AROS Is a Significant Biomarker for Tumor Aggressiveness in Non-cirrhotic Hepatocellular Carcinoma

Abstract

Despite a low risk of liver failure and preserved liver function, non-cirrhotic hepatocellular carcinoma (HCC) has a poor prognosis. In the current study, we evaluated an active regulator of SIRT1 (AROS) as a prognostic biomarker in non-cirrhotic HCC. mRNA levels of AROS were measured in tumor and non-tumor tissues obtained from 283 non-cirrhotic HCC patients. AROS expression was exclusively up-regulated in recurrent tissues from the non-cirrhotic HCC patients (P = 0.015) and also in tumor tissues irrespective of tumor stage (P < 0.001) or BCLC stage (P < 0.001). High mRNA levels of AROS were statistically significantly associated with tumor stage (P < 0.001), BCLC stage (P = 0.007), alpha fetoprotein (AFP) level (P = 0.013), microvascular invasion (P = 0.001), tumor size (P = 0.036), and portal vein invasion (P = 0.005). Kaplan-Meir curve analysis demonstrated that HCC patients with higher AROS levels had shorter disease-free survival (DFS) in both the short-term (P < 0.001) and long-term (P = 0.005) compared to those with low AROS. Cox regression analysis demonstrated that AROS is a significant predictor for DFS along with large tumor size, tumor multiplicity, vascular invasion, and poor tumor differentiation, which are the known prognostic factors. In conclusion, AROS is a significant biomarker for tumor aggressiveness in non-cirrhotic hepatocellular carcinoma.

Keywords: Biological Markers; Carcinoma, Hepatocellular; Prognosis.

Fig. 1. (A) AROS expression in HCC (T) compared to surrounding non-tumoral tissues (NT) in LC and NonLC. Both cirrhotic and non-cirrhotic tumors expressed significantly higher levels of AROS (P < 0.0001). (B) AROS expression in non-cirrhotic HCC (T) compared to surrounding non-tumoral tissues (NT) in total and across stages. mRNA levels of AROS were significantly up-regulated in tumors compared to non-tumors irrespective of tumor stages and BCLC stages. (C) Comparative analysis of AROS mRNA levels in HCC tissues with (recu) or without postoperative recurrence (non-recu) within 2 yr. AROS expression was higher in recurrent tumors than in non-recurrent tumors exclusively in NonLC, but not LC.

Fig. 2. Non-cirrhotic HCC patients with high levels of AROS expression have a shorter DFS for 2 yr. Kaplan-Meier curves for the DFS of patients who showed high expression and low expression of AROS. (A) AUC value of AROS expression at prediction of DFS was 0.576. (B) The AROS-high group showed a significantly shorter DFS time than the AROS-low group for 2 yr (P < 0.001). Thin lines, patients expressed higher levels of AROS (n = 71); broken lines, patients expressed lower levels of AROS (n = 212).