Cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes, while they concurrently play an essential role in cancer progression, invasion and metastasis. The purposes of our study were to: a) compare the expression levels of cathepsins B, H and L in the supernatants of colon cancer tissues from 74 patients versus the corresponding enzymic expressions of supernatants in the adjacent normal colorectal tissues; and b) correlate our results to the grade of the malignancy by using an enzyme-linked immunosorbent assay (ELISA). The findings indicated that cathepsins B, H and L of all malignant tissues exhibited significantly higher expression levels than their corresponding controls. Furthermore, cathepsin B expression levels doubled in all tumor samples and this increase remained quite steady with tumor stage advancement, in contrast to cathepsin H expression which rose significantly as malignancy progressed. Specifically, cathepsin H concentration was higher than the corresponding control: 155% in B1 stage and 204.44% in D stage. Among the three investigated proteases, cathepsin L has shown the highest increase, which in D stage stood 261.03% higher than the corresponding control. The results at hand suggested that cysteine protease H and L expression levels could be of critical value in the diagnosis and progression of colon cancer.
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A. Doxakis, A. Maria, P. Savvas and I. Zafiroula, "Assessment of the Roles of Cathepsins B, H and L in the Progression of Colorectal Cancer," Journal of Cancer Therapy, Vol. 4 No. 6, 2013, pp. 1-7. doi: 10.4236/jct.2013.46A2001.
 N. Cimerman, P. M. Brguljan, M. Krasovec, S. Suskovic and J. Kos, “Circadian Characteristics of Cathepsins B, H, L, and Stefins A and B, Potential Markers for Disease, in Normal Sera,” Clinica Chimica Acta, Vol. 282, No. 1-2, 1999, pp. 211-218. doi:10.1016/S0009-8981(99)00008-X
 N. Cimerman, P. M. Brguljan, M. Krasovec, S. Suskovic and J. Kos, “Twenty-Four Hour Variations of Cystatin C and Total Cysteine Proteinase Inhibitory Activity in Sera from Healthy Subjects,” Clinica Chimica Acta, Vol. 291, No. 1, 2000, pp. 89-95.
 N. G. Cloven, A. Kyshtoobayeva, R. A. Burger, I. R. Yu and J. P. Fruehauf, “In Vitro Chemoresistance and Biomarker proWles Are Unique for Histologic Subtypes of Epithelial Ovarian Cancer,” Gynecologic Oncology, Vol. 92, No. 1, 2004, pp. 160-166.
 D. Gabrijelcic, B. Svetic, D. Spaic, J. Skrk, M. Budihna, I. Dolenc, T. Popovic, V. Cotic and V. Turk, “Cathepsins B, H and L in Human Breast Carcinoma,” European Journal of Clinical Chemistry and Clinical Biochemistry, Vol. 30, No. 2, 1992, pp. 69-74.
 L. Herszenyi, M. Plebani, P. Carraro, et al., “The Role of Cysteine and Serine Proteases in Colorectal Carcinoma,” Cancer, Vol. 86, No. 7, 1999, pp. 1135-1142.
 J. E. Koblinski, M. Ahram and B. F. Sloane, “Unraveling the Role of Proteases in Cancer,” Clinica Chimica Acta, Vol. 291, No. 2, pp. 113-135.
 V. B. Astler and F. A. Coller, “The Prognostic Significance of Direct Extension of Carcinoma of the Colon and Rectum,” Annals of Surgery, Vol. 139, No. 6, 1954, pp. 846-852. doi:10.1097/00000658-195406000-00015
 R. Castino, D. Pace, M. Demoz, M. Gargiulo, C. Ariatta, E. Raiteri and C. Isidoro, “Lysosomal Proteases as Potential Targets for the Induction of Apoptotic Cell Death in Human Neuroblastomas,” International Journal of Cancer, Vol. 97, No. 6, 2002, pp. 775-779.
 J. L. Cox, “Cystatins and Cancer,” Frontiers in Bioscience, Vol. 14, 2009, pp. 463-474. doi:10.2741/3255
 E. Campo, J. Munoz, R. Miquel, A. Palacin, A. Cardesa, B. F. Sloane and M. Emmert-Buck, “Cathepsin B Expression in Colorectal Carcinomas Correlates with Progression and Shortened Patient Survival,” American Journal of Pathology, Vol. 145, No. 2, 1994, pp. 301-309.
 J. Lankelma, D. Voorend, T. Barwari, J. Koetsveld, A. Van der Spek, A. De Porto, G. Van Rooijen and C. Van Noorden, “Cathepsin L, Target in Cancer Treatment?” Life Sciences, Vol. 86, No. 7-8, 2010, pp. 225-233.
 L. Hazen, F. Bleeker, B. Lauritzen, J. Song, A. Jonker, B. Van Driel, et al., “Comparative Localization of Cathepsin B Protein and Activity in Colorectal Cancer,” Journal of Histochemistry & Cytochemistry, Vol. 48, No. 10, 2000, pp. 1421-1430. doi:10.1177/002215540004801012
 L. Herszenyi, M. Plebani, P. Carraro, M. De Paoli, G. Roveroni, R Cardin, et al., “The Role of Cysteine and serine Proteases in Colorectal Carcinoma,” Cancer, Vol. 86, No. 7, 1999, pp. 1135-1142.
 A. M. Troy, K. Sheahan, H. E. Mulcahy, M. J. Duffy, J. M. Hyland and D. P. O’Donoughe, “Expression of Cathepsin B and L Antigen and Activity Is Associated with Early Colorectal Progression,” European Journal of Cancer, Vol. 40, No. 10, 2004, pp. 1610-1616.
