Skip to main content

Advertisement

SpringerLink
Log in

Serum AKR1B10 as an indicator of unfavorable survival of hepatocellular carcinoma

  • Original Article―Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background and Aims

A large-scale multicenter study validated aldo–keto reductase 1B10 (AKR1B10) as a new serum marker of hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic value of serum AKR1B10 in HCC.

Methods

273 naïve HCC patients enrolled for serum AKR1B10 tests were followed up for 2 years. Survival and clinical data were collected. Kaplan–Meier survival analysis and log-rank tests were used to estimate correlation of patient survival with serum AKR1B10. Univariate and multivariate COX regression analyses were used to evaluate the prognostic value of serum AKR1B10 level independently or in combination with other clinicopathological factors. α-fetoprotein (AFP) was analyzed in parallel for comparison.

Results

Serum AKR1B10 associated with tumor stage (p = 0.012), size (p = 0.004), primary tumor number (p = 0.019), and Child–Pugh classification (p = 0.003). HCC patients with a high level of serum AKR1B10 (≥ 267.9 pg/ml) had median survival (MS) of 25 months (95% confidence interval [CI] 20.788–29.212) vs. MS of 34 months (CI 28.911–39.089) in patients with normal serum AKR1B10 (p < 0.001). Univariate and multivariate COX regression analyses showed that serum AKR1B10 level was an unfavorable prognostic marker of HCC independently (HR 1.830, 95% CI 1.312–2.552; p < 0.001) or in combination with other clinical factors (HR 1.883, 95% CI 1.264–2.806; p = 0.002), such as TNM stage, tumor size and portal invasion. In the same cohort of HCC patients, AFP exhibited prognostic value at a cut-off of 400 ng/ml, but not at 20 ng/ml and 200 ng/ml.

Conclusions

Serum AKR1B10 is a new prognostic marker of HCC, better than AFP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Akinyemiju T, Abera S, Global Burden of Disease Liver Cancer C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA Oncol. 2017;3:1683–91.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ozakyol A. Global epidemiology of hepatocellular carcinoma (HCC Epidemiology). J Gastrointest Cancer. 2017;48:238–40.

    Article  PubMed  Google Scholar 

  3. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol 2018 69:182–236.

  4. Luo DX, Huang MC, Ma J, et al. Aldo-keto reductase family 1, member B10 is secreted through a lysosome-mediated non-classical pathway. Biochem J. 2011;438:71–80.

    Article  CAS  PubMed  Google Scholar 

  5. Luo D, Bu Y, Ma J, et al. Heat shock protein 90-alpha mediates aldo-keto reductase 1B10 (AKR1B10) protein secretion through secretory lysosomes. J Biol Chem. 2013;288:36733–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liu Z, Yan R, Al-Salman A, et al. Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells. Biochem J. 2012;442:273–82.

    Article  CAS  PubMed  Google Scholar 

  7. Cao D, Fan ST, Chung SS. Identification and characterization of a novel human aldose reductase-like gene. J Biol Chem. 1998;273:11429–35.

    Article  CAS  PubMed  Google Scholar 

  8. Tsuzura H, Genda T, Sato S, et al. Expression of aldo-keto reductase family 1 member b10 in the early stages of human hepatocarcinogenesis. Int J Mol Sci. 2014;15:6556–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heringlake S, Hofdmann M, Fiebeler A, et al. Identification and expression analysis of the aldo-ketoreductase1-B10 gene in primary malignant liver tumours. J Hepatol. 2010;52:220–7.

    Article  CAS  PubMed  Google Scholar 

  10. Ye X, Li C, Zu X, et al. A large-scale multicenter study validates AKR1B10 as a new prevalent serum marker for detection of hepatocellular carcinoma. Hepatology. 2019;64:2489.

    Article  Google Scholar 

  11. Shen Y, Zhong L, Johnson S, et al. Human aldo-keto reductases 1B1 and 1B10: a comparative study on their enzyme activity toward electrophilic carbonyl compounds. Chem Biol Interact. 2011;191:192–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yan R, Zu X, Ma J, et al. Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention. Int J Cancer. 2007;121:2301–6.

    Article  CAS  PubMed  Google Scholar 

  13. Balendiran GK, Martin HJ, El-Hawari Y, et al. Cancer biomarker AKR1B10 and carbonyl metabolism. Chem Biol Interact. 2009;178:134–7.

    Article  CAS  PubMed  Google Scholar 

  14. Zhong L, Liu Z, Yan R, et al. Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels. Biochem Biophys Res Commun. 2009;387:245–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zu X, Yan R, Robbins S, et al. Reduced 293T cell susceptibility to acrolein due to aldose reductase-like-1 protein expression. Toxicol Sci. 2007;97:562–8.

    Article  CAS  PubMed  Google Scholar 

  16. Zu X, Yan R, Pan J, et al. Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds. Mol Carcinog. 2017;56:118–29.

    Article  CAS  PubMed  Google Scholar 

  17. Ruiz FX, Porte S, Pares X, et al. Biological role of aldo-keto reductases in retinoic Acid biosynthesis and signaling. Front Pharmacol. 2012;3:58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ruiz FX, Gallego O, Ardevol A, et al. Aldo-keto reductases from the AKR1B subfamily: retinoid specificity and control of cellular retinoic acid levels. Chem Biol Interact. 2009;178:171–7.

