Skip to main content

Evaluation of serum thioredoxin as a hepatocellular carcinoma diagnostic marker

Abstract

Background

Hepatocellular carcinoma (HCC) is one of the most prevalent and fatal malignancies worldwide. Following an increase in reactive oxygen species (ROS), cancer cells enter an oxidative stress state. As a result, these cells experience an increase in antioxidant activity to counteract oxidative stress. The thioredoxin (TRX) system is a ubiquitous mammalian antioxidant system that neutralizes ROS and maintains intracellular reduction oxidation (redox) balance, which is essential for HCC growth. However, the role of TRX protein in HCC remains largely unknown. Hence, we aimed to assess the diagnostic utility of serum TRX in patients with HCC. A total of 50 patients were consecutively recruited in this observational study. They were classified into three groups: an HCC group (25 patients), a cirrhosis group (15 patients with liver cirrhosis on top of chronic HCV infection), and a control group (10 healthy individuals). Serum TRX levels were measured using ELISA.

Results

Higher serum TRX levels were detected in the HCC group than in the cirrhosis and control groups (140.96 ± 12.70 vs 88.33 ± 10.34 vs 73.10 ± 13.22 ng/mL, respectively; P < 0.001). TRX was independently associated with the presence of HCC (P < 0.001). Regarding the detection of HCC, TRX at a cut-off value of 114 ng/mL had superior diagnostic performance to AFP with an AUC of 1.000, sensitivity of 100%, and specificity of 100%, whereas AFP at a cut-off value of 20.5 ng/mL had an AUC of 1.000, sensitivity of 100%, and specificity of 47%.

Conclusion

Thioredoxin has the potential to be an HCC diagnostic marker. The clinical significance of thioredoxin in HCC requires further investigation.

Background

Hepatocellular carcinoma (HCC) is the fifth most common type of malignancy worldwide and the third most common cause of cancer-related mortality [1]. Metabolic reprogramming is currently recognized as a hallmark of cancer [2]. Therefore, elucidating the molecular pathogenesis of HCC is critical for identifying potential targets for diagnosing and treating HCC [3].

HCC is a complicated tumour influenced by numerous variables [4]. A common characteristic of hepatocarcinogenesis is that chronic hepatic inflammation, regardless of its aetiology, results in dysregulation in the hepatic reduction–oxidation (redox) homeostasis, causing oxidative stress, which promotes hepatocarcinogenesis by inducing DNA mutations and genetic instability [5]. However, an overabundance of reactive oxygen species (ROS) is harmful because it damages cellular components such as DNA, lipids, and proteins, resulting in cell cycle arrest and apoptosis [6]. Therefore, to lower ROS levels to a favourable range for tumour progression, cancer cells must actively upregulate several antioxidant mechanisms [7].

The thioredoxin (TRX) system is one of the essential redox control systems. It consists of the small redox protein TRX, nicotinamide adenine dinucleotide phosphate in its reduced form (NADPH), and thioredoxin reductase (TRXR), a large homodimeric selenzoenzyme controlling the redox state of TRX [8]. This pathway begins with electron donation from NADPH. TRXR transfers the electron to TRX, which then transfers it for ROS scavenging [9].

Accumulating evidence shows that TRX is an essential modulator in HCC development [10]. Its upregulation stimulates hypoxia-inducible factor-1α, which increases the expression of vascular endothelial growth factor-A, promoting angiogenesis and tumour cell proliferation [11]. Additionally, positive correlations were found between TRX mRNA expression and the upregulation of the tumour-promoting genes, specifically mTORC1, E2F targets, and Myc targets [12].

Furthermore, TRX/TRXR overexpression has been reported in HCC and closely correlated with aggressive tumour phenotype, metastasis, poor patient survival, and resistance to chemotherapy [12,13,14,15,16,17]. Nevertheless, the expression of the thioredoxin-interacting protein (TRXIP), an endogenous inhibitor of TRX, was downregulated [12, 18].

In addition, the blockade of the TRX/TRXR system results in intracellular ROS accumulation, which promotes HCC cell apoptosis [19,20,21]. Additionally, sorafenib, a kinase inhibitor drug approved for the treatment of HCC, upregulates TRXIP while downregulating the TRX/TRXR pathway. In addition, in SNU475 cells treated with sorafenib, TRX downregulation has a notable synergistic pro-apoptotic effect on proteome rearrangement [15, 22]. Hence, the current study aims to assess the diagnostic utility of serum TRX in patients with HCC.

