Abstract
BackgroundLong noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown.MethodsReal-time PCR and in situ hybridization were used to detect the expression of HOXD-AS1 in CRC tissue samples and cell lines. Gain- and loss-of-function experiments were performed to investigate the biological roles of HOXD-AS1 in CRC cell line. RNA pull down, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to investigate the mechanisms underlying the functions of HOXD-AS1 in CRC.ResultsWe observed that HOXD-AS1 was located in the nucleus of CRC cells and that nuclear HOXD-AS1 was downregulated in most CRC specimens and cell lines. Lower levels of nuclear HOXD-AS1 expression were associated with poor outcomes of CRC patients. HOXD-AS1 downregulation enhanced proliferation and migration of CRC cells in vitro and facilitated CRC tumourigenesis and metastasis in vivo. Mechanistic investigations revealed that HOXD-AS1 could suppress HOXD3 transcription by recruiting PRC2 to induce the accumulation of the repressive marker H3K27me3 at the HOXD3 promoter. Subsequently, HOXD3, as a transcriptional activator, promoted Integrin β3 transcription, thereby activating the MAPK/AKT signalling pathways.ConclusionOur results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin β3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression.
Highlights
Long noncoding RNAs have been indicated to play critical roles in cancer development and progression
Nuclear HOXD-AS1 expression is reduced in CRC and negatively associated with poor prognosis in CRC patients To investigate the role of HOXD-AS1 in CRC, we first assessed HOXD-AS1 expression levels in 35 paired primary CRC tissue and matched adjacent nontumor tissue samples by real-time PCR
Nuclear and cytoplasmic RNA fractions were prepared from CRC and FHC cells to observe the subcellular localization of HOXD-AS1
Summary
Long noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. The expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown. A better understanding of the molecular mechanisms underlying CRC carcinogenesis and progression is essential for the development of CRC-specific diagnostic markers and novel effective therapies for CRC patients. Accumulating evidence has revealed the dysregulation of lncRNAs expression in a variety of human diseases, including cancer [3, 4]. Understanding the precise molecular mechanisms by which lncRNAs function in various cancers will be critical for exploring new strategies for cancer diagnosis and therapy
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