Hepatocellular Carcinoma Subtypes Revealed by Molecular-Protein Interactions

Hepatocellular Carcinoma Subtypes Revealed by Molecular-Protein Interactions
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Hepatocellular carcinoma (HPP) is the most common type of liver cancer, accounting for 80% of cases worldwide. The World Health Organization classifies HCC according to five different subtypes based on molecular and cytogenic differences. But researchers from China have developed an alternative method: one based on metabolite-protein interactions (MPIs) that they hope may prove useful for guiding personalized HCC treatment.

Metabolic alterations in cancer cells can promote cancer development and progression through certain MPIs interactions. “Consequently, the metabolic landscape, composed of metabolites, proteins and the interactions between them, is highly-variable in different cancer types, subtypes, or even the same cancer type under different conditions,” the authors write in their paper in Advanced Science. “The diversity and heterogeneity of HCC metabolic alterations make it difficult to understand the HCC metabolic landscape. Understanding the metabolic alterations and their relevant adaptive MPIs can provide meaningful insights into cancer metabolism and potential therapeutic targets.”

A research group led by Prof. Piao Hailing from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) constructed an integrative MPI network in HCC subtyping.

To understand the differences, the group constructed a directed MPI network from four data resources including Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactive, Human-GEM, and BRENDA. The MPI network included 31236 unique MPIs covering 1870 metabolites and 4132 proteins (represented by the encoding genes).

Based on the expressions of hub proteins on the MPI and multimaps data from the cancer genome atlas (TCGA)  two robust prognosis-distinctive HCC subtypes and their corresponding biological and clinical characters were identified that showed substantial differences in prognosis and hypoxia.

The poor prognostic metabolic HCC subtype was associated with remarkable hypoxia, DNA hypermethylation of metabolism enzymes, unsaturated fatty acid accumulation (like linoleic acid and arachidonic acid), immune pathway up-regulation, and exhausted T-cell infiltration. The authors believe the immune pathway up-regulation is probably induced by interactions between accumulated unsaturated fatty acids  and immunoregulatory proteins like SRC and TGFB1.

HCC of the poor prognostic subtype also possessed more mutations in three well-known tumor suppressors including TP53 and BAP1.  And, in general, the poorer prognostic subtype expressed fewer hepatocytes, preadipocytes, adipocytes, and hematopoietic stem cells but more epithelial cells, activated dendritic cells, mesenchymal stem cells (MSCs),smooth muscle cells, and various immune cells like Type 1 T helper, Type 2 T helper, natural killer T, and CD8+ T cells than the better prognostic HCC subtype.

Additional study revealed the poor prognostic subtype could be further segregated into two other subtypes, called S1 and S2 in the study, based on  tumor microenvironments.  “The pathway analysis showed various metabolic pathways especially the fatty acid metabolism pathways were down-regulated in the mRNA level for S1 compared to S2,” the authors write. S1 contained significantly decreased levels in hypoxia as well as multiple immune relevant proteins (SRC, MMP1, IL12A) that the author speculate could prove potential therapeutic targets for this subtype. The S1 subtype was also more likely to accumulate unsaturated fatty acids compared to S2.

The researchers compared the subtypes with their prognosis differences based on other HCC cohorts. The S1-subtype HCC patients were most likely to double the HCC tumor size and the S1-like cirrhosis patients were most likely to progress into HCC. S2 was the next, and the better prognostic subtype showed the most favorable outcome.

“These significant metabolism, immune, and clinical differences across the three subtypes further highlight that the close interactions between fatty acid metabolism and the SRC-centered immune regulations can promote HCC development and progression,” the authors write.