRNA expression levels in both directions, we selected these two miRNAs for a thorough investigation of their role in resistance and tumor biology in esophageal squamous cell carcinoma (ESCC). We conducted analyses on chemotherapy response and biological behaviour, followed by a detailed analysis of targets and targeted pathways
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