EGFR is phosphorylated at Ty845 in hepatocellular carcinoma

Abstract

Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of hepatocellular carcinomas. Recent studies of EGFR inhibitors to treat hepatocellular carcinoma have been encouraging and better understanding of EGFR signaling may lead to more effective strategies for inhibiting this key pathway. The EGFR can be phosphorylated at different tyrosine sites, leading to subsequent activation of different pathways. Cell line and animal studies have shown that MAPK and STAT-3 are important mediators of the EGFR signal in liver cells. However, little is known about EGFR phosphorylation and subsequent signaling in primary hepatocellular carcinoma. We investigated the site of EGFR phosphorylation by Western blot in 18 hepatocellular carcinomas. Fourteen of 18 hepatocellular carcinomas had detectable EGFR by Western blotting and 13 of 14 showed phosphorylation at tyrosine 845. In contrast, no EGFR phosphorylation was detected at tyrosine 998, tyrosine 1045, or tyrosine 1068, which signal through other pathways including STAT-3 and MAPK. These findings were further explored by examination of EGFR expression and signaling pathway activation in tissue arrays comprised of 73 hepatocellular carcinomas using antibodies that recognize phosphorylated (or activated) proteins. Tissue array studies also found no correlation between EGFR expression (29% of cases) and STAT-3 nuclear positivity (16%), AKT (4%), MAPK (3%), or STAT-5 (3%) positivity, all P40.05. EGFR expression was correlated with hepatitis B infection, but not with tumor size, nuclear grade, or proliferative rate. We conclude that EGFR is phosphorylated at tyrosine 845 in most hepatocellular carcinomas and that EGFR expression by immunohistochemistry does not correlate well with STAT-3, STAT-5, MAPK, or AKT immunostaining.

Association of serum levels of epidermal growth factor with disease severity in patients with unresectable hepatocellular carcinoma

“…This was confirmed by Sung et al [26] who concluded that serum EGFR level was a potential biomarker of liver cancer. Kannangai et al [14] added that EGFR can be considered as a marker for predicting the metastasis and recurrence of HCC. Wu et al [27] found that EGF was a promoting factor for hepatoma cells stressing on the critical role in EGFinduced proliferation.…”

“…[12] Additionally, a functional polymorphism in the EGF gene is reported to be associated with the risk of development of HCC. [13] Kannangai et al [14] reported overexpression of EGFR associated with late-stage HCC, increased cell proliferation, and degree of tumor differentiation. All these reports support our hypothesis that EGF is a viable candidate for screening for different cirrhotic populations for early detection of HCC.…”

Overexpression of syntenin enhances hepatoma cell proliferation and invasion: Potential roles in human hepatoma

“…It is generally believed that egFR is overexpressed in several cancers, including colorectal cancer, HCC and urothelial carcinoma, and can activate a cascade of multiple signaling pathways that facilitate the tumor growth process (16)(17)(18). The fact that syntenin can promote hepatoma cell proliferation was demonstrated above.…”

“…EGFR overexpression has been confirmed in multiple carcinomas including breast cancer, urothelial cell carcinoma and hepatoma (10,16). It is believed that egFR can trigger a cascade of multiple signaling pathways to regulate cancer cell proliferation, maintenance, invasion, metastasis, survival and prognosis (16,17,25,26). Furthermore, egFR elicits a vital role in MDA-9/ syntenin-induced urothelial carcinoma cell proliferation (14).…”

Signaling Pathways Coupled to Activation of the Kinin B1 Receptor

“…Similarly, different cell lines and animal studies have shown that MAPK and signal transducers like STAT-3 are important mediators of EGFR signaling after phosphorylation of different tyrosine residues in liver cells and hepatocellular carcinoma. Interestingly, it has been shown that homogenates of hepatocellular carcinomas present phosphorylation at Tyr845, but no EGFR phosphorylation at Tyr998, Tyr1045 or Tyr1068 (Kannangai et al, 2006). On the other hand, the SH2 domain of PLC binds at phospho-Tyr992, resulting in activation of PLC -mediated downstream signaling (Emlet et al, 1997).…”