MEDICINE AND HEALTH

Studies reveal clinically relevant molecular characteristics of paracancerous tissues of hepatocellular carcinoma


Most of the existing oncology studies focus on tumor tissue, usually using adjacent tissues as a control, and rarely conduct in-depth research. However, gene sequencing and transcriptome analysis showed that there were certain gene mutations and chromatin copy number variations in adjacent tissues, which were significantly different from normal tissues and were considered to be an intermediate state between normal tissues and tumor tissues. Primary liver cancer is the fourth most common and second highest mortality malignant tumor in China. Early studies reported prognosis-related gene expression signatures in FFPE samples of paracancerous tissues of hepatocellular carcinoma through transcriptome sequencing, revealing the molecular heterogeneity of paracancerous tissues. Protein is the main executor of life activities and is the target of more than 95% of drugs, and there is still a lack of systematic research on paracancerous tissues of hepatocellular carcinoma from the proteome level.

On June 2, 2023, the team of Zhou Hu, a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and the team of Professor Fan Jia and Gao Qiang of Zhongshan Hospital affiliated to Fudan University published a report entitled “Proteomics of adjacent-to-tumor samples uncovers clinically relevant biological” in the journal National Science Review (NSR). Events in Hepatocellular Carcinoma”, which uses proteomics technology to systematically reveal the molecular characteristics associated with the clinical features of paracancerous tissues of hepatocellular carcinoma, and deeply explores the proteomic differences between paracancerous tissues and normal liver tissues of liver cancer.

The researchers divided hepatocellular carcinoma into three subtypes, namely metabolism-driven, microenvironmental dysregulation and proliferation-driven (Cell, 2019), and proteome analysis of the paired paracancerous tissues of the three subtypes found that they had the molecular typing characteristics of the corresponding cancer tissues, suggesting that the proteome of the adjacent tissues was molecular heterogeneity (Figure A). Based on this, the researchers used an unsupervised clustering method to divide the adjacent tissues into two subtypes S1 and S2 according to proteome data. Among them, S2 patients accounted for about 15% of the total number of patients, and the patients were older, had higher ALT and γ-GT content, had a poor prognosis and a higher risk of recurrence. The highly expressed proteins in S2 paracancerous tissues were significantly enriched into the ECM-receptor interaction pathway, antigen processing and presentation, cell adhesion, and PI3K-Akt signaling pathway, while the low-expression proteins were significantly enriched into various metabolism-related pathways. The above paracancerous tissue typing criteria were verified in the high-quality liver cancer adjacent proteome dataset (Nature, 2019) published by the team of Academician He Fuchu and Academician Fan Jia (Figure B). Using the deconvolution algorithm, the research team predicted the composition of tissue-infiltrating immune cells in adjacent tissues, and found that the content of dendritic cells, CD8+ T cells, fibroblasts, etc. in S2 type paracancerous tissues was high, and multiplex fluorescence immunohistochemistry was used to verify them in adjacent tissue chips (Figure C). Further, the team used DIA-MS technology to conduct quantitative proteomic analysis on normal liver tissue, two subtypes of paracancerous tissues and their paired cancerous tissues, and the cluster analysis found that S1 type paracancerous tissue was similar to normal liver tissue, while S2 type paracancerous tissue was closer to cancer tissue. Compared with normal tissues, there were 112 upregulated proteins and 71 downregulated proteins in S1 type paracancerous tissues. Among them, 13 upregulated proteins were secreted proteins, which could be used as potential blood biomarkers for the early diagnosis of liver cancer. Other differential proteins may be involved in remodeling the immune microenvironment of the tumor or promoting tumor recurrence (Figure D).

In recent years, through cooperation and multi-omics technology with proteomics as the core, Professor Zhou Hu’s team has achieved a series of scientific research results in the genome study of liver cancer tumor proteins (Cell, 2019; Cancer Cell, 2022), the discovery and functional research of important proteins related to the occurrence and development of liver cancer (Advanced Science, 2023). These research results provide a theoretical basis for the occurrence and development mechanism of liver cancer and the potential precision targeted treatment regimen, and the high-quality big data sets produced by the research will provide important support for the basic and clinical research of liver cancer.

Dr. Zhu Hongwen, associate researcher of Shanghai Institute of Materia Medica, Dr. Lin Youpei of Zhongshan Hospital affiliated to Fudan University, Dr. Lu Dayun of Nanjing University of Chinese Medicine, and Dr. Wang Shisheng of West China Hospital of Sichuan University are co-first authors of the paper. Hongwen Zhu, Professor Gao Qiang and Professor Hu Zhou are co-corresponding authors of the paper. This work has been strongly supported by Academician Fan Jia of Zhongshan Hospital, Professor Gao Daming of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Professor Bing Zhang of Baylor College of Medicine, Professor Li Ding of University of Washington School of Medicine, and Professor Pei Wang of Icahn School of Medicine at Mount Sinai. The study relies on the major scientific research output of the Public Technology Center of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. The research was funded by the National Key Research and Development Program of the Ministry of Science and Technology, the Young Scientific and Technological Talents Program of the Shanghai Municipal Science and Technology Commission, the Youth Innovation Promotion Association of the Chinese Academy of Sciences, and Sanofi Outstanding Young Scientific and Technological Talents. (Source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

Related paper information:https://doi.org/10.1093/nsr/nwad167

Figure Systematic analysis of proteome heterogeneity in paracancerous tissues of hepatocellular carcinoma

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