Long Noncoding RNA HOXA11-AS and Transcription Factor HOXB13 Modulate the Expression of Bone Metastasis-Related Genes in Prostate Cancer

Abstract

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, which play fundamental roles in cancer development. In this study, we found that homeobox A11 antisense RNA (HOXA11-AS), a highly expressed lncRNA in cell lines derived from prostate cancer bone metastases, promoted the cell invasion and proliferation of PC3 prostate cancer cells. Transcription factor homeobox B13 (HOXB13) was identified as an upstream regulator of HOXA11-AS.HOXA11-AS regulated bone metastasis-associated C-C motif chemokine ligand 2 (CCL2)/C-C chemokine receptor type 2 (CCR2) signaling in both PC3 prostate cancer cells and SaOS2 osteoblastic cells. The HOXB13/HOXA11-AS axis also regulated integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis. HOXB13, in combination with HOXA11-AS, directly regulated the integrin-binding sialoprotein (IBSP) promoter. Furthermore, conditioned medium containing HOXA11-AS secreted from PC3 cells could induce the expression of CCL2 and IBSP in SaOS2 osteoblastic cells. These results suggest that prostate cancer HOXA11-AS and HOXB13 promote metastasis by regulation of CCL2/CCR2 cytokine and integrin signaling in autocrine and paracrine manners.

RETRACTED ARTICLE: Long non-coding RNA HOXA11 antisense RNA upregulates spermatogenesis-associated serine-rich 2-like to enhance cisplatin resistance in laryngeal squamous cell carcinoma by suppressing microRNA-518a

“…Homeobox (HOX) A11 antisense lncRNA (HOXA11-AS), a highly conserved lncRNA [ 11 ], has been reported to be associated with the drug resistance of different cancers. For example, HOXA11-AS enhanced CDDP resistance of human lung adenocarcinoma cells via regulating miR-454-3p/Stat3 axis [ 12 ].…”

Downstream of the HOX genes: Explaining conflicting tumour suppressor and oncogenic functions in cancer

“…First, based on mechanistic studies, it becomes apparent that the majority of HOX genes have an oncogenic function. Most HOX genes, including HOXB7, 15‐47 HOXB8 48‐54 and HOXC10 55‐72 are only reported to have oncogenic functions, while only two, HOXA5 73‐83 and HOXB13, 84‐108 are notable for having oncogenic functions reported in around 50% of publications, and tumour suppressor functions in the other 50%. Only one HOX gene, HOXD10, seems to act almost exclusively as a tumour suppressor, albeit with a notable exception in head and neck squamous cell carcinoma (HNSCC) 109‐121 …”

“…In studies where HOXB13 is identified as promoting oncogenesis, it is frequently because it has a role in driving metastasis. In prostate cancer, this is through increasing the expression of integrin subunits (ITGAV and ITGB1) specific to prostate cancer bone metastasis, 96 by preventing the expression of prostate‐derived Ets factor (PDEF) which inhibits metastasis, 90 through blocking the transport of zinc ions which in turn increases NF‐κB‐mediated signalling by reducing inhibitor of NF‐κB alpha (IκBα) activity, 92 and by promoting expression of the epithelial to mesenchymal transition (EMT)‐inducing Slug transcription factor 105 . Conversely, tumour‐suppressor functions of HOXB13 in prostate cancer seem to depend on its ability to block cell division through the downregulation of cyclin D1 through competition for TCF4 binding to its promoter, 87,88 and androgen signalling through direct interaction with the androgen receptor 89,122 .…”

Bioinformatics analysis for the identification of key genes and long non-coding RNAs related to bone metastasis in breast cancer

“…The lncRNA transcription factor homeobox B13 (HOXB13) has been identified as an upstream regulator of bone metastasis-related signals in prostate cancer. HOXB13 promotes the bone metastasis of metastatic prostate cancer by regulating the production of CCL2/CCR2 cytokines and integrin signals in an autocrine and paracrine manner [ 11 ].…”