Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and MicroRNA regulation

Biomaterials. 2015 Mar;44:71-81. doi: 10.1016/j.biomaterials.2014.12.023. Epub 2015 Jan 12.

Abstract

Long non-coding RNAs (lncRNAs) play regulatory roles in cancers. LncRNA PTENP1 is a pseudogene of the tumor suppressor gene PTEN but its roles in hepatocellular carcinoma (HCC) have yet to be explored. Here we confirmed that PTENP1 and PTEN were downregulated in several HCC cells, thus we constructed Sleeping Beauty (SB)-based hybrid baculovirus (BV) vectors for sustained PTENP1 lncRNA expression. Co-transduction of HCC cells with the SB-BV vector expressing PTENP1 elevated the levels of PTENP1 and PTEN, which suppressed the oncogenic PI3K/AKT pathway, inhibited cell proliferation, migration/invasion as well as induced autophagy and apoptosis. The overexpressed PTENP1 decoyed oncomirs miR-17, miR-19b and miR-20a, which would otherwise target PTEN, PHLPP (a negative AKT regulator) and such autophagy genes as ULK1, ATG7 and p62, indicating that PTENP1 modulated the HCC cell behavior and gene networks by miRNA regulation. Injection of the PTENP1-expressing SB-BV vector into mice bearing HCC tumors effectively mitigated the tumor growth, suppressed intratumoral cell proliferation, elicited apoptosis, autophagy and inhibited angiogenesis. These data collectively unveiled the molecular mechanisms of how PTENP1 repressed the tumorigenic properties of HCC cells and demonstrated the potential of the SB-BV hybrid vector for PTENP1 lncRNA modulation and HCC therapy.

Keywords: Baculovirus; Cancer therapy; Hepatocellular carcinoma; PTENP1; lncRNA; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Autophagy / genetics
  • Baculoviridae / metabolism*
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology*
  • Cell Survival
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neovascularization, Pathologic / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Signal Transduction / genetics
  • Transposases / metabolism

Substances

  • MicroRNAs
  • RNA, Long Noncoding
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Transposases
  • sleeping beauty transposase, human