lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA

Biochim Biophys Acta Mol Cell Res. 2017 Oct;1864(10):1887-1899. doi: 10.1016/j.bbamcr.2017.08.001. Epub 2017 Aug 2.

Abstract

Accumulating evidences indicate that long noncoding RNAs (lncRNAs) might play important roles in tumorigenesis and metastasis. EMT (epithelial-to-mesenchymal transition) is considered as a critical step in invasion and metastasis of various tumors including bladder cancer (BC). Recent researches have showed that lncRNA H19 is implicated in metastasis through regulating EMT and the reverse MET (mesenchymal-to-epithelial transition). However, underlying mechanisms remain largely unknown. Here, we screened lncRNA and mRNA expression profiles of BC with microarray assay. We found that H19 and DNMT3B displayed a higher co-expression in BC tissues and cells. Functionally, we demonstrated that H19 could increase proliferation, invasion and migration, regulate EMT as well as rearrange cytoskeleton of BC cells in vitro. Moreover, ectopic expression of H19 promoted tumorigenesis, angiogenesis and pulmonary metastasis in vivo, whereas knockdown of H19 has a contrary role in vivo and in vitro. Mechanistically, we proved that H19 could directly bind to miR-29b-3p (miR-29b) and derepress the expression of target DNMT3B. H19 and miR-29b-3p showed a co-localization. More importantly, up-regulating H19 antagonized miR-29b-3p-mediated proliferation, migration and EMT suppression in BC cells. Furthermore, H19 knockdown partially reversed the function of miR-29b-3p inhibitor on DNMT3B and facilitated miR-29b-3p-induced MET. Taken together, we demonstrated for the first time that H19 might function as ceRNA (competing endogenous RNA) for miR-29b-3p and relieve the suppression for DNMT3B, which led to EMT and metastasis of BC. Our findings highlight a novel mechanism of H19 in progression of BC and provide H19/miR-29b-3p/DNMT3B axis as a promising therapeutic target for BC.

Keywords: Bladder cancer; EMT; Metastasis; ceRNA; lncRNA H19; miR-29.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics*
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis
  • RNA / genetics
  • RNA, Long Noncoding / genetics*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology

Substances

  • H19 long non-coding RNA
  • MIRN29a microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B