Methods

In this observational study, 50 patients were consecutively recruited from the Internal Medicine and Hepatology inpatient wards and outpatient clinics at Ain Shams University Hospitals from June 2021 to February 2022. The patients were classified into three groups: an HCC group (25 patients), a cirrhosis group (15 patients with liver cirrhosis on top of chronic HCV infection), and a control group (10 healthy individuals).

Patients with cirrhosis due to causes other than chronic HCV infection were excluded. Additionally, individuals with medical conditions which could alter serum TRX levels including diabetes, previous/concomitant neoplasm, chronic kidney disease, inflammatory conditions, severe burn injuries, and cardiovascular diseases, were excluded [23,24,25,26].

Diagnosis of HCC and cirrhosis

Clinical signs, laboratory parameters, and/or histological criteria were used to diagnose cirrhosis [27]. According to the practice guidelines, HCC was identified by contrast-enhanced imaging and/or histological criteria [28].

Serum human TRX measurement

Serum TRX level was measured using ELISA according to the manufacturer's instructions (Immuno-Biological Laboratories Co., Ltd, Gunma, Japan). The measurement range was 3.91–250 ng/mL and sensitivity was 0.43 ng/mL. The coefficients of variation for the intra- and interassays were 7.2–10% and 6.0–9.1%.

Alpha-fetoprotein (AFP) measurement

The AFP was measured using ELISA (Monobind Inc., Lake Forest, CA 92630, USA) with a sensitivity of 0.01 ng/mL.

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and its appendices and was approved by the ethics committee of the Faculty of Medicine, Ain Shams University (FMASU MSO 38/2021/2022-FWA 000017585). Written informed consent was obtained from all participants.

Statistical analysis

The data were analyzed using IBM SPSS Statistics for Windows (version 20.0; IBM Corp., Armonk, NY, USA). They were then presented as mean ± standard deviation (SD) for quantitative data and frequency and distribution for qualitative data.

Statistical significance was set at P < 0.05 in the statistical comparison between the different groups. The significance of difference was tested using one of the following:

  1. 1-

    Student's t-test: to compare the means of two groups of quantitative data

  2. 2-

    ANOVA and Tukey's post hoc test: to compare the means of more than two sets of quantitative data

  3. 3-

    Chi-square test and Fisher’s exact test: to compare categorical data between groups

  4. 4-

    Pearson's correlation coefficient: to determine the relationships between variables

  5. 5-

    Receiver operating characteristic (ROC) curve with the estimation of Youden's index: to assess the diagnostic performance of TRX and AFP

Results

The current study included 25 patients with HCC, 15 patients with cirrhosis, and 10 healthy controls. They were 42 (84%) males and eight (16%) females with a mean age of 44.18 ± 10.1 years. Regarding age and sex, insignificant differences were observed between the groups (P ≥ 0.05). In HCC group, the mean tumour foci size was 6.1 ± 2.5 cm. Multifocal HCC and portal vein thrombosis were detected in 19 (76%) and 3 (12%) patients, respectively. In cirrhosis group, 3 (20%), 4 (26.6%), and 8 (53.3%) patients were classified into Child–Pugh class A, B, and C, respectively. Study participant characteristics are shown in Table 1.

Table 1 Comparison of the laboratory test results between the HCC, cirrhosis, and control groups

Significant differences were observed between the groups, with TRX and AFP being highest in the HCC group (Table 1 and Fig. 1). There was no difference in serum TRX levels between patients with solitary and multifocal HCC (139.947 ± 12.747 vs 144.167 ± 13.152 ng/mL, respectively, P = 0.4898). In addition, in the cirrhosis group, serum TRX levels were significantly higher in Child–Pugh class B and C patients as compared to class A patients (81.33 ± 15.17 vs 97 ± 6.27 vs 97 ± 5.80 ng/mL, P = 0.03). Both TRX and AFP were independently correlated with the presence of HCC (Table 2).

Fig. 1
figure 1

Serum thioredoxin levels in all groups

Table 2 Candidate blood markers independently associated with the existence of HCC

A significant negative correlation was observed between TRX and aspartate aminotransferase (AST) among the HCC group and between TRX and alanine aminotransferase (ALT) among the cirrhosis group (Table 3).

