Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450

Abstract

Hepatocellular carcinoma (HCC) remains a highly prevalent and deadly disease, being among the top causes of cancer-related deaths worldwide. Despite the fact that the liver is the major site of biotransformation, studies on drug metabolizing enzymes in HCC are scarce. It is known that malignant transformation of hepatocytes leads to a significant alteration of their metabolic functions and overall deregulation of gene expression. Advanced stages of the disease are thus frequently associated with liver failure, and severe alteration of drug metabolism. However, the impact of dysregulation of metabolic enzymes on therapeutic efficacy and toxicity in HCC patients is largely unknown.

Here we demonstrate a significant down-regulation in European Caucasian patients of cytochromes P450 (CYPs), the major xenobiotic-metabolizing enzymes, in HCC tumour samples as compared to their surrounding non-cancerous (reference) tissue. Moreover, we report for the first time the association of the unique CYP profiles with specific transcriptome changes, and interesting correlations with expression levels of nuclear receptors and with the histological grade of the tumours. Integrated analysis has suggested certain co-expression profiles of CYPs with lncRNAs that need to be further characterized. Patients with large tumours with down-regulated CYPs could be more vulnerable to drug toxicity; on the other hand, such tumours would eliminate drugs more slowly and should be more sensitive to pharmacotherapy (except in the case of pro-drugs where activation is necessary).

Introduction

Biotransformation is one of the key processes maintaining homeostasis at both cellular and whole organism level. Rational pharmacotherapy should be necessarily based on deep knowledge of the biotransformation systems and enzymes. It should personalize treatment based on inter-individual (and sometimes intra-individual) variability of the biotransformation capacity. Whereas genetic polymorphisms in drug-metabolizing enzymes have been widely studied, complex genetic alterations that occur during carcinogenesis and which may have a deleterious effect on the whole drug-metabolizing enzyme system are far less understood.

It is widely accepted that the primary organ of biotransformation is the liver due to its size and high concentration of biotransformation enzymes. The metabolic capacity of the liver is relatively oversized while the hepatocytes are sensitive to damage. In a significant number of patients, liver cancer (hepatocellular carcinoma, HCC) develops in the wake of chronic damage, either infectious or toxic. HCC is also one of the major indications for liver transplantation. It is an aggressive tumour, with less than 30% of patients eligible for potential curative treatment at the time of diagnosis [1], and average overall survival from diagnosis of only 3–6 months. HCC incidence varies significantly in different parts of the world. In 2018, HCC was estimated as the sixth most common cancer and fourth leading cause of cancer-related death, with about 841,000 new cases and 782,000 deaths annually according to GLOBOCAN statistics [3], [4]. In Southeast Asia and sub-Saharan Africa, HCC is the most common cancer with an early age of onset. In Western countries, HCC is generally rare, but its incidence and mortality are increasing. This variability is in part due to the different patterns of hepatitis B and hepatitis C incidence, as these infections appear to be the most significant causes of HCC worldwide. In Western countries, where hepatitis infections are less frequent than in Asia [2], other types of chronic liver injury increase the risk of HCC, especially in patients who develop cirrhosis where the 5-year cumulative risk of developing HCC ranges between 5% and 30% [5], [6].

HCC originates in the key cell population for biotransformation, namely the hepatocytes. Hepatocytes require a very special environment to maintain their activity. The tissue architecture, especially the tight junctions and close communication of the cells, is very important. If necrosis is taking place in the HCC tumour, it could affect the “healthy” non-cancerous liver tissue and impair biotransformation, with consequences for pharmacotherapy of the HCC patients.

The data published on the expression of drug-metabolizing enzymes in HCC suggests alterations in the major drug-metabolizing system, the cytochrome(s) P450 (CYPs) [8], [9]. However, most of the data comes from the hepatitis B or C regions (mostly China) while in Europe detailed data are missing, due to lower incidence and a tendency to diagnose and treat HCC non-invasively, which makes target tissue samples difficult to collect. Our study describes for the first time CYP expression profiles of HCC tumours selectively in European Caucasian patients, and brings a new perspective for the study of the underlying mechanisms associated with deregulation of CYP expression.