Abstract
BackgroundDue to the poor prognosis for advanced renal cell carcinoma (RCC), there is an urgent need for new therapeutic targets and for prognostic markers to identify high risk tumors. MicroRNAs (miRNAs) are frequently dysregulated in tumors, play a crucial role during carcinogenesis and therefore might be promising new biomarkers. In previous studies, we identified miR-141-3p and miR-145-5p to be downregulated in clear cell RCC (ccRCC). Our objective was to investigate the functional association of these miRNAs, focusing on the cooperative regulation of new specific targets and their role in ccRCC progression.MethodsThe effect of miR-141-3p and miR-145-5p on cell migration was examined by overexpression in 786-O cells. New targets of both miRNAs were identified by miRWalk, validated in 786-O and ACHN cells and additionally characterized in ccRCC tissue on mRNA and protein level.ResultsIn functional analysis, a tumor suppressive effect of miR-141-3p and miR-145-5p by decreasing migration and invasion of RCC cells could be shown. Furthermore, co-overexpression of the miRNAs seemed to result in an increased inhibition of cell migration. Both miRNAs were recognized as post-transcriptional regulators of the targets EAPP, HS6ST2, LOX, TGFB2 and VRK2. Additionally, they showed a cooperative effect again as demonstrated by a significantly increased inhibition of HS6ST2 and LOX expression after simultaneous overexpression of both miRNAs. In ccRCC tissue, LOX mRNA expression was strongly increased compared to normal tissue, allowing also to distinguish between non-metastatic and already metastasized primary tumors. Finally, in subsequent tissue microarray analysis LOX protein expression showed a prognostic relevance for the overall survival of ccRCC patients.ConclusionThese results illustrate a jointly strengthening effect of the dysregulated miR-141-3p and miR-145-5p in various tumor associated processes. Focusing on the cooperative effect of miRNAs provides new opportunities for the development of therapeutic strategies and offers novel prognostic and diagnostic capabilities.
Highlights
Renal cell carcinoma (RCC) is the most common kidney tumor in adults, representing approximately 3% of all malignant tumors in humans [1]
We identified miR-141-3p and miR-145-5p to be downregulated in clear cell RCC
In clear cell renal cell carcinoma (ccRCC) tissue, LOX mRNA expression was strongly increased compared to normal tissue, allowing to distinguish between nonmetastatic and already metastasized primary tumors
Summary
Renal cell carcinoma (RCC) is the most common kidney tumor in adults, representing approximately 3% of all malignant tumors in humans [1]. There is a well-founded hope to use a better insight into molecular patterns in order to ensure an adequate risk stratification. This will identify tumors with an increased risk for the transition from a local disease to a tumor generating distant metastasis. There is still an urgent need for new molecular targets to develop specific agents for targeted therapy with fewer side effects. Due to the poor prognosis for advanced renal cell carcinoma (RCC), there is an urgent need for new therapeutic targets and for prognostic markers to identify high risk tumors. Our objective was to investigate the functional association of these miRNAs, focusing on the cooperative regulation of new specific targets and their role in ccRCC progression
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