<p>LncRNA DANCR Promotes Sorafenib Resistance via Activation of IL-6/STAT3 Signaling in Hepatocellular Carcinoma Cells</p>

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the major malignancies and the second most common cause of cancer-related death worldwide. Sorafenib, an approved first-line systematic treatment agent for HCC, is capable to effectively improve the survival of patients with advanced HCC. The long-noncoding RNA (lncRNA) differentiation antagonizing non-protein coding RNA (DANCR) has been reported to exert oncogenic functions in several kinds of human cancers. However, the role of lncRNA DANCR in sorafenib resistance in HCC remains unknown. Methods: The expression levels of DANCR in HCC tissues were detected by qRT-PCR. DANCR overexpression and knockdown models were established and utilized to investigate the functional role of DANCR on sorafenib resistance in HCC cells. The MS2-binding sequences-MS2-binding protein-based RNA immunoprecipitation assay, RNA pull-down and luciferase reporter assay was used to detect the association between DANCR and PSMD10 mRNA. The activation of DANCR transcription mediated by STAT3 was assessed by luciferase reporter and chromatin immunoprecipitation assays. Results: We found that DANCR was significantly overexpressed in HCC tissues and associated with prognosis of HCC patients. Overexpression and knockdown experiments demonstrated that DANCR promoted sorafenib resistance in HCC cells in vitro and in vivo. Mechanistically, the role of DANCR relied largely on the association with PSMD10. DANCR stabilized PSMD10 mRNA through blocking the repressing effect of several microRNAs on PSMD10. Besides, DANCR activated IL-6/STAT3 signaling via PSMD10. Furthermore, we revealed that DANCR transcription was enhanced by the activation of IL-6/ STAT3 signaling, indicating a positive feedback loop of DANCR and IL-6/STAT3 signaling. Conclusion: Collectively, our study is the first to elucidate the mechanism of DANCRmediated sorafenib resistance via PSMD10-IL-6/STAT3 signaling axis, which provides a promising target for developing new therapeutic strategy for sorafenib tolerance of HCC.

Crosstalk between lncRNA DANCR and miR-125b-5p in HCC cell progression

“…This is in agreement with former studies that show the aberrant upregulation of DANCR in HCC and the involvement of DANCR dysregulation in HCC progression. 26,27 Furthermore, this study confirmed that DANCR knockdown greatly inhibits Huh7 and HepG2 cell proliferation and increases cell apoptosis, which is consistent with the previous study. 28 The anti-apoptosis effect of DANCR can also found in cholangiocarcinoma, which showed that suppression of DANCR could induce the expression of cleaved-caspase-3 and promote apoptosis both in vitro and in vivo.…”

Long Non-coding RNA DANCR in Cancer: Roles, Mechanisms, and Implications

“…It was implicated that DANCR played an essential role in HCC progression. For example, a high level of DANCR was associated with stemness features (Yuan et al, 2016), metastasis (Wen et al, 2020), and chemotherapeutic drug resistance in HCC (Liu et al, 2020a). In addition, the ROC (receiver operating characteristic) analysis showed that plasma DANCR and exosomal DANCR exhibited good discriminatory ability, suggesting it could be a promising diagnostic marker (Ma et al, 2016;Wang S.C. et al, 2020; Table 2).…”

“…For example, DANCR was verified to interact with 3 UTR of CTNNB1 mRNA in hepatocellular carcinoma, thus competitively blocking miRNA site and reversing miRNA-mediated CTNNB1 suppression (Yuan et al, 2016). Similarly, in sorafenib-resistant HCC, DANCR could bind with PSMD10 mRNA to stabilize its expression via blocking the miRNA binding site (Liu et al, 2020a). In the case of binding to proteins, it is interesting that DANCR could regulate both protein stability (Wen et al, 2020) and protein degradation (Xie et al, 2020).…”

“…DANCR could act as sponges for multiple miRNAs including miR-216a-5p , miR-27a-3p , miR-125b-5p (Yang et al, 2020), miR-140-3p (Wen et al, 2020) and miR-222-3p (Wang X. et al, 2020) in HCC. DANCR could also stabilize PSMD10 (Liu et al, 2020a) and CTNNB1 (Yuan et al, 2016) mRNAs by binding to their 3 UTR region to prevent its degradation by miRNAs. Wen et al (2020) found that DANCR could not only improve HNRNPA1 expression via DANCR/miR-140-3p/HNRNPA1 axis but also bind to HNRNPA1 protein and inhibit its degradation.…”

Prognostic and Genomic Analysis of Proteasome 20S Subunit Alpha (PSMA) Family Members in Breast Cancer

“…Integrating multiple datasets from these databases can provide a high degree of evidence from various studies in different populations using either raw or processed data, such as the Gene Expression Omnibus (GEO) ( accessed on 1 February 2021), a biomedical repository providing transcriptomic datasets for both microarray and next-generation sequencing platforms [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Changes in the mRNA expression levels of genes, sometimes an order of magnitude higher or lower in tumors than in normal matched tissues, illustrate, respectively, their roles as either oncogenes or tumor suppressors in cancer [ 33 , 34 , 35 ]. Applying this concept to BRCA and PSMA family genes, we used multiple datasets from public databases to study the expressions of PSMA genes in multiple subtypes of BRCA together with interaction networks to trace potential coexpressed targets with PSMA genes.…”