Table 3 Correlation between thioredoxin and other variables among HCC and cirrhosis groups

To assess the diagnostic performance of serum TRX and AFP in identifying patients with HCC from those with liver cirrhosis, a ROC curve was plotted. TRX had an AUC of 1.000, sensitivity of 100%, and specificity of 100% at a cut-off value of 114 ng/mL, whereas AFP had an AUC of 1.000, sensitivity of 100%, and specificity of 47% at a cut-off value of 20.5 ng/mL (Table 4 and Fig. 2).

Table 4 ROC curve analysis for the detection of HCC
Fig. 2
figure 2

ROC curve analysis for the diagnosis of hepatocellular carcinoma

Discussion

Despite significant advancements in detecting and treating HCC, the majority of patients were diagnosed with the disease at advanced stages [29]. The most frequently utilized blood marker for diagnosing HCC to date is AFP [30]. The sensitivity of AFP ranges from 60 to 80% at a cut-off serum value of 20 ng/mL [31]. However, unless other diagnostic methods are used, up to 40% of advanced HCC and at least one-third of small HCC may go undetected [32]. Additionally, a significant increase in serum AFP levels (20–200 ng/mL) was detected in a large number of patients with chronic hepatitis and cirrhosis [33]. In an earlier study [34], AFP concentrations were increased in 11–58% of patients with cirrhosis and chronic hepatitis. Similarly, in the current study, 53% of patients with cirrhosis had an AFP > 20 ng/mL. This necessitated the development of a reliable biomarker to diagnose HCC.

In the present study, higher serum TRX levels were detected in the HCC group than in the cirrhosis and control groups. In agreement with the results, Li et al. [34] reported that TRX could be a diagnostic marker of HCC, with significantly higher serum TRX levels in patients with HCC than those in patients with liver cirrhosis, patients with chronic liver diseases, and healthy subjects (45.1 [28.2–56] vs 9 [6.1–11.9] vs 8.1 [5–10.2] vs 7.5 [6–9.2] ng/mL, respectively; P < 0.0001). In addition, although serum AFP levels were increased in the HCC group, as expected, significant increases were also observed in patients with liver cirrhosis and chronic liver diseases compared to the control group (142 [18–548] vs 15.4 [8.7–30.2] vs 13.6 [6.8–24.4] vs 6.6 [4.0–9.2] ng/mL, respectively; P < 0.0001).

Similar to the current findings, a previous study has reported significantly higher TRX levels in the HCC group than in the liver cirrhosis group (129.5 [112–135] vs 84.5 [37–126] ng/mL, respectively; P < 0.001). Additionally, the authors have found that the increase in serum AFP and TRX levels was significantly correlated to the presence of HCC (P < 0.05) [35].

In agreement with the current study, no influence of age, sex, ALT, AST, total bilirubin, prothrombin time, and AFP was detected on serum TRX levels in patients with HCC (P > 0.05) [34].

Our findings indicate that serum TRX complements AFP measurement in the detection of HCC. Similar to the present study, Li et al. [34] reported that TRX was superior to AFP in diagnosing HCC (P < 0.001). TRX at a cut-off value of 20.5 ng/mL differentiated HCC from chronic liver diseases and cirrhosis with an AUC of 0.906, 95% CI = 0.870–0.925, sensitivity of 78.7%, and specificity of 87.8%, whereas AFP at a cut-off value of 20 ng/mL had an AUC of 0.840, 95% CI = 0.820–0.884, sensitivity of 74%, and specificity of 79.1%. In another study investigating the diagnosis of HCC [35], AFP at a cut-off value of 400 U/L only had an AUC of 0.69, 95% CI = 0.59–0.77, sensitivity of 29%, and specificity of 100% (P < 0.0001), whereas TRX at a cut-off value of 120 ng/mL had an AUC of 0.79, 95% CI = 0.69–0.89, sensitivity of 74%, and specificity of 71% (P < 0.0001). However, the diagnostic performance of TRX was better in the current study than in previous reports. This discrepancy in results may be attributed to the use of different cut-off values.

The current study is limited by the small sample size and lack of TRX assessment in histologic specimens in correlation with serum levels. Whether serum TRX levels reflect similar changes in the hepatic tissue remains uncertain. The relationship between serum and tissue TRX levels warrants further investigation. Additional research with a larger sample size is needed to validate TRX diagnostic value and determine the optimum cut-off value.

