Liver cancer is the most rapidly increasing type of cancer and also one of the most deadly in the US, but understanding its etiology and treatment remains a major challenge. Various studies suggest a putative liver tumor suppressor gene at the human chromosome 8p23, a common integration site of hepatitis B virus, a major risk factor for liver cancer, although its identity and function remains elusive. One unique feature for most cancer cells, including liver tumor cells, is activation of telomerase. Telomerase overexpression has been shown to promote cancer development in mice and its inhibition has been proposed as an attractive new idea for anticancer therapies. I have recently identified the first mammalian telomerase inhibitor PinX1, which is located at the human chromosome 8p23. I have also demonstrated that whereas overexpression of PinX1 and its telomerase inhibitory domain inhibits telomerase activity of cancer cells and their tumorigenicity, PinX1 downregulation increases telomerase activity and tumorigenicity of cancer cells. A splicing variant of PinX1 was independently isolated as a putative liver tumor suppressor and PinX1 expression is reduced or absent in approximately 50% of human liver cancer tissues. These results suggest that PinX1 might be a tumor suppressor. Thanks to NCI for giving me a R21 award (R21CA100301). I have just created conventional and conditional PinX1 knockout mice using Cre- and loxP-recombination. So far, most PinX1 - deficient (PinX1-/-) mice were embryonic lethal and, strikingly, most mice carrying a likely hypomorphic PinX1/pflox-neo targeted allele developed various types of tumors, with 50% mice having liver tumors. These results lead us to hypothesize that PinX1 is an important tumor suppressor for liver cancer, which will be tested in this proposal. Aim 1 will continue to generate a hypomorphic series of PinX1 mutant mice, including liver-specific PinX1 knockout mice, to examine if partial or complete loss of PinX1 function in the liver increases the susceptibility to liver cancer. Aim 2 will determine the role of telomerase in PinX1-related liver cancer development using in vitro and in vivo models, including TERT-/- mice. Aim 3 will evaluate the potency of PinX1 and especially its telomerase inhibitory domain to inhibit liver tumor growth using in vitro and in vivo models, including PinX1 liver tumor mouse models. These studies would establish new animal models for studying liver cancer and provide novel insight into the etiology and treatment of liver cancer.