Mechanisms by which TLR4 and endotoxin promote hepatocellular carcinoma require further investigation§


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Mechanisms by Which TLR4 and Endotoxin Promote Hepatocellular Carcinoma Require Further Investigation

To the Editor:

Despite being impressed by the interesting hypothesis and the abundant amount of data, we would like to raise serious doubts about the validity and conclusions of the study “Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents” by Yu and colleagues.1

Although the title of this study states that endotoxin accumulation prevents carcinogen-induced apoptosis, the authors show exactly the opposite in Fig. 7B and Supporting Fig. 8A in which reduction of endotoxin by antibiotic treatment prevents carcinogen-induced liver injury and apoptosis. The findings in Fig. 7B and Supporting Fig. 8A not only directly contradict the title of the article, but are also opposite to findings in Figs. 3A and 6A, and Supporting Figs. 3 and 7A in which the authors show that deletion of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) increases carcinogen-induced liver injury. It is virtually impossible that inhibition at the level of the ligand (i.e., reduction of endotoxin by antibiotics as shown in Fig. 7A) and at the level of the receptor (deletion of TLR4) have opposite effects on the liver. If this were the case, then antibiotics should promote hepatocellular carcinoma (HCC), and TLR4 deletion should prevent HCC. However, Yu et al. show similar effects on HCC development with both TLR4 deletion and treatment with antibiotics. Because of this conflicting data, one not only has to doubt the validity of the title but of the presented mechanisms and the proposed role of diethylnitrosamine (DEN)-induced liver injury and apoptosis. These doubts are further substantiated when considering that Karin and coworkers have shown that inhibition of nuclear factor-κB increases liver injury after DEN, and that this increase in injury translates to enhanced carcinogenesis in the DEN model.2 In contrast to the well-established concept, Yu et al. argue that decreased injury after DEN leads to an increase in HCC.

Because of the conflicts between the title of the study and parts of the presented data, the authors need to make a definite statement whether (1) endotoxin accumulation prevents carcinogen-induced apoptosis or (2) whether the reduction of endotoxin accumulation by treatment with antibiotics prevents carcinogen-induced apoptosis. A study with a wrongly stated title and conflicting data will not only confuse the readership of HEPATOLOGY, but also presents an obstacle to scientific progress in this relevant research area. If the authors cannot demonstrate the validity of their title and the mechanism suggested by both the title and their article, they should take additional time to investigate the role of endotoxin in carcinogen-induced apoptosis.

Ali Mencin M.D.*, Geum-Youn Gwak M.D., Ph.D.*, Robert F. Schwabe M.D.*, * Department of Medicine Columbia University New York, NY.