Abstract
Simple SummaryIndividual patients with liver cancer have a highly variable clinical course. Hence, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Expression of two key enzymes in pyrimidine synthesis was analyzed in a large, well-characterized cohort of patients with liver cancer. Dysregulated expression of these enzymes was associated with shorter survival of the patients. A combined score of both markers was found to be a statistically independent prognostic marker.Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Recently, it has been demonstrated that dysregulation of the urea cycle (UC) is a common phenomenon in multiple types of cancer. Upon UC dysregulation, nitrogen is diverted toward the multifunctional enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), and increases pyrimidine synthesis. In this study, we investigated the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate-limiting enzyme of the UC highly expressed in hepatocytes, in HCC. We created a tissue microarray to analyze expression of both enzymes by immunohistochemistry in a large and well-characterized overall cohort of 871 HCCs of 561 patients that underwent surgery. CAD was induced in recurrent HCCs, and high expression predicted shorter overall survival. CPS1 was downregulated in HCC and further reduced in recurrent tumors and distant metastases. Additionally, low CPS1 was associated with short overall survival. A combined score of both enzymes was an independent prognostic marker in a multivariate Cox regression model (HR = 1.37, 95% confidence interval 1.06–1.75, p = 0.014). Inhibition of pyrimidine synthesis may represent a novel therapeutic strategy for HCC.
Highlights
This article is an open access articlePrimary liver cancer is the fourth most common cause of cancer-related death worldwide, with about 782,000 deaths in 2018 [1]
In order to elucidate the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1) and their effect on prognosis in hepatocellular carcinoma (HCC), we investigated the expression of both enzymes in a large collective of
While CAD has been demonstrated to be induced on the mRNA level in HCC tissue in the Cancer Genome Atlas (TCGA) cohort [15], increased mRNA levels did not translate into an increase in CAD protein levels in primary HCCs
Summary
Primary liver cancer is the fourth most common cause of cancer-related death worldwide, with about 782,000 deaths in 2018 [1]. Hepatocellular carcinoma (HCC) accounts for the vast majority of cases of primary liver cancer. Clinical prognosis assessment and decision processes are currently based on one of the several tumor staging systems (for example, the Barcelona Clinic Liver Cancer (BCLC), Japan Integrated Staging (JIS), or distributed under the terms and conditions of the Creative Commons. These staging systems allow quite robust stratification in different prognostic groups, the clinical course of individual patients suffering from HCC is highly variable, and there is still room for refinement in the evaluation of prognosis, especially in early tumor stages [2]. More accurate prognostic markers are needed to determine prognosis and select specific treatment options
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