Lipid Biomarkers Identified for Liver Cancer
The integration of metabolic and transcriptomic data of human liver tissues is represented by the background gene expression heat map overlayed with correlating metabolic structures. This integrative strategy led to the identification of a lipogenic signature involving stearoyl-coA desaturase (SCD), the enzyme responsible for conversion of saturated palmitic acid (SPA) to its monounsaturated form, palmitoleic acid (MUPA), which contributes to and serves as a biomarker for liver tumorigenesis.
Hepatocellular carcinoma (HCC) is an aggressive cancer of the liver with poor prognosis and growing incidence in developed countries. Pathology and genetic profiles of HCC are heterogeneous, suggesting that it can begin growing in different cell types. Although human tumors such as HCC have been profiled in-depth by genomics-based studies, not much is known about their overall metabolite modifications and how these changes can form a network that leads to aggressive disease and poor outcome.
Cancer metabolite profiling, or cancer metabolomics, is a promising new approach to help understand the biological mechanisms responsible for cancer development and progression. A systemic analysis of the pathways in which these genes and biochemical molecules interact may lead to identification of key biomarkers or drug targets for clinical intervention.
Previous gene expression studies led by Xin Wei Wang, Ph.D., in CCR’s Laboratory of Human Carcinogenesis, identified an aggressive subtype of HCC expressing stem cell-like gene expression traits linked to poor prognosis, called hepatic stem cell HCC (HpSC-HCC). HpSC-HCC is different from the mature hepatocyte subtype (MH-HCC) which expresses differentiated gene expression traits that are associated with good prognosis. Understanding the complicated molecular networks that characterize aggressive HCC may improve techniques used to identify and treat this aggressive disease. Wang along with Anuradha Budhu, Ph.D., a Staff Scientist in his lab, and colleagues combined metabolomics and transcriptomics of HpSC-HCC versus MH-HCC to identify the key atypical biochemical and molecular signaling networks related to HCC patient outcome.
The researchers began their investigation by performing metabolomics profiling of tumor and nontumor tissue samples from patients. They found that biochemical end products could distinguish tumor from nontumor tissue. To identify the biochemical pathways linked to aggressive HCC, they limited their search to metabolites that were associated with tumor tissues, tumor subtypes, and patient survival. They discovered that the majority of measurable metabolic changes seemed to happen in tumor tissues. Twenty-eight of the 48 metabolites identified were associated significantly with overall survival. After transcriptomic profiling of the samples used for metabolomics, 169 genes were found that significantly discriminates HpSC-HCC from MH-HCC tumors.
Since 28 metabolites and 169 genes identified are linked to aggressive HCC, the researchers thought that these genomic products are probably connected within the same altered molecular pathway. They used an integrative data analysis approach that showed the existence of enriched interconnected gene-metabolite pairs, which may make up an aggressive HCC signaling network. Further analysis of the gene-metabolite pairs showed that a cluster of metabolites were mainly fatty acid-related. The researchers found 273 genes in the fatty acid-related metabolite cluster that could predict HpSC-HCC and MH-HCC subtypes. The 273 gene signature was also associated significantly with overall survival. The team concluded that the fatty acid genes are associated with stem-like HCC and metastasis-related prognosis.
The next step was to assess the biological networks affected by the 273 genes. One of the genes was identified as stearoyl-CoA-desaturase (SCD), the enzyme responsible for conversion of saturated palmitic acid (SPA) to its monounsaturated form, palmitoleic acid (MUPA). Two of the metabolic products of SPA were present among the fatty acid-related metabolites cluster and increased in HpSC tumors, particularly MUPA and 15-methylpalmitate. SCD expression was significantly correlated with the expression of these SPA products in HCC tissues. The researchers found that patients with high levels of SCD in their tumors had worse survival compared with those with low levels of SCD. Also, SCD expression in tumors was associated significantly with disease-free survival, while the level in nontumor tissue was not associated with overall or disease-free survival.
Based on these results, the research team sought to determine how SCD and its related fatty acids, MUPA and SPA, functionally contribute to aggressive HCC and how altering SCD activity may improve this effect. They found that MUPA levels were increased in aggressive HCCs, and that MUPA increased migration and invasion of cultured HCC cells and colony formation by HCC cells. Furthermore, HCC cells that had reduced SCD had decreased migration and colony formation in culture and reduced tumorigenicity in mice.
The researchers wanted to determine if prognosis prediction could be improved by combining SCD with α-fetoprotein, which is the only clinically available HCC prognostic marker, or with BCLC staging, because it was an independent predictor of HCC survival. They found that adding SCD to established clinical parameters may improve clinical risk prediction, and determine treatment regimens, particularly for early-stage patients.
This paper identifies a monounsaturated lipid metabolite, MUPA, as well as its activating enzyme, SCD, as key role players in aggressive HCC progression and patient outcomes. In addition, insight into how modulation of SCD’s activity could be pursued to clinically address aggressive HCC is provided.Summary Posted: 05/2013
Budhu A, Roessler S, Zhao X, Yu Z, Forgues M, Ji J, Karoly E, Qin LX, Ye QH, Jia HL, Fan J, Sun HC, Tang ZY, Wang XW. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology. 2013 May PubMed Link