Conclusions

Thioredoxin has the potential to be a diagnostic marker of HCC. The clinical significance of thioredoxin in HCC remains to be comprehensively examined.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AFP:

Alpha fetoprotein

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

HCC:

Hepatocellular carcinoma

NADPH:

Nicotinamide adenine dinucleotide phosphate

ROS:

Reactive oxygen species

TRX:

Thioredoxin

TRXIP:

Thioredoxin-interacting protein

TRXR:

Thioredoxin reductase

References

  1. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, Heimbach JK (2018) Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 68(2):723–750. https://doi.org/10.1002/hep.29913. (PMID: 29624699)

    Article  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013. (PMID: 21376230)

    Article  CAS  PubMed  Google Scholar 

  3. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, Waljee AK, Singal AG (2018) Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology. 154(6):1706-1718.e1. https://doi.org/10.1053/j.gastro.2018.01.064. (Epub 2018 Feb 6. PMID: 29425931; PMCID: PMC5927818)

    Article  CAS  PubMed  Google Scholar 

  4. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30. https://doi.org/10.3322/caac.21442. (Epub 2018 Jan 4 PMID: 29313949)

    Article  PubMed  Google Scholar 

  5. Fu B, Meng W, Zeng X, Zhao H, Liu W, Zhang T (2017) TXNRD1 Is an Unfavorable Prognostic Factor for Patients with Hepatocellular Carcinoma. Biomed Res Int. 2017:4698167. https://doi.org/10.1155/2017/4698167. (Epub 2017 PMID: 28536696; PMCID: PMC5425838)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947

    Article  CAS  PubMed  Google Scholar 

  7. Senft D, Ronai ZA (2016) Adaptive Stress Responses During Tumor Metastasis and Dormancy. Trends Cancer 2:429–442. https://doi.org/10.1016/j.trecan.2016.06.004

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bian M, Fan R, Zhao S, Liu W (2019) Targeting the Thioredoxin System as a Strategy for Cancer Therapy. J Med Chem 62(16):7309–7321. https://doi.org/10.1021/acs.jmedchem.8b01595. (Epub 2019 Apr 16 PMID: 30963763)

    Article  CAS  PubMed  Google Scholar 

  9. Lee D, Xu IM, Chiu DK, Lai RK, Tse AP, Lan Li L, Law CT, Tsang FH, Wei LL, Chan CY, Wong CM, Ng IO, Wong CC (2017) Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Invest. 127(5):1856–1872. https://doi.org/10.1172/JCI90253. (Epub 2017 Apr 10. PMID: 28394261; PMCID: PMC5409797)

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhang J, Li X, Han X, Liu R, Fang J (2017) Targeting the Thioredoxin System for Cancer Therapy. Trends Pharmacol Sci 38(9):794–808. https://doi.org/10.1016/j.tips.2017.06.001. (PMID: 28648527)

    Article  CAS  PubMed  Google Scholar 

  11. Reichl P, Mikulits W (2016) Accuracy of novel diagnostic biomarkers for hepatocellular carcinoma: An update for clinicians (Review). Oncol Rep 36(2):613–625. https://doi.org/10.3892/or.2016.4842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cho SY, Kim S, Son MJ, Rou WS, Kim SH, Eun HS, Lee BS (2019) Clinical Significance of the Thioredoxin System and Thioredoxin-Domain-Containing Protein Family in Hepatocellular Carcinoma. Dig Dis Sci 64(1):123–136. https://doi.org/10.1007/s10620-018-5307-x. (Epub 2018 Oct 4 PMID: 30288659)

    Article  CAS  PubMed  Google Scholar 

  13. Cao MQ, You AB, Cui W, Zhang S, Guo ZG, Chen L, Zhu XD, Zhang W, Zhu XL, Guo H, Deng DJ, Sun HC, Zhang T (2020) Cross talk between oxidative stress and hypoxia via thioredoxin and HIF-2α drives metastasis of hepatocellular carcinoma. FASEB J 34(4):5892–5905. https://doi.org/10.1096/fj.202000082R. (Epub 2020 Mar 10 PMID: 32157720)

    Article  CAS  PubMed  Google Scholar 

  14. Abdel-Hamid NM, Mahmoud TK, Abass SA, El-Shishtawy MM (2018) Expression of thioredoxin and glutaredoxin in experimental hepatocellular carcinoma-Relevance for prognostic and diagnostic evaluation. Pathophysiology 25(4):433–438. https://doi.org/10.1016/j.pathophys.2018.08.008. (Epub 2018 Sep 12 PMID: 30224102)

