Long Noncoding RNA lncARSR Promotes Doxorubicin Resistance in Hepatocellular Carcinoma via Modulating PTEN‐PI3K/Akt Pathway

Abstract

Hepatocellular carcinoma (HCC) is generally resistant to chemotherapy due to intrinsic or acquired drug resistances. Many molecules and signaling pathways are involved in chemo-resistance of HCC cells. However, the contribution of long noncoding RNA (lncRNA) to chemo-resistance of HCC cells is still largely unknown. In this study, we revealed the critical roles of long noncoding RNA lncARSR in chemo-resistance of HCC cells. lncARSR is upregulated in HCC, associated with large tumor size and advanced BCLC stage, and indicts poor prognosis. Functional assays showed that overexpression of lncARSR enhances doxorubicin resistance of HCC cells in vitro and in vivo. And while knockdown of lncARSR increases sensitivity of HCC cells to doxorubicin in vitro and in vivo. Mechanistically, we found that lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3K/Akt pathway. PTEN is downregulated in HCC, and the expression of PTEN is negatively correlated with lncARSR in HCC tissues. Furthermore, the effects of lncARSR overexpression on doxorubicin resistance could be reversed by PI3K/Akt pathway inhibitor, and lncARSR knockdown-induced doxorubicin sensitivity could be reversed by PTEN depletion. Taken together, our results showed that upregulated lncARSR promotes doxorubicin resistance in HCC via modulating PTEN-PI3K/Akt pathway, and implied that lncARSR may serve as a promising prognostic biomarker and therapeutic target for HCC chemo-resistance. J. Cell. Biochem. 118: 4498-4507, 2017. © 2017 Wiley Periodicals, Inc.

The LncRNA H19/miR‐193a‐3p axis modifies the radio‐resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1

“…Recent advances regarding genomes have demonstrated that lncRNAs could regulate various critical pathophysiological processes, such as cell proliferation, cell migration, and metastasis within cancers . It was also demonstrated that lncRNAs counted much in modifying the chemo‐sensitivity, for instance, up‐regulated lncRNA lncARSR was observed to promote doxorubicin resistance in HCC via modulating PTEN‐PI3K/Akt pathway . Of note, lncRNA H19, a paternally imprinted gene located in 11p15.5, was increasingly found to be over‐expressed within various cancers, including HCC, glioblastoma, gallbladder cancer, gastric cancer, and so on .…”

“…8,9 It was also demonstrated that lncRNAs counted much in modifying the chemo-sensitivity, for instance, up-regulated lncRNA lncARSR was observed to promote doxorubicin resistance in HCC via modulating PTEN-PI3K/Akt pathway. 10 Of note, lncRNA H19, a paternally imprinted gene located in 11p15.5, was increasingly found to be over-expressed within various cancers, including HCC, glioblastoma, gallbladder cancer, gastric cancer, and so on. [11][12][13][14] To be specific, inhibition of lncRNA H19 and miR-675 expression may promote migration and invasion of HCC cells though AKT/GSK-3β/Cdc25A signaling pathways.…”

Long non-coding RNA Gm12664 up-regulates CAV1 expression to promote hepatocellular lipid accumulation by sponging miR-295-5p

“…For instance, lncRNA MEG3 regulated hepatic lipid mechanism through AKT-mTOR signalling pathway [20] . Long noncoding RNA lncARSR was found to promote hepatic lipogenesis via Akt/SREBP-1c pathway and contribute to the pathogenesis of nonalcoholic steatohepatitis [18] . LncRNA SRA was reported to promote hepatic steatosis through repressing the expression of ATGL [19] .…”

“…Long non-coding RNAs (lncRNAs) are a class of transcripts with lengths greater than 200 nucleotides and act as guides, scaffolds, decoys and tethers of other biological molecules which are involved in various biological processes [12][13][14] . In recent years, emerging evidence has revealed that LncRNAs act as important regulators during the pathophysiology of NAFLD [15][16][17][18][19] . Long noncoding RNA lncARSR was found to promote hepatic lipogenesis via Akt/SREBP-1c pathway and contribute to the pathogenesis of nonalcoholic steatohepatitis [18] .…”

“…In recent years, emerging evidence has revealed that LncRNAs act as important regulators during the pathophysiology of NAFLD [15][16][17][18][19] . Long noncoding RNA lncARSR was found to promote hepatic lipogenesis via Akt/SREBP-1c pathway and contribute to the pathogenesis of nonalcoholic steatohepatitis [18] . LncRNA SRA was reported to promote hepatic steatosis through repressing the expression of ATGL [19] .…”