Hepatic remnant and normal liver function after liver resection and hence, surgical resection is not applicable for many patients. Another concern is the high recurrence rate after surgical resection. Fifty to eighty percent of patients suffer disease recurrence, which could be intrahepatic metastasis or multicentric occurrence, within five years after resection. Chemotherapy is an alternative treatment of HCCs. Nutlin-3 However, only marginal efficacy has been observed and severe side effects are hurdle to the feasibility of chemotherapy. Several important intracellular signaling pathways including the mitogen-activated protein kinases comprising the ERK, JNK and p38 have been recognized to be involved in hepatocarcinogenesis. In addition, several growth factors and angiogenic factors such as EGF and VEGF have been suggested to contribute to HCC. However, the molecular pathogenesis of HCC has not been well characterized yet. It is a major global health problem, and the prognosis is dismal. The need for better understanding of the cellular and molecular mechanisms of the disease is obvious and crucial to disease prevention and management. Recently, the advanced cDNA microarray technology has greatly facilitated the genome-wide expression profiling in many complex diseases such as cancers. Understanding the gene expression profiles in HCC may provide new insights in identifying novel candidate biomarkers for early diagnosis and discovery of therapeutic targets for cancer treatment. Our earlier cDNA microarray study revealed differential gene expression patterns in HCC and non-tumor liver tissues. Granulin-epithelin precursor expression was observed in over 70% of HCC. Functional studies revealed that GEP controlled cancer cells proliferation, invasion and chemo-resistance. We therefore investigated the potential of GEP as a therapeutic target. Anti-GEP monoclonal antibodies were developed and demonstrated to be able to inhibit the growth of hepatoma cells but no effect on normal liver cells. In nude mice model transplanted with human HCC, dose-dependent inhibitory effect was demonstrated with the anti-GEP monoclonal antibodies, providing evidences that GEP is a therapeutic target for HCC treatment. GEP expression has also been reported in a number of aggressive tumors, involved in various biological processes including wound healing, murine fetal development, and mutation associated with frontotemporal lobar dementia. GEP has been reported to interact with Tat proteins of Human Immunodeficiency Virus, with COMP and TNF receptors in chondrocyte. Nonetheless, the GEP interacting partners/receptors have yet to be identified in cancer cells. To further understand the GEP signaling mechanism, the present study aims to identify its novel predominant interacting partners. Proteins that interact with GEP were examined using coimmunoprecipitation and mass-spectrometry. The GEP interacting protein had been further examined in additional cell lines and clinical samples using western blot, immunohistochemistry and real-time quantitative PCR.