    Article  CAS  PubMed  Google Scholar 

  15. López-Grueso MJ, González R, Muntané J, Bárcena JA, Padilla CA (2019) Thioredoxin Downregulation Enhances Sorafenib Effects in Hepatocarcinoma Cells. Antioxidants (Basel). 8(10):501. https://doi.org/10.3390/antiox8100501. (Published 2019 Oct 22. doi:10.3390/antiox8100501)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lei H, Wang G, Zhang J, Han Q (2018) Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity. Oncol Rep. 40(6):3447–3457. https://doi.org/10.3892/or.2018.6740. (Epub 2018 Sep 27. PMID: 30272318; PMCID: PMC6196602)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zheng X, Ma W, Sun R, Yin H, Lin F, Liu Y, Xu W, Zeng H (2018) Butaselen prevents hepatocarcinogenesis and progression through inhibiting thioredoxin reductase activity. Redox Biol. 14:237–249. https://doi.org/10.1016/j.redox.2017.09.014. (Epub 2017 Sep 22. Erratum in: Redox Biol. 2020 May;32:101526. PMID: 28965082; PMCID: PMC5633849)

    Article  CAS  PubMed  Google Scholar 

  18. Li W, Xin X, Li X, Geng J, Sun Y (2021) Exosomes secreted by M2 macrophages promote cancer stemness of hepatocellular carcinoma via the miR-27a-3p/TXNIP pathways. Int Immunopharmacol. 101(Pt A):107585. https://doi.org/10.1016/j.intimp.2021.107585. (Epub 2021 Sep 30. PMID: 34601333)

    Article  CAS  PubMed  Google Scholar 

  19. Fan R, Bian M, Hu L, Liu W (2019) A new rhodium(I) NHC complex inhibits TrxR: In vitro cytotoxicity and in vivo hepatocellular carcinoma suppression. Eur J Med Chem. 183:111721. https://doi.org/10.1016/j.ejmech.2019.111721. (Epub 2019 Sep 21. PMID: 31577978)

    Article  CAS  PubMed  Google Scholar 

  20. Bian M, Wang X, Sun Y, Liu W (2020) Synthesis and biological evaluation of gold(III) Schiff base complexes for the treatment of hepatocellular carcinoma through attenuating TrxR activity. Eur J Med Chem. 193:112234. https://doi.org/10.1016/j.ejmech.2020.112234. (Epub 2020 Mar 14. PMID: 32213395)

    Article  CAS  PubMed  Google Scholar 

  21. Lee D, Xu IM, Chiu DK, Leibold J, Tse AP, Bao MH, Yuen VW, Chan CY, Lai RK, Chin DW, Chan DF, Cheung TT, Chok SH, Wong CM, Lowe SW, Ng IO, Wong CC (2019) Induction of oxidative stress through inhibition of thioredoxin reductase 1 is an effective therapeutic approach for hepatocellular carcinoma. Hepatology 69:1768–1786

    Article  CAS  PubMed  Google Scholar 

  22. González R, Rodríguez-Hernández MA, Negrete M, Ranguelova K, Rossin A, Choya-Foces C, Cruz-Ojeda P, Miranda-Vizuete A, Martínez-Ruiz A, Rius-Pérez S, Sastre J, Bárcena JA, Hueber AO, Padilla CA, Muntané J (2020) Downregulation of thioredoxin-1-dependent CD95 S-nitrosation by Sorafenib reduces liver cancer. Redox Biol. 34:101528. https://doi.org/10.1016/j.redox.2020.101528. (Epub 2020 Apr 4. PMID: 32388267; PMCID: PMC7210585)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kakisaka Y, Nakashima T, Sumida Y, Yoh T, Nakamura H, Yodoi J, Senmaru H (2002) Elevation of serum thioredoxin levels in patients with type 2 diabetes. Horm Metab Res 34:160–164

    Article  CAS  PubMed  Google Scholar 

  24. Tsuchikura S, Shoji T, Shimomura N, et al (2010) Serum C-reactive protein and thioredoxin levels in subjects with mildly reduced glomerular filtration rate. BMC Nephrol 11:7. https://doi.org/10.1186/1471-2369-11-7

