Liver cancer is the fastest growing cause of cancer-related deaths in the US; its incidence has almost tripled since 1980. Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer. Latino/Hispanic (LA) populations are disproportionately affected by HCC compared to Caucasians (CA) with respect to prevalence, progression, drug response, and mortality. In addition to infectious and metabolic diseases, socio-behavioral factors (smoking, alcohol consumption, stress) are the major risk factors for HCC. Although ethnic differences in HCC progression and treatment outcome are known, the responsible molecular mechanisms are not understood. The interplay of these risk factors with oncogenic mechanisms in relation to this disparity are also unknown. Our group has identified a novel oncogenic protein, MUC13 mucin, which is highly overexpressed and aberrantly localized in some cancers. This protein is associated with tumorigenic/metastatic phenotypes and is correlated with smoking, alcohol consumption, and biochemical stress factors. Preliminary data suggest a markedly higher expression/aberrant localization of MUC13 in HCC LA samples than CA samples. However, the clinical functional significance and regulatory mechanisms of MUC13 expression in HCC are unknown. The association of socio- behavioral factors (smoking, alcohol consumption, stress) with MUC13 expression pattern in relation to this disparity has not been investigated. Sorafenib is a clinically used chemotherapy for HCC; it blocks the Raf/MEK/ERK pathway, whereas MUC13 overexpression induces this oncogenic signaling axis. Our group has developed reagents related to MUC13, including unique monoclonal antibodies. Moreover, our group has access to a liver cancer bio-specimen repository that has HCC samples from different groups including LA and CA populations. We propose to investigate the role of MUC13 in HCC disparity and elucidate the etiological factors that are responsible for aberrant MUC13 expression in HCC. We hypothesize that the differential/aberrant expression of MUC13 is a critical molecular determinant associated with health disparities in HCC. Additionally, we hypothesize that socio-behavioral factors influence MUC13 expression in HCC. Aim 1 will determine how the MUC 13 expression patterns in HCC tissue samples retrospectively collected from LA and CA populations differ among different stages of disease and between the populations, and will correlate MUC13 expression patterns with disease progression, metastasis, and patient prognosis and survival. Aim 2 will determine the association between socio-behavioral factors (smoking, alcohol consumption, biochemical measures of stress) and MUC13 expression/phosphorylation patterns in HCC samples from the two patient populations. Aim 3 will ascertain the role of MUC13 in HCC progression, metastasis, and Sorafenib responsiveness, and its disparities between LA and CA HCC, via the use of patient-derived cells, organoids, and patie...