Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

Abstract

Heterogeneous biological characteristics of hepatocellular carcinoma may be attributed to the cellular origin of the tumor. Patients with hepatocellular carcinoma probably derived from hepatic progenitor cells had early tumor recurrence after surgical resection or liver transplantation, suggesting that these tumors have aggressive characteristics. Ezrin, a member of the ERM (ezrin-radixin-moesin) cytoskeleton-associated protein family, is highly expressed in several types of human cancers and correlations between its immunoreactivity and patient outcome have been shown. In this study, ezrin expression, as well as cytokeratin19 and cytokeratin 7 expression, which are regarded as progenitor cell/ductular markers were immunohistochemically assessed in cases of hepatocellular carcinoma. In normal livers, ezrin expression was not found in any cell types, whereas cytokeratin 7 and cytokeratin 19 were exclusively stained in bile duct cells. In contrast, in livers with chronic hepatitis or cirrhosis, positive ezrin expression was observed in ductular reactions with strong intensity and intermediate hepatobiliary cells with various intensity. Of 77 cases of hepatocellular carcinoma, 28 (36%) had positive ezrin expression, 32 (42%) had cytokeratin 7 expression, and 11 (14%) had cytokeratin 19 expression. Ezrin expression in hepatocellular carcinoma was significantly associated with cytokeratin 19 expression, but not with cytokeratin 7 expression. Patients with ezrin-positive hepatocellular carcinoma had a significantly higher prevalence of elevated serum a-fetoprotein. Patients with immunohistochemical ezrin-positive hepatocellular carcinoma demonstrated significantly shorter recurrence-free and overall survival compared to patients with ezrin-negative hepatocellular carcinoma. Multivariate analysis revealed positive ezrin expression and multiple tumors to be independently associated with early recurrence in patients with hepatocellular carcinoma after curative surgical resection. These results suggested that hepatocellular carcinoma with ezrin expression might be at least partly derived from hepatic progenitor cells. Measurement of ezrin expression might be used to identify patients with an increased risk of early recurrence.

Is wider surgical margin justified for better clinical outcomes in patients with resectable hepatocellular carcinoma?

“…19,20 Ezrin overexpression increased the risk of early recurrence. 21 Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in HCC. 22 Increased CD4 (þ) CD25 (þ) Fox P3(þ) Treg may impair the effect or function of CD8(þ) T cells, promoting disease progression.…”

Increased Expression of Yes-Associated Protein 1 in Hepatocellular Carcinoma with Stemness and Combined Hepatocellular-Cholangiocarcinoma

“…HCCs expressing stemness-related markers, including epithelial cell adhesion molecule (EpCAM), keratin 19 (K19), CD90, and CD133, are known to exhibit more aggressive biological behavior and worse prognosis than HCCs that express no stemness-related markers [5], [9]–[11]. As well, cHC-CCs, which also express stemness-related markers, have been reported to show more aggressive behavior than HCCs [12], [13]…”

Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma

“…Strong cytoplasmic immunohistochemical staining for ezrin, a member of the ezrin-radixin-moesin (ERM) subfamily of Protein 4.1 [6], has been associated with decreased survival in upper aerodigestive tract squamous cell carcinoma [7]. Additionally, ezrin positivity has been associated with decreased survival rates and incidence-free periods in hepatocellular carcinoma [8]. In prostatic adenocarcinoma specifically, its expression has been correlated with decreased tumor differentiation [9].…”