 F. Farinati, L. Herszenyi, M. Plebani, P. Carraro, R. Cardin, M. De Paoli, G. Roveroni, M. Rugge, D. Nitti and R. Naccarato, “Increased Levels of Cathepsin B and L, Urokinase-Type Plasminogen Activator and Inhibitor Type-1 as an Early Event in Gastric Carcinogenesis,” Carcinogenesis, Vol. 17, No. 12, 1996, pp. 2581-2587.
 M. Talieri, S. Papadopoulou, A. Scorilas, D. Xynopoulos, N. Arnogianaki, G. Plataniotis, J. Yotis and N. Agnanti, “Cathepsin B and Cathepsin D Expression in the Progression of Colorectal Adenoma to Carcinoma,” Cancer Letters, Vol. 205, No. 1, 2004, pp. 97-106.
 S. Krueger, T. Kalinski, H. Wolf, U. Kellner and A. Roessner, “Interactions between Human Colon Carcinoma Cells, Fibroblasts and Monocytic Cells in Coculture-Regulation of Cathepsin B Expression and Invasiveness,” Cancer Letters, Vol. 223, No. 2, 2005, pp. 313-322.
 C. Jedeszko and B. F. Sloane, “Cysteine Cathepsins in Human Cancer,” Biological Chemistry, Vol. 385, No. 11, 2004, pp. 1017-1027.
 M. M. Mohamed and B. F. Sloane, “Cysteine cathepsins: Multifunctional Enzymes in Cancer,” Nature Reviews Cancer, Vol. 6, No. 10, 2006, pp. 764-775.
 V. Turk, B. Turk and D. Turk, “Lysosomal Cysteine Proteases: Facts and Opportunities,” The EMBO Journal, Vol. 20, No. 17, 2001, pp. 4629-4633.
 C.-C. Chan, C.-W. Fan, Y.-B. Kuo, Y.-H. Chen, P.-Y. Chang, K.-T. Chen, R.-P. Hung and E.-C. Chan, “Multiple Serological Biomarkers for Colorectal Cancer Detection,” International Journal of Cancer, Vol. 126, No. 7, 2010, pp. 1683-1690.
 L. Herszenyi, F. Farinati, R. Cardin, G. Istvan, L. D. Molnar, I. Hritz, M. De Paoli, M. Plebani and Z. Tulassay, “Tumor Marker Utility and Prognostic Relevance of Cathepsin B, Cathepsin L, Urokinase-Type Plasminogen Activator, Plasminogen Activator Inhibitor Type-1, CEA and CA 19-9 in Colorectal Cancer,” BMC Cancer, Vol. 8, 2008, p. 194. doi:10.1186/1471-2407-8-194
 V. Gocheva, W. Zeng, D. Ke, D. Klimstra, T. Reinheckel, C. Peters, D. Hanahan and J. A. Joyce, “Distinct Roles for Cysteine Cathepsin Genes in Multistage Tumorigenesis,” Genes & Development, Vol. 20, No. 5, 2006, pp. 543-556.
 J. A. Joyce, A. Baruch, K. Chehade, N. Meyer-Morse, E. Giraudo, F. Y. Tsai, D. C. Greenbaum, J. H. Hager, M. Bogyo and D. Hanahan, “Cathepsin cysteine Proteases Are Effectors of Invasive Growth and Angiogenesis during Multistage Tumorigenesis,” Cancer Cell, Vol. 5, No. 5, 2004, pp. 443-453.
 O. Vasiljeva, T. Reinheckel, C. Peters, D. Turk and V. Turk, B. Turk, “Emerging Roles of Cysteine Cathepsins in Disease and Their Potential as Drug Targets,” Current Pharmaceutical Design, Vol. 1, No. 4, 2007, pp. 387-403.
 J. A. Joyce, “Therapeutic Targeting of the Tumor Microenvironment,” Cancer Cell, Vol. 7, No. 6, 2005, pp. 513-520.
 J. S. Rao, “Molecular Mechanisms of Glioma Invasiveness: The Role of Proteases,” Nature Reviews Cancer, Vol. 3, No. 7, 2003, pp. 489-501. doi:10.1038/nrc1121
 C. S. Gondi, S. S. Lakka, D. H. Dinh, W. C. Olivero, M. Gujrati and J. S. Rao, “RNAi-Mediated Inhibition of Cathepsin B and uPAR Leads to Decreased Cell Invasion, Angiogenesis and Tumor Growth in Gliomas,” Oncogene, Vol. 23, No. 52, pp. 8486-8496.
 J. A. Foekens, J. Kos, H. A. Peters, M. Krasovec, M. P. Look, N. Cimerman, M. E. Meijer-van Gelder, S. C. Henzen-Logmans, W. L. van Putten and J. G. Klijn, “Prognostic Significance of Cathepsins B and L in Primary Human Breast Cancer,” Clinical Oncology, Vol. 16, No. 3, pp. 1013-1021.
 L. Herszényi, M. Plebani, P. Carraro, M. De Paoli, G. Roveroni, M. Rugge, R. Cardin, R. Naccarato and F. Farinati, “Role and Behavior of Cathepsin B and Cathepsin L in Gastric Cancer,” Orvosi Hetilap, Vol. 136, No. 25, 1995, pp. 1315-1318.
 A. Schweiger, I. J. Christensen, H. J. Nielsen, S. Sorensen, N. Brünner and J. Kos, “Serum Cathepsin H as a Potential Prognostic Marker in Patients with Colorectal Cancer,” The International Journal of Biological Markers, Vol. 19, No. 4, 2004, pp. 289-294.