Overexpression of promyelocytic leukemia protein is correlated with poor prognostic markers in hepatocellular carcinoma

Background and aims: Promyelocytic leukemia protein (PML), a tumor suppressor in acute promyelocytic leukemia (APL), has a variable expression and distribution pattern in human solid neoplasms. We assessed PML expression and roles in 488 pairs of hepatocellular carcinomas (HCCs) and adjacent non-neoplastic liver tissues. Methods: PML immunoreactivities were correlated with clinicopathological prognostic parameters. Expression levels of the alternatively transcribed PML isoforms were analyzed using real-time PCR and Western blot assays in representative cases. Results: The PML expression level was increased in tumors from 483 patients (99.0%) compared with non-neoplastic liver tissues. Staining patterns were variable. PML overexpression was significantly correlated with histological grade, increase in alpha-fetoprotein and tumor necrosis that was associated with patients' survival. Although mRNA expression levels of PML were not correlated with the immunoreactivities of total PML, mRNA expression levels of PML4 tended to decrease in PML-high HCCs, and increase in PML-low HCCs, compared with adjacent non-neoplastic liver tissues. Conclusions: The significant correlation of the PML overexpression with clinicopathological prognostic markers, and the inverse relationship between the expression levels of PML4 and total PML indicate that the total amount of PML expressed may not be a major factor, but that the isoform-specific expression of PML, especially of PML4, plays an important role as a tumor suppressor in human hepatocarcinogenesis.