  25. Abdiu A, Nakamura H, Sahaf B, Yodoi J, Holmgren A, Rosén A (2000) Thioredoxin blood level increases after severe burn injury. Antioxid Redox Signal 2:707–716

    Article  CAS  PubMed  Google Scholar 

  26. Miyamoto S, Kawano H, Sakamoto T, Soejima H, Kajiwara I, Hokamaki J, et al (2004) Increased plasma levels of thioredoxin in patients with coronary spastic angina. Antioxid Redox Signal 6(1):75–80. https://doi.org/10.1089/152308604771978363

  27. Heidelbaugh JJ, Bruderly M (2006) Cirrhosis and chronic liver failure: part I Diagnosis and evaluation. Am Fam Physician 74:756–762 ([PMID: 16970019])

    PubMed  Google Scholar 

  28. European Association for the Study of the Liver (2018) EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 69:182–236. https://doi.org/10.1016/j.jhep.2018.03.019

    Article  Google Scholar 

  29. Erstad DJ, Tanabe KK (2019) Prognostic and Therapeutic Implications of Microvascular Invasion in Hepatocellular Carcinoma. Ann Surg Oncol 26(5):1474–1493. https://doi.org/10.1245/s10434-019-07227-9. (PMID: 30788629)

    Article  PubMed  Google Scholar 

  30. Bai DS, Zhang C, Chen P, Jin SJ, Jiang GQ (2017) The prognostic correlation of AFP level at diagnosis with pathological grade, progression, and survival of patients with hepatocellular carcinoma. Sci Rep 7:12870–12878

    Article  PubMed  PubMed Central  Google Scholar 

  31. Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, Filmus J (2003) Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 125:89–97

    Article  CAS  PubMed  Google Scholar 

  32. Jeng JE, Tsai MF, Tsai HR, Chuang LY, Lin ZY, Hsieh MY, Chen SC, Chuang WL, Wang LY, Yu ML, Dai CY, Tsai JF (2014) Urinary transforming growth factor α and serum α-fetoprotein as tumor markers of hepatocellular carcinoma. Tumor Biology 35:3689–3698

    Article  CAS  PubMed  Google Scholar 

  33. Zhang J, Hao N, Liu W, Lu M, Sun L, Chen N, Wu M, Zhao X, Xing B, Sun W, He F (2017) In-depth proteomic analysis of tissue interstitial fluid for hepatocellular carcinoma serum biomarker discovery. Br J Cancer. 117(11):1676–1684. https://doi.org/10.1038/bjc.2017.344. (Epub 2017 Oct 12. PMID: 29024941; PMCID: PMC5729441)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li J, Cheng ZJ, Liu Y, Yan ZL, Wang K, Wu D, Wan XY, Xia Y, Lau WY, Wu MC, Shen F (2015) Serum thioredoxin is a diagnostic marker for hepatocellular carcinoma. Oncotarget 6(11):9551–9563. https://doi.org/10.18632/oncotarget.3314.PMID:25871387;PMCID:PMC4496238

    Article  PubMed  PubMed Central  Google Scholar 

  35. Omran MM, Farid K, Omar MA, Emran TM, El-Taweel FM, Tabll AA (2020) A combination of α-fetoprotein, midkine, thioredoxin and a metabolite for predicting hepatocellular carcinoma. Ann Hepatol. 2:179–185. https://doi.org/10.1016/j.aohep.2019.09.002. (Epub 2019 Oct 1. PMID: 31648804)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

Authors

Contributions

KA, WI, SS designed the study; AE participated in the acquisition of data; KA, WI, SS, AE, GM participated in the analysis and interpretation of the data; KA, WI, SS, GM revised the article critically for important intellectual content; GM wrote the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Ghada Abdelrahman Mohamed.

Ethics declarations

Ethics approval and consent to participate

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and its appendices and was approved by the ethics committee of the Faculty of Medicine, Ain Shams University (FMASU MSO 38/2021/2022-FWA 000017585). Informed written consent was obtained from each participant before enrollment in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

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

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdelwahab, K.M., Ibrahim, W.A., Saleh, S.A.B. et al. Evaluation of serum thioredoxin as a hepatocellular carcinoma diagnostic marker. Egypt Liver Journal 14, 3 (2024). https://doi.org/10.1186/s43066-024-00309-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43066-024-00309-8

Keywords