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.
Highlights
Several studies have shown that HOXA11-AS exhibited oncogenic roles through different mechanisms in various types of cancers [8,9,10,11,29,30,31,32,33,34]
HOXA11-AS is highly expressed in prostate cancer cell lines derived from bone metastases (PC3 and VCaP cells), and that it contributes to prostate cancer cell proliferation and invasion
We identified homeobox B13 (HOXB13) as an upstream regulator of HOXA11-AS, and found that
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that demonstrate no protein-coding capacity [6]. They contribute to epigenetic activation and repression by opening large chromatin domains, maintaining the chromatin state, or modulating RNA interference-mediated silencing processes (e.g., by acting as molecular sponges through both cis and trans mechanisms) [7]. We found that lncRNA HOXA11-AS was highly expressed in cell lines derived from prostate cancer bone metastases, where it promoted cell invasion and proliferation. In cooperation with HOXB13, HOXA11-AS regulated the expression of chemokines, integrins, and related genes (e.g., integrin-binding sialoprotein (IBSP)) to promote the bone-specific metastasis of prostate cancer. We propose that prostate cancer cell-derived HOXA11-AS acts in a paracrine manner to modulate cytokine signaling in osteoblastic cells within the bone marrow milieu
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