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Post-transcriptional Modifications Contribute to the Upregulation of Cyclin D2 in Multiple Myeloma

Irena Misiewicz-Krzeminska1, María E Sarasquete2, Carolina Vicente-Dueñas3

  • 1Centro de Investigacion del Cancer-IBMCC (USAL-CSIC), Salamanca, Spain. Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain. National Medicines Institute, Warsaw, Poland.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 6, 2015
PubMed
Abstract

Insights

Shortened CCND2 mRNA 3'UTRs in multiple myeloma lead to altered miRNA regulation and increased gene expression. This occurs via alternative polyadenylation, impacting cancer progression.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • Dysregulation of D-cyclin genes is common in multiple myeloma.
  • Mechanisms of CCND2 (Cyclin D2) upregulation in multiple myeloma are not fully understood.
  • Post-transcriptional regulation via microRNAs (miRNAs) is a potential factor.

Purpose of the Study:

  • To investigate the role of miRNA interactions with CCND2 3 e202UTR binding sites in CCND2 overexpression.
  • To explore the impact of 3 e202UTR length variations on CCND2 regulation in multiple myeloma.
  • To elucidate the mechanisms behind CCND2 upregulation in multiple myeloma.

Main Methods:

  • Analysis of miRNA-mRNA interactions using 3 e202UTR-luciferase plasmid assays.
  • Detection and characterization of CCND2 mRNA isoforms using qRT-PCR, Northern blot, mRNA FISH, and 3 e202RACE-PCR.
  • Study included 11 myeloma cell lines and 45 primary myeloma samples.

Main Results:

  • Short CCND2 mRNA isoforms with truncated 3 e202UTRs were detected in multiple myeloma cells.
  • Alternative polyadenylation was identified as the cause of CCND2 3 e202UTR length variations.
  • Shorter CCND2 mRNA isoforms correlated with higher CCND2 expression and reduced miRNA binding sites.
  • Cyclin D1 and D3 overexpression influenced CCND2 polyadenylation, suggesting a regulatory role.

Conclusions:

  • CCND2 3 e202UTR shortening significantly impacts miRNA-dependent regulation of CCND2 in multiple myeloma.
  • Alternative polyadenylation of CCND2 contributes to its overexpression in multiple myeloma.
  • Findings highlight a novel mechanism of gene regulation in multiple myeloma progression.

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