Prospective Clinical Application of Thioredoxin Reductase as a Novel Diagnostic Tumor Marker

Suofu Ye, Nong Yang, Weiwei Ma, Yanran Fu, Lin Wu, Yueqin Li, Lihui Liu, Yi Hui, Yu Qiu, Siqing Mei, Yan Li, Huihui Zeng

1Health Science Center, Peking University, Beijing, China 2State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
1Health Science Center, Peking University, Beijing, China 2State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China 4Keaise Clinical Examination Lab, Wuhan, China.
5Keaise Medicine (Tianjin) Co., Ltd, Tianjin, China 6Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin, China.
Department of Clinical Laboratory, Renmin Hospital, Wuhan University, Wuhan, China.
Department of Medical Oncology, Hunan Provincial Tumor Hospital, Changsha, China.
Keaise Clinical Examination Lab, Wuhan, China.

DOI: 10.4236/jbm.2014.24008                

Abstract

Background: Developing a novel, efficient biomarker for detecting malignant tumors is essential for the early diagnosis of cancers. Our aim was to assess the diagnostic value of a potential plasma tumor marker, thioredoxin reductase (TR), which is expressed in many types of malignant tumor, for the non-invasive detection of cancers. Methods: The plasma activities of TR were measured in 1513 patients with common clinical diseases, 59 patients with benign tumors, and 154 patients with cancers and 586 healthy controls. The area under the ROC curve (AUC) of TR and logistic regression results of different groups were compared by sensitivity, specificity and Youden’s index. Diagnostic cut-offs and clinical reference intervals were established via ROC curve analysis. Results: The logistic regression indicated that TR activity can discriminate between cancers and benign tumors or other common diseases very well (p < 0.0001), with an area under the curve from the receiver-operator characteristics between 0.91 and 0.96. The positive critical value was 2.51 and the cancer critical value was 9.90. The diagnostic gray zone (2.51 - 9.90) may be associated with benign tumors and some common clinical diseases. Conclusions: As a novel potential marker of malignant tumors with quantitative evaluation of proliferation, TR activity detection has an excellent diagnostic potential for early-stage malignant tumors. Impact: The convenient, economical, relatively non-invasive, and reproducible detection method of TR activity makes it suitable for routine clinical practice.

Keywords

Thioredoxin Reductase, Diagnostic Marker, Cancer, Malignant Tumor, TR Activity, Abnormal Hyperplasia, Proliferation

