S1575 Blockade of Endogenous CD26 Activity Augments the Therapeutic Potential of Marrow Stem Cells for Mouse Liver Cirrhosis

Abstract

Stathmin is one of the microtubule-destabilizing proteins involved in cell cycle control, progression and proliferation. During liver regeneration, proliferating hepatocytes express stathmin and its overexpression is considered an early protumorigenic event in HCC. Although disruption of microtubule polymerization does not necessarily lead to apoptosis, it is an important event in its induction. Aim: this study aimed to clarify the role of stathmin in HCV-related hepatocellular carcinoma (HCC) and chronic liver disease (CH) by evaluating the relationships between stathmin and mediators involved in the apoptotic process. We studied the mRNA expression of Fas and FasL (extrinsic mediators) and Bcl-2, Bax, Bad and BI-1(intrinsic mediators) in liver biopsies and surgical specimens from patients with different degrees of liver damage. Methods: 43 patients with HCV-related disease were examined, i.e. 31 with CH, 6 with cirrhosis (CIRR), 6 with HCC, plus 3 controls (CONTR), quantifying mRNA by quantitative absolute Real-Time PCR using β-actin as the housekeeping gene. Results: A statistically significant difference (p= 0.006) in stathmin expression emerged between the different groups using the Kruskal Wallis test. Stathmin transcripts in CONTR tissue (0.472±0.26) were significantly lower than in CH (1.054±0.3: p= 0.019), CIRR (1.453±0.4: p=0.023), or HCC (4.318±3.0: p=0.05). Among the pathological samples, only HCC expressed a greater increase in stathmin expression than CH (p=0.010). In cases of HCV-related CH, positive correlations emerged between stathmin and Fas (r=0.45; p=0.008), FasL (r=0.47; p=0.005), Bcl-2 (r=0.42; p=0.017), and Bax (r=0.47; p=0.006), while an inverse correlation was seen with Bad (r=-0.38; p=0.030) mRNAs. In cirrhotic tissue surrounding HCC, positive correlations were again found between stathmin and Bax (r=0.77; p=0.041) and Bad (r=0.77; p=0.038), whereas there were no such correlations between stathmin and these mediators in HCV-related HCC. Conclusions: stathmin increases in all stages of HCV-related liver damage involving inflammatory and proliferative processes. The positive correlations found between stathmin and apoptotic factors reveal a link between microtubule destabilization and the modulation of apoptosis, especially in the early stages of HCV-induced liver damage. Stathmin overexpression confirms its important role in neoplastic cell proliferation and tumor progression, particularly in the advanced stages of the disease.