The molecular mechanism of LncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma

Abstract

Background Bone metastasis (BM) has long been recognized as a major threat to the quality of life of hepatocellular cancer (HCC) patients. While LncRNA34a (Lnc34a) has been shown to regulate colon cancer stem cell asymmetric division, its effect on HCC BM remains unknown. Methods In situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of Lnc34a in HCC tissues and cell lines. Ventricle injection model was constructed to explore the effect of Lnc34a on BM in vivo. The methylation of miR-34a promoter and histones deacetylation were examined by using bisulfate-sequencing PCR and chromatin immunoprecipitation assays. RNA pull down and RNA immunoprecipitation were performed to investigated the interaction between Lnc34a and epigenetic regulators. Dual-luciferase reporter assay was conducted to find miR-34a target. The involvement of TGF-β pathway in the BM from HCC was determined by qRT-PCR, western, and elisa assays. Results We found that Lnc34a was significantly overexpressed in HCC tissues and associated with BM. Both in vitro and in vivo experiments indicate that the restoration or knockdown of Lnc34a expression in HCC cells had a marked effect on cellular migration, invasion, and metastasis. Mechanistic analyses suggested that Lnc34a epigenetically suppresses miR-34a expression through recruiting DNMT3a via PHB2 to methylate miR-34a promoter and HDAC1 to promote histones deacetylation. On the other hand, miR-34a targets Smad4 via the TGF-β pathway, followed by altering the transcription of the downstream genes (i.e., CTGF and IL-11) that are associated with BM. Conclusions Our study is the first to document the pro-bone metastatic role of Lnc34a in BM of HCC and reveal a novel mechanism for the activation of the TGF-β signaling pathway in HCC BM, providing evidence of a potential therapeutic strategy in HCC BM. Electronic supplementary material The online version of this article (10.1186/s12943-019-1044-9) contains supplementary material, which is available to authorized users.

Diagnostic and prognostic nomograms for bone metastasis in hepatocellular carcinoma

“…Therefore, it appears to be important for clinical decision-making to explore the risk factors for BM from HCC patients. In the molecular level, the expression of Chemokine receptor CXCR4 [23], MicroRNA-34a, [24] and LncRNA34a [25] were identified to be associated with BM in HCC patients. Nevertheless, these biomarkers were difficult and unpractical to apply immediately to clinical decisions.…”

Regulation of TGFβ/SMAD signaling by long non-coding RNAs in different cancers: Dark Knight in the Castle of molecular oncology

“…miR-34a is a tumor suppressor and negatively regulates SMAD4 [ 37 ]. However, Lnc34a worked synchronously with DNMT3a, HDAC1 and PHB2 for the epigenetic inactivation of miR-34a.…”

“…However, Lnc34a worked synchronously with DNMT3a, HDAC1 and PHB2 for the epigenetic inactivation of miR-34a. miR-34a overexpression significantly inhibited bone metastasis, whereas overexpression of SMAD4 not only increased the invasion of cancer cells to the bones and but also accelerated bone damage [ 37 ].…”

Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma

“…Mechanistically, a long noncoding RNA activated by TGF-β (lncRNA-ATB) that is upregulated in HCC and is able to induce the epithelial–mesenchymal transition binds to the IL-11 mRNA and triggers STAT3 signaling through the autocrine induction of IL-11 production [89]. In addition, the long noncoding RNA Lnc34a is also overexpressed in HCC tissue and has a pro-metastatic function, at least partly by altering the TGF-β-induced IL-11 expression [90]. Recently, transmembrane p24 trafficking protein 3 (TMED3) has been shown to be upregulated in HCC and to be associated with poor prognosis for the patients.…”