Key enzymes in pyrimidine synthesis, CAD and CPS1, predict prognosis in hepatocellular carcinoma

Background and Aims Individual 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 wanted to analyze the role of CAD and carbamoyl-phosphate synthetase 1 (CPS1), a rate limiting enzyme of the UC highly expressed in hepatocytes, in HCC.

Methods We created a tissue microarray to analyze expression of CAD and CPS1 by immunohistochemistry in a large and clinicopathologically well characterized cohort of HCC patients (n=561) that underwent surgery.

Results CAD was induced in recurrent HCC tumors and high expression predicted shorter overall survival. CPS1 was downregulated in HCC, was further reduced in recurrent tumors and distant metastases, and additionally, low CPS1 levels were associated with short overall survival. A combined score of both enzymes was found to be an independent prognostic marker in a multivariate cox regression model (HR 1.37, 95 % confidence interval 1.06-1.75, p=0.014).

Conclusion Two key enzymes in pyrimidine synthesis, CAD and CPS1 are dysregulated in HCC development and progression, and dysregulation is associated with short survival. Inhibition of pyrimidine synthesis may represent a novel strategy in the treatment of HCC.

Publication History

Article published online:
04 January 2021