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Berggren, M., Gallegos, A., Gasdaska, J.R., Gasdaska, P.Y., Warneke, J. and Powis, G. (1996) Thioredoxin and Thi-oredoxin Reductase Gene Expression in Human Tumors and Cell Lines, and the Effects of Serum Stimulation and Hypoxia. Anticancer Research, 16, 3459-3466.
[2]	Lincoln, D.T., Emadi, E.M.A., Tonissen, K.F. and Clarke, F.M. (2003) The Thioredoxin-Thioredoxin Reductase System: Over-Expression in Human Cancer. Anticancer Research, 23, 2425-2433.
[3]	Soini, Y., Kahlos, K., Napankangas, U., Kaarteenaho-Wiik, R., Saily, M., Koistinen, P., et al. (2001) Widespread Expression of Thioredoxin and Thioredoxin Reductase in Non-Small Cell Lung Carcinoma. Clinical Cancer Research, 7, 1750-1757.
[4]	Nguyen, P., Awwad, R.T., Smart, D.D.K., Spitz, D.R. and Gius, D. (2006) Thioredoxin Reductase as a Novel Molecular Target for Cancer Therapy. Cancer Letters, 236, 164-174. http://dx.doi.org/10.1016/j.canlet.2005.04.028
[5]	Kahlos, K., Soini, Y., Saily, M., Koistinen, P., Kakko, S., Paakko, P., et al. (2001) Up-Regulation of Thioredoxin and Thioredoxin Reductase in Human Malignant Pleural Mesothelioma. International Journal of Cancer, 95, 198-204. http://dx.doi.org/10.1002/1097-0215(20010520)95:3<198::AID-IJC1034>3.0.CO;2-F
[6]	Kemerdere, R., Kacira, T., Hanimoglu, H., Kucur, M., Tanriverdi, T. and Canbaz, B. (2013) Tissue and Plasma Thi-oredoxin Reductase Expressions in Patients with Glioblastoma Multiforme. Journal of Neurological Surgery Part A—Central European Neuro-surgery, 74, 234-238.
[7]	Lincoln, D.T., Al-Yatama, F., Mohammed, F.M.A., Al-Banaw, A.G., Al-Bader, M., Burge, M., et al. (2010) Thiore-doxin and Thioredoxin Reductase Expression in Thyroid Cancer Depends on Tumour Aggressiveness. Anticancer Research, 30, 767-775.
[8]	Iwasawa, S., Yamano, Y., Takiguchi, Y., Tanzawa, H., Tatsumi, K. and Uzawa, K. (2011) Upregulation of Thioredox-in Reductase 1 in Human Oral Squamous Cell Carcinoma. Oncology Reports, 25, 637-644..
[9]	Cadenas, C., Franckenstein, D., Schmidt, M., Gehrmann, M., Hermes, M., Geppert, B., et al. (2010) Role of Thiore-doxin Reductase 1 and Thioredoxin Interacting Protein in Prognosis of Breast Cancer. Breast Cancer Research, 12.
[10]	Yan, C., Shieh, B., Reigan, P., Zhang, Z., Colucci, M.A., Chilloux, A., et al. (2009) Potent Activity of Indolequinones against Human Pancreatic Cancer: Identification of Thioredoxin Reductase as a Potential Target. Molecular Pharmacology, 76, 163-172.
[11]	Singh, S.S., Li, Y., Ford III, O.H., Wrzosek, C.S., Mehedint, D.C., Titus, M.A., et al. (2008) Thioredoxin Reductase 1 Expression and Castration-Recurrent Growth of Prostate Cancer. Translational Oncology, 1, 153-157.
[12]	Cunnea, P., Fernandes, A.P., Capitanio, A., Eken, S., Spyrou, G. and Bjornstedt, M. (2007) Increased Expression of Specific Thioredoxin Family Proteins; A Pilot Immuno-histochemical Study on Human Hepatocellular Carcinoma. International Journal of Immunopathology and Pharma-cology, 20, 17-24.
[13]	Haapasalo, H., Kylaniemi, M., Paunu, N., Kinnula, V.L. and Soini, Y. (2003) Expression of Antioxidant Enzymes in Astrocytic Brain Tumors. Brain Pathology, 13, 155-164.
[14]	Biaglow, J.E. and Miller, R.A. (2005) The Thioredoxin Reductase/Thioredoxin System—Novel Redox Targets for Cancer Therapy. Cancer Biology & Therapy, 4, 6-13.
[15]	Luo, Y., Ma, W.W., Yang, J., Wu, L., Li, Y.Q., Zhao, Y.Y. and Zeng, H.H. (2012) Clinical Value of Thioredoxin Reductase Detection Kit for Diagnosis of Cancers. International Journal of Laboratory Medicine, 33, 13.
[16]	Zhang, X.T. and Xiong, Y.M. (2004) The Progress in Studies of Thioredoxin Reductase. Foreign Medical Sciences-Section of Medgeography, 25, 4.
