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Clinical Significance of the Thioredoxin System and Thioredoxin-Domain-Containing Protein Family in Hepatocellular Carcinoma

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Abstract

Background

Oxidative stress occurs due to the excessive generation of cellular reactive oxygen species and antioxidant system dysfunction. The thioredoxin (TXN) system and TXN-domain-containing protein (TXNDC) family form networks maintaining the cellular reducing environment. Recently, the importance of these genes in the tumor environment has been emphasized.

Aim

To investigate the clinical significance of TXNs and TXNDC family members in HCC.

Methods

Genomic data from 367 hepatocellular carcinoma (HCC) patients who underwent hepatic resections were analyzed to determine genetic alterations in mRNA and protein levels between patients and healthy controls. In addition, functional enrichment and survival analyses were performed.

Results

HCC patients were shown to have enhanced expression of TXN, TXNRD1, and TXNDC7/9/14 mRNA and protein compared with controls. In accordance with the survival analyses, strong associations were found that patients with TXN, TXNRD1, and TXNDC1/7/9 alterations were proven to have poor prognosis in overall survival. Moreover, gene set enrichment analysis and network analyses revealed that positive correlations were found in mRNA expression of TXN, TXNRD1, and TXNDC7/9 genes with upregulation of the tumor-promoting genes, specifically mTORC1, E2F targets, and Myc targets. On the other hand, elevated expressions of TXNIP and TXNDC11 genes were correlated with suppression of the above tumor-promoting genes.

Conclusions

TXN system and TXNDC family gene panel obtained from the resected tissue of the HCC patients could be used to predict survival prognosis of HCC, and these genes could be considered as potential therapeutic targets for improving HCC survival.

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Funding

This work was supported by a grant from the Korea Institute of Oriental Medicine (K18123) and the National Research Foundation of Korea funded by the Korea Government (NRF-2017R1C1B1004924).

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Author notes

  1. Sang Yeon Cho and Sungha Kim have contributed equally to this work.

Authors and Affiliations

  1. School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, 35015, Republic of Korea

    Sang Yeon Cho

  2. Department of Clinical Research, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea

    Sungha Kim & Mi-Ju Son

  3. Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, 34952, Republic of Korea

    Woo Sun Rou, Seok Hyun Kim, Hyuk Soo Eun & Byung Seok Lee

  4. Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, 35015, Republic of Korea

    Woo Sun Rou, Seok Hyun Kim, Hyuk Soo Eun & Byung Seok Lee

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  1. Sang Yeon Cho
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Corresponding authors

Correspondence to Hyuk Soo Eun or Byung Seok Lee.

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The authors declare no conflict of interest and financial arrangements.

Availability of data and materials

The datasets analyzed during the current study are available in TCGA (http://cancergenome.nih.gov/) and Firebrowse (http://firebrowse.org/).

Ethics approval and consent to participate

Ethical approval was not required as the study used data available on the database Firebrowse (http://firebrowse.org/).

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Cho, S.Y., Kim, S., Son, MJ. et al. Clinical Significance of the Thioredoxin System and Thioredoxin-Domain-Containing Protein Family in Hepatocellular Carcinoma. Dig Dis Sci 64, 123–136 (2019). https://doi.org/10.1007/s10620-018-5307-x

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  • DOI: https://doi.org/10.1007/s10620-018-5307-x

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