Abstract
Simple Summary5-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.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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with high morbidity and mortality [1]
As 5-MTP controls cancer cell proliferation and migration, we proposed that hydroxyindole O-methyltransferase (HIOMT) expression in hepatocellular carcinoma (HCC) tissues is linked to HCC growth and mortality
HIOMT mRNA levels in 150 paired HCC and adjacent normal tissues were measured by real time PCR
Summary
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies with high morbidity and mortality [1]. Multiple approaches are taken to stratify HCC based on metabolic network, gene expression profiling and acetone utilization [4,5]. Those studies suggest that metabolic and genetic profiling are useful in classification of HCC. Recent reports implicate kynurenine (Kyn) and its synthetic enzymes, indoleamine 2, 3 dioxygenase (IDO) as prognostic biomarkers of HCC [6]. It is unknown whether other tryptophan metabolites are associated with the prognosis of HCC
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