Abstract
BackgroundMolecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker.MethodsWe analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection.ResultsGPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences.ConclusionsDownregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection.
Highlights
Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC)
We focus on G protein-coupled receptor 155 (GPR155) because it is recognized as a transmembrane marker possibly associated with the transport of growth factors and anticancer drugs, and no published data of GPR155 expression in HCC
Expression, methylation, and copy number alteration of GPR155 in cell lines GPR155 showed differential mRNA expression with decreased levels of expression in all HCC cell lines except for HuH1 compared with the control non-tumorigenic cell line FHs74 (Fig. 1a)
Summary
Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). Liver resection has been the mainstay of treatment for HCC, the recurrence rate after curative resection remains high at approximately 70% [2,3,4]. Complete cure of this disease is quite challenging even though various therapeutic modalities have been developed. Some patients are long-term survivors after resection of advanced HCC without adjuvant therapy. To address these clinical issues, development of a novel molecular marker able to reflect potential characteristics of the tumor is required [10].
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