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PLoS One. 2015 Aug 19;10(8):e0135991. doi: 10.1371/journal.pone.0135991. eCollection 2015.

The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels.

Author information

1
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden.
2
Umeå University, Departments of Surgical and Perioperative Sciences, Urology and Andrology, Umeå, Sweden.
3
Lund University, Department of Laboratory Medicine, Division of Translational Cancer Research, Medicon Village, Lund, Sweden.

Abstract

BACKGROUND:

High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.

METHODOLOGY AND RESULTS:

Using western blot, flow cytometry, and RT-qPCR, we showed that Axl mRNA and protein are downregulated in 786-O cells by miR-34a and miR-34c but not by miR-34b. A luciferase reporter assay demonstrated direct interaction between the Axl 3' UTR and miR-34a and miR-34c. The levels of miR-34a/b/c were measured in tumor tissue in a cohort of 198 RCC patients, and the levels of miR-34a were found to be upregulated in clear cell RCC (ccRCC) tumors, but not associated with patient outcome. Neither of the miR-34 family members correlated with Axl mRNA, soluble Axl protein in serum, nor with immunohistochemistry of Axl in tumor tissue. In addition, we measured mRNA levels of a known miR-34a target, HNF4A, and found the HNF4A levels to be decreased in ccRCC tumors, but unexpectedly correlated positively rather than negatively with miR-34a.

CONCLUSIONS:

Although miR-34a and miR-34c can regulate Axl expression in vitro, our data indicates that the miR-34 family members are not the primary regulators of Axl expression in RCC.

PMID:
26287733
PMCID:
PMC4546115
DOI:
10.1371/journal.pone.0135991
[Indexed for MEDLINE]
Free PMC Article

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