    Article  CAS  PubMed  Google Scholar 

  19. Ma J, Yan R, Zu X, et al. Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells. J Biol Chem. 2008;283:3418–23.

    Article  CAS  PubMed  Google Scholar 

  20. Wang C, Yan R, Luo D, et al. Aldo-keto reductase family 1 member B10 promotes cell survival by regulating lipid synthesis and eliminating carbonyls. J Biol Chem. 2009;284:26742–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang C, Xu C, Sun M, et al. Acetyl-CoA carboxylase-alpha inhibitor TOFA induces human cancer cell apoptosis. Biochem Biophys Res Commun. 2009;385:302–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huang C, Cao Z, Ma J, et al. AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells. Mol Carcinog. 2018;57:1300–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fukumoto S-I, Yamauchi N, Moriguchi H, et al. Overexpression of the Aldo-keto reductase family protein AKR1B10 Is highly correlated with smokers’ non-small cell lung carcinomas. Clin Cancer Res. 2005;11:1776–85.

    Article  CAS  PubMed  Google Scholar 

  24. Ma J, Luo DX, Huang C, et al. AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker. Int J Cancer. 2012;131:E862–71.

    Article  CAS  PubMed  Google Scholar 

  25. Chung YT, Matkowskyj KA, Li H, et al. Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma. Mod Pathol. 2012;25:758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang C, Verhulst S, Shen Y, et al. AKR1B10 promotes breast cancer metastasis through integrin alpha5/delta-catenin mediated FAK/Src/Rac1 signaling pathway. Oncotarget. 2016;7:43779–91.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shi J, Chen L, Chen Y, et al. Aldo-keto reductase family 1 member B10 (AKR1B10) overexpression in tumors predicts worse overall survival in hepatocellular carcinoma. J Cancer. 2019;10:4892–901.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sato S, Genda T, Hirano K, et al. Up-regulated aldo-keto reductase family 1 member B10 in chronic hepatitis C: association with serum alpha-fetoprotein and hepatocellular carcinoma. Liver Int. 2012;32:1382–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Murata A, Genda T, Ichida T, et al. Pretreatment AKR1B10 expression predicts the risk of hepatocellular carcinoma development after hepatitis C virus eradication. World J Gastroenterol. 2016;22:7569–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mori M, Genda T, Ichida T, et al. Aldo-keto reductase family 1 member B10 is associated with hepatitis B virus-related hepatocellular carcinoma risk. Hepatol Res. 2017;47:E85–93.

    Article  CAS  PubMed  Google Scholar 

  31. Schmitz KJ, Sotiropoulos GC, Baba HA, et al. AKR1B10 expression is associated with less aggressive hepatocellular carcinoma: a clinicopathological study of 168 cases. Liver Int. 2011;31:810–6.

    Article  CAS  PubMed  Google Scholar 

  32. Ha SY, Song DH, Lee JJ, et al. High expression of aldo-keto reductase 1B10 is an independent predictor of favorable prognosis in patients with hepatocellular carcinoma. Gut Liver. 2014;8:648–54.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sonohara F, Inokawa Y, Hishida M, et al. Prognostic significance of AKR1B10 gene expression in hepatocellular carcinoma and surrounding non-tumorous liver tissue. Oncol Lett. 2016;12:4821–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang YY, Qi LN, Zhong JH, et al. High expression of AKR1B10 predicts low risk of early tumor recurrence in patients with hepatitis B virus-related hepatocellular carcinoma. Sci Rep. 2017;7:42199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. DiStefano JK, Davis B. Diagnostic and Prognostic Potential of AKR1B10 in Human Hepatocellular Carcinoma. Cancers (Basel). 2019;11:486.

    Article  CAS  PubMed  Google Scholar 

  36. Zhu R, Xiao J, Luo D, et al. Serum AKR1B10 predicts the risk of hepatocellular carcinoma a retrospective single-center study. Gastroenterol Hepatol. 2019;42:619.

    Article  Google Scholar 

  37. Han C, Gao L, Zhao L, et al. Immunohistochemistry detects increased expression of aldo-keto reductase family 1 member B10 (AKR1B10) in early-stage hepatocellular carcinoma. Med Sci Monit. 2018;24:7414–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang W, Li H, Yang Y, et al. Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway. Cancer Lett. 2014;355:273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Light of Life Biotechnology Ltd., China for providing time‐resolved fluorescent kits for measurements of serum AKR1B10 protein.

Funding

This work was supported in part by Special Projects of Changzhutan National Independent Innovation Demonstration Zone (2018XK2106) and Changsha Municipal Natural Science Foundation (kq2202467).

Author information

Author notes

  1. Chenglin Xie and Xu Ye have contributed equally.

Authors and Affiliations

  1. Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Changsha, 410013, Hunan, China

    Chenglin Xie, Xu Ye, Li Zeng & Deliang Cao

  2. The Affiliated Hospital of Hunan Research Institute of Traditional Chinese Medicine, 58 Lushan Road, Changsha, 410006, Hunan, China

    Chenglin Xie

  3. Hunan Province Key Laboratory of Cancer Cellular and Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, 28W Changsheng Road, Hengyang, 421001, Hunan, China

    Xi Zeng & Deliang Cao

Authors
  1. Chenglin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xu Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xi Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deliang Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XY and DC designed the study. CX and LZ served in data collection. XY, XZ and CX analyzed and interpreted the data and drafted the manuscript. DC revised and finalized the manuscript.

Corresponding authors

Correspondence to Xi Zeng or Deliang Cao.

Ethics declarations

Conflicts of interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, C., Ye, X., Zeng, L. et al. Serum AKR1B10 as an indicator of unfavorable survival of hepatocellular carcinoma. J Gastroenterol 58, 1030–1042 (2023). https://doi.org/10.1007/s00535-023-02011-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-023-02011-9

Keywords

Search

Navigation