High Efficiency Capture of Biomarker miRNA15a for Noninvasive Diagnosis of Malignant Kidney Tumors - Beyond the Abstract

miRNA15a – beyond being just a diagnostic marker for RCCs

While miRNAs have been proposed as biomarkers in a variety of diseases and tumor entities, in their majority there has not been any further characterisation as to their intracellular effects. In contrast, from miRNA15a we know though research from others and from us1 that it is induced mainly via the A type receptor of Endothelin-1, being a well-known activator in renal cell carcinoma.2,3

This activation prevents a complex formation consisting of protein kinase C (PKC) alpha with mitogen-activated protein kinase (MAPK) p38 alpha. This complex would be able to migrate from the cytoplasm into the nucleus, due to the nuclear location sequence of MAPK to gain nuclear access.4 This lack of migration has two effects: i) the control of the stability of intranuclear levels of pri-mRNA15a is lost; ii) the third partner of the cytoplasmic complex, nuclear factor kappa B (NF-kB) is unrestrictedly able to transmigrate into the nucleus, upregulating inflammatory genes having a NF-kB binding site in their promoter (i.e. VCAM-1,5 IL-6,6 fractalkine,7 as well as ET-1,8). Nuclear PKC alpha levels become low, pri-miRNA15a is activated, released into the cytoplasm to become a mature miRNA. As a novel mechanism this miRNA is remigrating into the nucleus, where it leads to a DNA truncation of MAPK,9 resulting in a protein known as Mxi-2 in the literature. Mxi-2 has several effects in the cytoplasm: it serves as transcription factor together with ETS-1 and ERK to induce proliferation after translocating into the nucleus, where the complex binds via ETS1 to the ETS-binding site in the p16INK4a promoter, initiating p16INK4a gene expression.10

Furthermore, it leads to p53 downregulation in a complex together with Ago2 and miRNA1285,11 counteracting tumor growth [unpublished]. Subsequently, in the urines of renal carcinoma one can find upregulated miRNA15a levels and low PKC alpha and Mxi-2 levels.12,13 Low levels of p16INK4a14 and p5315 have been described in ccRCCs and are associated with an improved diagnosis.

Written by: 

  • Sanjay Mathur, FACerS, FASM, FEurASc, FNA, Institute of Inorganic Chemistry, University of Cologne, Cologne, Germany
  • Jochen W. U. Fries, MD, Institute of Pathology, University of Cologne, Cologne, Germany


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