Abstract
BackgroundThioredoxin reductase 1 (TXNRD1) is an antioxidant enzyme reportedly overexpressed in hepatocellular carcinoma (HCC); however, the detailed function and mechanisms of TXNRD1 in HCC remain obscure. In this study, we investigated the miR-125b-5p-specific regulation of TXNRD1 levels and its effect on HCC cells.MethodsWe detected miR-125b-5p levels in human HCC tissue samples through quantitative reverse transcription polymerase chain reaction (qRT-PCR), and in vitro experiments were employed to investigate the effect of miR-125b-5p on HCC cell proliferation, migration, and invasion. Additionally, we examined miR-125b-5p-mediated changes in TXNRD1 levels by qRT-PCR and western blotting, and a dual luciferase-reporter assay was conducted to confirm direct targeting of the 3′ untranslated region of TXNRD1 mRNA by miR-125b-5p.ResultsmiR-125b-5p expression was reduced in HCC tissues relative to that in matched para-carcinoma tissues; this finding was verified in HCC cohorts from the Gene Expression Omnibus and The Cancer Genome Atlas. Additionally, low miR-125b-5p expression was associated with poor prognosis in HCC patients, and gene-set enrichment analysis indicated that miR-125b-5p levels were associated with HCC proliferation and metastasis. As predicted, overexpressing miR-125b-5p restrained the proliferation, migration, and invasion of Huh7 and SK-Hep-1 cells and forced expression of the miR-125b-5p-downregulated TXNRD1 mRNA and protein levels in HCC cells. Moreover, dual luciferase-reporter assays revealed that miR-125b-5p targets TXNRD1 to directly regulate its expression, whereas TXNRD1 overexpression abolishes the inhibitory effect of miR-125b-5p on HCC cell proliferation, migration, and invasion.ConclusionsThese results demonstrated miR-125b-5p as a tumor suppressor in HCC through its inhibition of TXNRD1, thereby suggesting it as a potential target for the clinical treatment of HCC.
Highlights
Thioredoxin reductase 1 (TXNRD1) is an antioxidant enzyme reportedly overexpressed in hepatocellular carcinoma (HCC); the detailed function and mechanisms of TXNRD1 in HCC remain obscure
Results miR‐125b‐5p levels are downregulated in HCC tissues and cell lines We found that miR-125b-5p levels were significantly reduced in HCC tissues relative to those in precancerous non-tumor or normal liver tissues, according to data from five gene expression omnibus (GEO) datasets and a The Cancer Genome Atlas (TCGA) cohort (Fig. 1a–f )
We investigated targets reportedly upregulated in HCC according to the TGCA cohort, including TXNRD1, protein phosphatase Mg2+/ Mn2+-dependent-1F, and Cbl proto-oncogene B. qRTPCR analysis of their mRNA levels in miR-125b-5poverexpressing or silenced HCC cells revealed that only TXNRD1 was regulated by miR-125b-5p (Fig. 4a, b)
Summary
Thioredoxin reductase 1 (TXNRD1) is an antioxidant enzyme reportedly overexpressed in hepatocellular carcinoma (HCC); the detailed function and mechanisms of TXNRD1 in HCC remain obscure. We investigated the miR-125b-5p-specific regulation of TXNRD1 levels and its effect on HCC cells. The mechanisms underlying the miRNA-specific regulation of tumor progression have not been completely investigated. Thioredoxin-1 (TRX1) is a key contributor to intracellular redox homeostasis and promotes energy and carbohydrate metabolism [8]. Thioredoxin reductase-1 (TXNRD1) is uniquely capable of utilizing electrons from NADPH to recover the reduced state of TRX1. TXNRD1 is upregulated in many human malignancies and promotes cancer progression [10], and attenuation of TXNRD1 levels effectively suppresses the growth of tumor cells [11]
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