Constitutive activation of nuclear factor-kappa B (NF-kB) signaling pathway in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) is an aggressive neoplasm due to high frequency of recurrence after surgical resection and resistance to chemotherapy and radiation therapy. Activation of transcription factor NF-kB signaling pathway has been recognized for involvement in progression of various malignant neoplasms. The role of NF-kB pathway in FLHCC has not been studied to date. Formalin-fixed, paraffin-embedded tissue sections of 8 FLHCC, 10 normal liver tissues (NLT) were evaluated immunohistochemically for the expression of p-NF-kBp65 using phosphospecific antibody directed against phosphorylated (p)-NF-kBp65 (Ser 536). The level of p-NF-kBp65 (Ser 536) expression was categorized into four grades: 0 (background), 1+ (weak), 2+ (moderate), or 3+ (strong) based on intensity of intranuclear staining, and was further assessed using two scales: high expression (2+ or 3+) and low expression (0 or 1+). Only high expression of p-NF-kBp65 (Ser 536) in cells with nuclear translocation was considered as constitutive NF-kB activation. High expression of p-NF-kBp65 (Ser 536) was found in 88 % (7/8) of FLHCC tissue. In contrast, only 10 % (1/10) of NLT showed high expression for p-NF-kBp65 (Ser 536). The differences in p-NF-kBp65 nuclear expression between FLHCC tissue and NLT were significant (P < 0.001). There was no significant correlation between the expression of intranuclear p-NF-kBp65 and the stage of FLHCC. Constitutive NF-kB activation was observed in FLHCC. The findings suggest that NF-kB activation is involved in the tumorigenesis of FLHCC and may represent novel targets for therapeutic intervention to FLHCC.