[17]	Fernandes, A.P., Capitanio, A., Selenius, M., Brodin, O., Rundlof, A.K. and Bjornstedt, M. (2009) Expression Profiles of Thioredoxin Family Proteins in Human Lung Cancer Tissue: Correlation with Proliferation and Differentiation. Histopathology, 55, 313-320.
[18]	Sun, X.J., Dobra, K., Bjornstedt, M. and Hjerpe, A. (2000) Upregulation of 9 Genes, Including That for Thioredoxin, during Epithelial Differentiation of Mesothelioma Cells. Differentiation, 66, 181-188.
[19]	Rundlof, A.-K., Fernandes, A.P., Selenius, M., Babic, M., Shariatgorji, M., Nilsonne, G., et al. (2007) Quantification of Alternative mRNA Species and Identification of Thiore-doxin Reductase 1 Isoforms in Human Tumor Cells. Differentiation, 75, 123-132.
[20]	Takagi, Y., Gon, Y., Todaka, T., Nozaki, K., Nishiyama, A., Sono, H., et al. (1998) Expression of Thioredoxin Is Enhanced in Atherosclerotic Plaques and during Neointima Formation in Rat Arteries. Laboratory Investigation, 78, 957- 966.
[21]	Choi, H., Tostes, R.C. and Webb, R.C. (2011) Thioredoxin Reductase Inhibition Reduces Relaxation by Increasing Oxidative Stress and S-Nitrosylation in Mouse Aorta. Journal of Cardiovascular Pharmacology, 58, 522-527.
[22]	Schulze, P.C., Yoshioka, J., Takahashi, T., He, Z.H., King, G.L. and Lee, R.T. (2004) Hyperglycemia Promotes Oxidative Stress through Inhibition of Thioredoxin Function by Thioredoxin-Interacting Protein. Journal of Biological Chemistry, 279, 30369-30374.
[23]	Yamamoto, H., Miyake, Y., Noura, S., Ogawa, M., Yasui, M., Ikenaga, M., et al. (2001) Tumor Markers for Colorectal Cancer. Gan to Kagaku Ryoho Cancer & Chemotherapy, 28, 1299-1305.
[24]	Tamakoshi, K., Kikkawa, F., Shibata, K., Tomoda, K., Obata, N.H., Wakahara, F., et al. (1996) Clinical Value of CA125, CA19-9, CEA, CA72-4, and TPA in Borderline Ovarian Tumor. Gynecologic Oncology, 62, 67-72.
[25]	Ni, X.G., Bai, X.F., Mao, Y.L., Shao, Y.F., Wu, J.X., Shan, Y., et al. (2005) The Clinical Value of Serum CEA, CA19-9, and CA242 in the Diagnosis and Prognosis of Pancreatic Cancer. Ejso, 31, 164-169.
[26]	Ma, S., Shen, L., Qian, N. and Chen, K. (2011) The Prognostic Values of CA125, CA19.9, NSE, and SCC for Stage I NSCLC Are Limited. Cancer Biomarkers, 10, 155-162.
[27]	Imada, T., Rino, Y., Takahashi, M., Hatori, S., Shiozawa, M., Tanaka, J., et al. (1997) Expression of CA19-9, SLX, STN and CEA in Relatively Early Gastric Carcinoma. Oncology Reports, 4, 899-904.
[28]	Huang, M.-S., Jong, S.-B., Tsai, M.-S., Lin, M.-S., Chong, I.-W., Lin, H.-C., et al. (1996) Comparison of Cytokeratin Fragment 19 (CYFRA 21-1), Tissue Polypeptide Antigen (TPA) and Carcinoembryonic Antigen (CEA) as Tumor Markers in Lung Cancer. European Journal of Cancer, 32A.
[29]	Hanagiri, T., Sugaya, M., Takenaka, M., Oka, S., Baba, T., Shigematsu, Y., et al. (2011) Preoperative CYFRA 21-1 and CEA as Prognostic Factors in Patients with Stage I Non-Small Cell Lung Cancer. Lung Cancer, 74, 112-117.
[30]	Changchine, C.S., Yung, C.Y. and Tzen, K.Y. (1991) Serum Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen (CA 19-9) Values in Patients with Pancreatic Cancer or Pancreatitis. Chang Gung Medical Journal, 14, 32-38.
[31]	Yao, F., Guo, J.M., Xu, C.F., Lou, Y.L., Xiao, B.X., Zhou, W.H., et al. (2005) Detecting AFP mRIVA in Peripheral Blood of the Patients with Hepatocellular Carci-noma, Liver Cirrhosis and Hepatitis. Clinica Chimica Acta, 361, 119- 127.
[32]	Takeshima, N., Shimizu, Y., Umezawa, S., Hirai, Y., Chen, J.T., Fujimoto, I., et al. (1994) Combined Assay of Serum Levels of CA125 and CA19-9 in Endometrial Carcinoma. Gynecologic Oncology, 54, 321-326.
[33]	Danaei, G., Vander Hoorn, S., Lopez, A.D., Murray, C.J.L. and Ezzati, M. (2005) Comparative Risk Assessment C. Causes of Cancer in the World: Comparative Risk Assessment of Nine Behavioural and Environmental Risk Factors. Lancet, 366, 1784-1793.