Abstract
Background: Gallbladder carcinoma (GBC) exhibits poor prognosis due to its detection at an advanced stage. Upregulation of lysosomal cysteine proteases cathepsin L (CTSL) and cathepsin B (CTSB) has been implicated in several tumorigenic processes. However, no such information in GBC was available. Therefore, the present study was planned to investigate the expression and clinical significance of these cathepsins in GBC.Methods: Activities of CTSL and CTSB were assayed in the gallbladder (GB) tissues obtained from GBC patients (n = 43) and control subjects (n = 69). Protein and mRNA levels were quantified using immunohistochemistry and real-time PCR (qPCR), respectively. Finally, serum levels of CTSL and CTSB were estimated by ELISA. Receiver operating characteristic (ROC) curve analysis was used for the assessment of sensitivity, specificity, and diagnostic accuracy of these cysteine cathepsins in GBC. The association of combined CTSL and CTSB activity with overall survival was assessed using Kaplan Meier survival analysis.Results: The expression and activity of both CTSL and CTSB were significantly increased (p < 0.050) in tumors of GBC patients as compared to controls. Enzymatic activity of CTSL+B and CTSB exhibited a strong positive association with tumor stage and lymph node involvement in GBC (p < 0.050). Interestingly, the elevated activity of combined CTSL+B was also associated with increased mortality in these patients. Furthermore, significantly enhanced levels of serum CTSL and CTSB were also observed in GBC (p < 0.050) as compared to controls. ROC analysis revealed high diagnostic significance of serum CTSB and CTSL for distinguishing GBC patients from controls with an area under the curve (AUC) of 82 and 77%, respectively.Conclusion: This study, for the first time, demonstrates the clinical significance of CTSL and CTSB overexpression in GBC. Our findings may help improve the clinical management of this carcinoma.
Highlights
Gallbladder carcinoma (GBC) is an aggressive neoplasm, accounting for 80–90% of all bile tract malignancies [1]
All patients included in this study underwent treatment at the Department of Gastrointestinal Surgery (GIS) at the All India Institute of Medical Sciences (AIIMS), New Delhi
Kaplan-Meier analysis revealed significantly reduced overall survival in patients with higher cathepsin L (CTSL)+B activity as compared to patients with lower values (p = 0.049, log-rank test, hazard ratio 2.93, 95% CI = 1.02–8.39, Figure 3B). These results indicate that a combined increase in the activities of CTSL+B correlates with the active disease and portends a poor prognosis in GBC
Summary
Gallbladder carcinoma (GBC) is an aggressive neoplasm, accounting for 80–90% of all bile tract malignancies [1]. Carcinoma of the gallbladder is associated with the worst prognosis mainly because of the high incidence of micrometastases into adjacent sites, including liver parenchyma, bile duct, blood vessels, and regional lymph nodes [5]. This critical process of tumor invasion into the surrounding tissue requires several modifications in the extracellular matrix (ECM) and is aided by the active participation of several proteases [6]. Upregulation of lysosomal cysteine proteases cathepsin L (CTSL) and cathepsin B (CTSB) has been implicated in several tumorigenic processes No such information in GBC was available.
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