Description
The major goal of the project “Hepatocellular carcinoma stratification based on noninvasive markers” (HEPMARK), in accordance the EEA Research Programme objectives, is to stimulate multidisciplinary research by creating and supporting a network for translational science that brings together scientists from Romania, Norway and France. HEPMARK proposes a concept of research that would identify using expression miRNAs expression, a high-risk group of patients with liver cancer who may develop intrahepatic recurrence/ distant metastasis. Thus, our hypothesis is that primary liver cancers release miRNAs within exosomes transported in the peripheral blood that facilitate the metastatic niche. We intend to use miRNA circulating and angiogenic panel for HCC patients’ stratification. More accurate preoperative selection criteria will allow better patient selection and better allocation of the HCC patients in case of curative treatment.
Summary of project results
The scientifically stated goal of the project was to identify a panel of specific markers for understanding and characterizing the evolution of hepatocellular carcinoma (HCC) before and after curative transplantation or resection. HEPMARK proposed a research concept that could identify, using the expression of miRNAs, a high-risk group of developing recurrence / metastasis at a distance between patients with liver cancer. The outcomes are as follows: identifying microRNAs as HCC biomarkers for detecting and evaluating aggressive disease in high-risk patients; developing a set of microRNA, proteins and imaging parameters as biomarkers of response in HCC therapy; prospective testing of candidate biomarkers for optimization and future transposition in clinical practice guidelines for stratification of patients, based on selected markers; integration of Romanian research groups into a strong network with HCC competence and translational research. A set of angiogenic markers, inflammatory marker and specific microRNAs for HCC tumors have been identified. Bioinformatics analysis allowed for the identification of correlations between these biomarkers and tumor processes. This was achieved by correlating biomarker results with clinical parameters such as survival or progression. Relevant biomarkers will be patented. After the final evaluation phase (and before publication), our data and preliminary findings will be exploited for potential commercial applications. Analytical mobility itself will be simplified in a tool for omics analysis - based on the discovery of biomarkers and disease modeling. We expect that microRNA, mRNA and epigenetic profiles are currently available in research clinics by the end of this project. The main obstacle to the routine use of these results will therefore probably be the data processing and analysis. We expect a simplified tool for integrating and analyzing these data to have a clear added value for many researchers. The miRNAs species that were significantly expressed miR-1269a (p= 2e-14), miR-183-5p (p= 3e-9) and miR-96-5p (p= 3e-8) (downregulated) and miR-139-5p (p= 2e-11), miR-10a-5p (p= 2e-10), miR-21-5p and miR-200b-3p (p= 2e-10) (upregulated). In conclusion, a panel of markers has been identified that can differentiate HCC patients with recurrence according to clinical characteristics.
Summary of bilateral results
The Norwegian partner was involved in the generation and use of sequencing and bioinformatics analysis tools to establish the signature of miRNA and mRNA. The resulting expression matrices were analyzed in a linear modeling framework developed for data analysis to identify miRNAs that are significantly associated with the different interest groups. The same linear modeling framework was used to analyze the microarray data of mRNA and miRNA. Profile of angiogenic biomarkers in HCC patients was correlated with Ob_2: characterization of angiogenic biomarkers in HCC plasma and imaging biomarkers in correlation with microRNA markers. The entire proposed project was based largely on the existence of a biobanks that includes human biological samples as well as associated medical data available at the Fundeni Clinical Institute. The project has strengthened the collaboration between high-quality research and technological development centers in Norway and Romania with experience in project development and management at European level. The research network has been exploited for better collaboration between Romanian and European research centers and to support the initiation of large-scale clinical trials. The project team was structured in specialized departments: molecular biology (PP, P1, and P2), genetics (PP, P3), bioinformatics (P3) and surgery (PP). Each partner has administrative departments and human resources with previous experience in project management, as a result of which the project was carried out with minor risks. The partner research infrastructure, along with the human resources involved in doctoral programs, has established high technical standards for research at HEPAMARK. These results set the basis for further translating research aimed at improving the survival of HCC patients. All of the above mentioned areas of expertise have been critical to the full understanding of HCC at the systemic and molecular level. HEPMARK facilitated the exchange of scientific ideas and knowledge among five research groups, three from Romania, one from Norway and one from France with solid expertise in genomics (Pasteur Institute), molecular biology (Constanta University of Medicine and Pharmacy, Titu Maiorescu University), Bioinformatics (Norwegian Institute of Science and Technology) and a medical clinic (Fundeni Clinical Institute). The project has created a high-quality network with qualified staff and increased attractiveness for Romanian partners.