In those cases the possible cause may be the deregulation of protein degradation or disruption of normal intercellular Diniconazole signaling pathways. In a study of Zhang et al., cyclin D1 was found to be negatively regulated by the orphan nuclear receptor SHP thus influencing cellular proliferation. They found enhanced hepatocyte proliferation and increased cyclin D1 expression in SHP knockout mice which resulted in tumorigenesis and spontaneous tumor formation. To date, there are no studies showing the SHP levels in different subtypes, i.e., fibrolamellar variant of HCC, as well as there are no correlation studies between the expression of SHP and cyclin D1 in human liver cancer. In a present study we performed a comprehensive immunohistochemical study of the SHP levels in hepatocellular carcinoma. Additionally, we performed a comparison study between the expression of the small heterodimer partner and the key cell cycle regulator, in different morphological variants of HCC and according to tumors grading. In our study we report that the nuclear receptor SHP expression is reduced in hepatocellular carcinoma tissue when compared to normal liver. We present for the first time that fibrolamellar carcinoma contains less SHP protein than typical hepatocellular carcinoma. Finally, we demonstrate a negative correlation between the expression of SHP and one of the most potent cell cycle regulator, cyclin D1, in high grade hepatocellular carcinomas. Together our studies are consistent with hypothesis that reduced SHP expression may play a significant role in hepatocellular and fibrolamellar carcinoma development. The involvement of nuclear receptors signaling in cancer pathogenesis was documented in prostate, breast, colon and lung cancer. In typical nuclear receptors the mechanism by which NR exert their function is Desacetyl-asperulosidic-acid direct binding to specific genes which control cell proliferation and survival. Since SHP does not possess DNA binding domain, it inhibits transcription process acting as a corepressor or coactivator competitor by direct binding to other nuclear proteins. The role of SHP as a tumor suppressor in hepatocellular carcinoma was recently postulated in a work of He et al.. The authors show that diminished SHP expression results from epigenetic inhibition of protein expression. In our study we found SHP localized mainly in the cytoplasm of both normal and malignant hepatocytes. For nuclear receptors that have known ligands, the cytoplasmic localization usually reflects a state when nuclear receptor is inactive. For example, androgen receptor, in a basal state is found mainly in the cytoplasm of prostate epithelial cells.