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The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1.
- Source :
-
Cell death & disease [Cell Death Dis] 2018 Feb 14; Vol. 9 (2), pp. 233. Date of Electronic Publication: 2018 Feb 14. - Publication Year :
- 2018
-
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.
- Subjects :
- Aged
Animals
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Line, Tumor
Cell Movement
Cell Proliferation
Computational Biology
Disease Progression
E2F1 Transcription Factor metabolism
Female
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 metabolism
RNA, Long Noncoding antagonists & inhibitors
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 metabolism
Urinary Bladder Neoplasms pathology
Urinary Bladder Neoplasms therapy
Xenograft Model Antitumor Assays
E2F1 Transcription Factor genetics
Feedback, Physiological
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins c-akt genetics
RNA, Long Noncoding genetics
Urinary Bladder Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 9
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 29445134
- Full Text :
- https://doi.org/10.1038/s41419-018-0275-9