Targetome profiling and functional genetics implicate miR-618 in lymphomagenesis

Epigenetics. 2014 May;9(5):730-7. doi: 10.4161/epi.27996. Epub 2014 Feb 6.

Abstract

Despite the voluminous body of observational evidence concerning the role of miRNAs in cancer, significant knowledge gaps remain concerning the molecular circumstances that underlie the miRNA-cancer connection. In this study, we employ a multidisciplinary approach to establish an association between miR-618 and non-Hodgkin lymphoma (NHL) in a human population and attempt to explicate this association at the molecular level. A high-throughput, transcriptome-wide RIP-Chip-based method was used to identify members of the miR-618 targetome, which were analyzed for functional relevance using a gene network-based approach. Findings were confirmed by genotyping a SNP (rs2682818) in the stem-loop sequence of miR-618 in a population-based case-control study of NHL (455 cases and 527 controls). Lastly, we analyzed the functional impact of rs2682818 on miR-618 expression and its consequent implications for the lymphomagenic process. A total of 128 miR-618 targets were identified, which were enriched for genes that have functional roles in lymphoma-relevant pathways. This is consistent with our finding of a significant association between rs2682818 G>T in the miR-618 stem-loop and follicular lymphoma (FL) (OR: 1.65, 95% CI: 1.05-2.60). In vitro analysis of rs2682818's functional impact revealed that the variant T allele resulted in reduced levels of mature miR-618, which in turn may lead to deregulation of miR-618-controlled pathways relevant to follicular lymphoma. Taken together, our findings implicate miR-618 in follicular lymphomagenesis, identify miR-618 as a potential risk biomarker for follicular lymphoma, and illuminate miR-618-regulated lymphomagenic pathways that can serve as therapeutic targets for follicular lymphoma.

Keywords: follicular lymphoma; lymphomagenesis; miR-618; pathway analysis; targetome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Biomarkers, Tumor / metabolism*
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Case-Control Studies
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies
  • Genomics
  • HeLa Cells
  • Humans
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / metabolism
  • Lymphoma, Follicular / pathology
  • Lymphoma, Non-Hodgkin / genetics
  • Lymphoma, Non-Hodgkin / metabolism*
  • Lymphoma, Non-Hodgkin / pathology
  • MicroRNAs / metabolism*
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / genetics*

Substances

  • Biomarkers, Tumor
  • MIRN618 microRNA, human
  • MicroRNAs
  • RNA, Messenger