Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling

Abstract

Background 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. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown. Methods Real-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. Results We 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. Conclusion Our results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin β3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression. Electronic supplementary material The online version of this article (10.1186/s12943-019-0955-9) contains supplementary material, which is available to authorized users.

A nuclear lncRNA Linc00839 as a Myc target to promote breast cancer chemoresistance via PI3K/AKT signaling pathway

“…Indeed, many lncRNAs have been identified to function in these pathways, such as TSLNC8, suppresses metastasis by inactivating the IL‐6/STAT3 signaling pathway 44 . HOXD‐AS1 inhibits colorectal cell growth and metastasis through inactivation of the MAPK/AKT signaling pathway 8 . Furthermore, we proved that Linc00839 overexpression could activate the phosphorylation of Akt, STAT3, and P38, but the expression level of p‐ERK1/2 was inactivated.…”

“…Long noncoding RNAs (lncRNAs) have been identified as crucial components in BC development, 3 suggesting their potential abilities as diagnostic and therapeutic biomarkers 4 . Studies have shown that dysregulation of lncRNAs contributes to tumorigenesis, 5,6 metastasis, 7,8 and chemoresistance, 9 by modulating cell proliferation, 10 and apoptosis 11 through different signaling pathways. Different types of lncRNAs localize to the cytoplasm or nucleus, participating in transcriptional and posttranscriptional gene expression 12 .…”

Overexpression of antisense long non‑coding RNA ZNF710‑AS1‑202 promotes cell proliferation and inhibits apoptosis of clear cell renal cell carcinoma via regulation of ZNF710 expression

“…increasing evidence suggests that long non-coding rnas (lncrnas) are involved in the occurrence and progression of ccrcc (2)(3)(4)6). lncrnas, defined as transcribed rna molecules >200 nt in length (9)(10)(11)(12), are an important class of non-coding rnas involved in several biological functions (12)(13)(14)(15)(16)(17).…”

“…antisense lncrnas (aS lncrnas), a subclass of lncrnas, are transcribed from complex genetic loci on the opposite strands of sense protein-coding genes (13)(14)(15)(18)(19)(20). aS lncrnas may overlap exons and/or introns of their associated sense protein-coding transcripts to regulate epigenetic silencing, transcription and mrna stability by forming sense-antisense pairs (18)(19)(20)(21)(22)(23)(24).…”

LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1

“…Long non-coding RNAs (lncRNAs) are de ned as a novel class of RNA molecules of length more than 200 nucleotides with narrow protein coding functions [4,5]. Recently, a growing body of research has revealed that lncRNAs have been implicated in the tumorigenicity of multiple cancers, including CRC [6][7][8]. Dysregulated lncRNAs have been demonstrated to work as oncogenes or tumor suppressors through affecting a wide spectrum of biological activities, such as cell growth, invasion, metastasis and autophagy [9,10].…”