Introduction Effective treatment of Hepatocellular carcinoma (HCC) still remains an unmet need. Inflammation plays a crucial role in the pathogenesis of HCC by causing repeated cell damage and creating a microenviroment rich in cytokines that can enhance cell replication, angiogenesis and invasion into the surrounding structures. Toll-like receptors (TLRs) are important pathogen recognition receptors. Stimulation of TLRs is followed by cascade of transcriptional and translational reactions resulting in activation of NF-kB which subsequently serves as a common- link between the chronic inflammation and tumour development.
Aim The aim of this study was to characterise the expression of TLR-9 along the HCC tumour genesis pathway including the normal liver, viral hepatitis, cirrhosis and HCC and the results were collated with cell proliferation as determined by Ki-67 staining.
Method We used a human tissue array platforms (Vbiolab, Cambridge, UK) which includes 102 cores of liver tissue including nine normal livers, 26 hepatitis (B, C and Non-b, Non-C hepatitis), 25 cirrhosis and 42 HCC. Immunohistochemistry was performed for the expression of TLR-9 and Ki-67. The scoring was performed in a blinded fashion by two individual pathologists. For the quantitation of Ki-67 expression, we counted the positively stained nuclei among 1000 hepatocytes in the highest expression area using a standardised grid.
Results TLR-9 expression was noticed as membranous staining in 2/9 cases in normal liver. 12/26 cases of hepatitis and 13/25 of cirrhosis. Weak cytoplasmic staining was noticed in 4/26 cases of hepatitis and one case in cirrhosis whereas the staining was predominantly cytoplasmic in HCC; weak (+1) in 17/42 cases and moderate to strong (+2 and+3) in 17/42 cases, whilst in eight cases it was negative. In 13/42 cases, it was found in both cytoplasm and cell membrane. There was a close correlation between the proliferative index (Ki-67 staining) and TLR-9 staining; r=0.8, p<0.001. The proliferative index was <100, 100–200, >200 in TLR9 negative, weak and moderate-to-strong cases, respectively.
Conclusion The results of our study show, for the first time, a strong correlation between the amount of cellular proliferation and TLR-9 expression in HCC. Also we found the shifting of TLR9 expression from the membranous type in hepatitis and cirrhosis into cytoplasmic in HCC. Our data suggest that TLR-9 might have a pivotal role in cellular proliferation in HCC and merits further studies to explore the possibility of exploiting it as a potential target for future therapy.
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