Association of Tumor Hydroxyindole O-Methyltransferase and Serum 5-Methoxytryptophan with Long-Term Survival of Hepatocellular Carcinoma

SIMPLE SUMMARY: 5-methoxytryptophan (5-MTP) is a tryptophan (Trp) metabolite synthesized by hydroxyindole O-methyltransferase (HIOMT). Expression of HIOMT is decreased in various tumors. However, whether HIOMT expression and serum 5-MTP concentration associate with prognosis of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to analyze HCC tissue HIOMT mRNA and serum 5-MTP and determine their association with survival following therapeutic liver resection. We found a significant association of serum 5-MTP or tissue HIOMT and serum kynurenine (Kyn) with overall and relapse free (RF) survival of HCC. The combination of serum 5-MTP and Kyn is a potential prognostic biomarker of HCC. ABSTRACT: 5-methoxytryptophan (5-MTP) is a recently discovered tryptophan (Trp) metabolite with anti-inflammatory and tumor-suppressing actions. Its synthesis is catalyzed by hydroxyindole O-methyltransferase (HIOMT). HIOMT levels were reported to be decreased in some patients with colorectal, pancreatic and breast cancer. It is unclear whether tissue HIOMT levels is altered in hepatocellular carcinoma (HCC). It is also unclear whether serum 5-MTP concentration is influenced by HCC. In this study, 150 HCC and adjacent normal liver tissues and serum samples were obtained from the HCC biobank established by a prospective multicenter study. Serum samples from 47 healthy subjects were included as a reference. HIOMT mRNA was measured by real time PCR. Serum 5-MTP and selected Trp metabolites were analyzed by quantitative LC-MS. HCC tissue HIOMT mRNA levels adjusted for adjacent normal tissue HIOMT mRNA levels was associated with overall and relapse-free (RF) survival. Combined serum 5-MTP or tissue HIOMT mRNA and serum kynurenine (Kyn) analysis predicted prolonged overall and RF survival following liver resection. A high serum 5-MTP or tissue HIOMT mRNA and low serum Kyn is associated with long-term survival. In conclusion, tumor tissue HIOMT mRNA and serum 5-MTP are potential biomarkers of HCC, especially when analyzed in combination with serum Kyn.