The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1

Cell Death Dis. 2018 Feb 14;9(2):233. doi: 10.1038/s41419-018-0275-9.

Abstract

Long non-coding RNAs (lncRNAs) have been identified as significant regulators in cancer progression. Positive feedback loops between lncRNAs and transcription factors have attracted increasing attention. Akt pathway plays a crucial role in bladder cancer growth and recurrence. In the present study, we demonstrate a novel regulatory pattern involving FOXD2-AS1, Akt, and E2F1. FOXD2-AS1 is highly expressed in bladder cancer and is associated with tumor stage, recurrence, and poor prognosis. Further experiments showed that FOXD2-AS1 promotes bladder cancer cell proliferation, migration, and invasion in vitro and in vivo. Microarray analysis demonstrated that FOXD2-AS1 negatively regulates the expression of Tribbles pseudokinase 3 (TRIB3), a negative regulator of Akt. Mechanistically, FOXD2-AS1 forms an RNA-DNA complex with the promoter of TRIB3, the transcriptional activity of which is subsequently repressed, and leads to the activation of Akt, which further increases the expression of E2F1, a vital transcription factor involved in the G/S transition. Interestingly, E2F1 could bind to the FOXD2-AS1 promoter region and subsequently enhance its transcriptional activity, indicating that FOXD2-AS1/Akt/E2F1 forms a feedback loop. In summary, this regulatory pattern of positive feedback may be a novel target for the treatment of bladder cancer and FOXD2-AS1 has the potential to be a new recurrence predictor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Computational Biology
  • Disease Progression
  • E2F1 Transcription Factor / genetics*
  • E2F1 Transcription Factor / metabolism
  • Feedback, Physiological*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Long Noncoding / antagonists & inhibitors
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recurrence
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Tumor Burden
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / therapy
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Repressor Proteins
  • TRIB3 protein, human
  • long non-coding RNA FOXD2-AS1, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt