1Division of Cancer Biology, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan.
During the past several decades, the percentage of excess bodyweight and obese adults and children has increased dramatically, and is becoming one of the most serious public health problems worldwide. Extensive epidemiological studies have revealed that there is a strong link between obesity and some common cancers. However, the exact molecular mechanisms linking obesity and cancer are not fully understood yet. Recently, we have reported that dietary or genetic obesity provokes alterations of gut microbiota profile, thereby increasing the levels of deoxycholic acid (DCA), a secondary bile acid produced solely by the 7α-dehydroxylation of primary bile acids carried out by gut bacteria. The enterohepatic circulation of DCA provokes DNA damage and consequent cellular senescence in hepatic stellate cells (HSCs) which, in turn, secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating hepatocellular carcinoma (HCC) development in mice. Interestingly, signs of senescence-associated secretory phenotypes were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis, implying that a similar pathway is likely to contribute to at least certain aspects of obesity-associated HCC development in humans as well. In this review, I will provide an overview of our recent work and discuss the next steps, focusing on the potential clinical implications of our findings.