Abstract

Chronic inflammation-mediated cell death/survival is an important risk factor to cancer development. However, the link between chronic inflammation and tumorigenesis is still unclear. Elucidating this link is needed for early diagnosis and development of therapeutics. Previously, we reported that SAG (sensitive to apoptosis gene) is a key regulator between immuneoveractivation and pro-tumorigenesis. Here, by retrospectively studying human primary hepatocellular carcinoma (HCC) tissues, we showed that SAG is up-regulated in the early stage of HCC, in conjunction with the increase in ubiquitination of specific suicide/apoptosis factors such as SARM and Noxa. We envisage that SAG-UPS (ubiquitin proteasome system) degrades apoptosis factors, thus conferring anti-apoptosis and uncontrolled cell survival strategy, which promotes liver cancer. We found that up-regulated SAG in HCC plays a key pro-tumorigenic role by perturbing the fine balance of the ratio of pro- and anti- apoptotic factors, as indicated by the production of pro- and anti-tumorigenic cytokines. This favors and exacerbates the vicious cycle of tumorigenic microenvironment for the progression of hepatoma. Our findings clearly established the power of SAG-UPS as a cell death/survival decision link between chronic inflammation and tumorigenesis. We propose SAGUPS to be an early diagnostic marker for HCC, and a potential target for therapeutics development.