Loss of the Orphan Nuclear Receptor SHP Is More Pronounced in Fibrolamellar Carcinoma than in Typical Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a major problem in oncology. The molecular mechanisms which underlie its pathogenesis are poorly understood. Recently the Small Heterodimer Partner (SHP), an orphan nuclear receptor, was suggested to be involved as a tumor suppressor in hepatocellular carcinoma development. To date, there are no such studies regarding fibrolamellar carcinoma, a less common variant of HCC, which usually affects young people and displays distinct morphological features. The aim of our project was to evaluate the SHP levels in typical and fibrolamellar hepatocellular carcinoma with respect to the levels of one of the cell cycle regulators, cyclin D1. We assessed the immunoreactivity levels of SHP and cyclin D1 in 48 typical hepatocellular carcinomas, 9 tumors representing the fibrolamellar variant, 29 non malignant liver tissues and 7 macroregenerative nodules. We detected significantly lower SHP immunoreactivity in hepatocellular carcinoma when compared to non malignant liver tissue. Moreover, we found that SHP immunoreactivity is reduced in fibrolamellar carcinoma when compared to typical hepatocellular carcinoma. We also found that SHP is more commonly lost in HCC which arises in the liver with steatosis. The comparison between the cyclin D1 and SHP expression revealed the negative correlation between these proteins in the high grade HCC. Our results indicate that the impact of loss of SHP protein may be even more pronounced in fibrolamellar carcinoma than in a typical form of HCC. Further investigation of mechanisms through which the loss of SHP function may influence HCC formation may provide important information in order to design more effective HCC therapy.

New Insights into Orphan Nuclear Receptor SHP in Liver Cancer

“…Additionally, the methylation of the SHP gene promoter blocks nuclear receptor LRH-1-induced SHP gene transcription, which is reversed by demethylation of the SHP promoter [ 49 ]. Consistent with our study, a significantly lower level of SHP was shown in HCC when compared to nonmalignant liver tissue [ 50 ]. This study also reveals that the loss of SHP is more pronounced in fibrolamellar carcinoma than in typical HCC [ 50 ].…”

“…Consistent with our study, a significantly lower level of SHP was shown in HCC when compared to nonmalignant liver tissue [ 50 ]. This study also reveals that the loss of SHP is more pronounced in fibrolamellar carcinoma than in typical HCC [ 50 ].…”

Small heterodimer partner 1 directly interacts with NS5A viral protein and has a key role in HCV related liver cell transformation

“…Finally, although SHP1 has been described to play antitumor role in the development of cancer [ 18 ] the heterogeneity of HCC subtypes linked to different oncogenic pathways, still represent the major barriers for HCC study.…”

Genomic analysis of fibrolamellar hepatocellular carcinoma

“…FL-HCCs also show elevated expression of epidermal growth receptor (EGFR) and Ras signaling as well as transforming growth factor b, compared with adult HCC (14)(15)(16)(17). There is also some immunohistochemical evidence that the nuclear factor kappa B pathway is activated in FL-HCC (18), and that expression of the small heterodimer partner orphan nuclear receptor is decreased (19). But overall, the list of FL-HCC markers is still limited and the (epi)genetic alterations driving the growth of these tumors have remained unknown.…”