Upregulated UCA1 contributes to oxaliplatin resistance of hepatocellular carcinoma through inhibition of miR-138-5p and activation of AKT/mTOR signaling pathway.
Pharmacol Res Perspect
; 9(1): e00720, 2021 02.
Article
in En
| MEDLINE
| ID: mdl-33565716
ABSTRACT
Hepatocellular carcinoma (HCC) inevitably developed oxaliplatin (OXA) resistance after long-term treatment, but the mechanism remains unclear. Here, we found that LncRNA UCA1 was upregulated in most of OXA-resistant HCC tissues and cells (HepG2/OXA and SMMC-7721/OXA). Follow-up analysis and online Kaplan-Meier Plotter revealed that HCC patients with high UCA1 level had a shorter survival compared with those with low expression. Overexpression of UCA1 increased OXA IC50 in HepG2 and SMMC-7721 cells, whereas knockdown of UCA1 decreased OXA IC50 in resistant counterparts. Moreover, dual luciferase reporter assay showed that co-transfection of UCA1-WT plasmid with miR-138-5p mimics enhanced fluorescence signals, whereas co-transfection of UCA1-Mut plasmid and miR-138-5p mimics did not induce any changes. Consistently, UCA1 levels in HepG2/OXA and SMMC-7721/OXA cells were downregulated after transfected with miR-138-5p mimics. UCA1 silencing or transfection of miR-138-5p mmics inhibited the activation of AKT and mTOR in HepG2/OXA and SMMC-7721/OXA cells, whereas UCA1 overexpression increased the phosphorylated AKT and mTOR levels in parental counterparts. Rapamycin or miR-138-5p mimics similarly suppressed the activation of AKT and mTOR, whereas UCA1 overexpression exert opposite roles. Interestingly, administration of rapamycin or miR-138-5p mimics apparently antagonized the effects of UCA1 on AKT and mTOR activation. Besides, depletion of UCA1 triggered more dramatic regression of HepG2 xenografts than that of HepG2/OXA xenografts with OXA treatment and impaired the p-AKT and p-mTOR levels in vivo. In conclusion, our findings provide the evidence that UCA1 may contribute to OXA resistance via miR-138-5p-mediated AK /mTOR activation, suggesting that UCA1 is a potential therapeutic target for HCC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma, Hepatocellular
/
Drug Resistance, Neoplasm
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RNA, Long Noncoding
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Oxaliplatin
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Liver Neoplasms
/
Antineoplastic Agents
Limits:
Animals
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Humans
/
Male
Language:
En
Journal:
Pharmacol Res Perspect
Year:
2021
Document type:
Article