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Liver Transplantation With Two-stage Liver Resection in Unresectable Liver Cancer , Metastases or Emd-stage Liver Disease (LTLR-LC)

ABSTRACT: Colon cancer and primary liver cancer are common malignant tumors with low survival rate worldwide, and unresectable primary liver cancer and colon cancer liver metastases have worse prognosis. End-stage liver disease is equated with advanced liver disease, liver failure and decompensated cirrhosis because they are generally irreversible. Liver transplantation is a treatment option for the above-mentioned patients and is expected to improve the prognosis of the patients, but the biggest problem faced by such patients is the shortage of donor livers. Recently, a new surgical modality, resection and partial liver segment 2-3 transplantation with delayed total hepatectomy (RAPID), can greatly alleviate these problems.Based on clinical surgical experience, our center proposes and designs a clinical study of adjuvant liver transplantation combined with two-stage hepatectomy in the treatment of patients with unresectable primary liver cancer, colorectal cancer liver metastases, or end-stage liver disease. By improvement of RAPID operation, the safety and efficacy of this treatment method in patients with those disease were evaluated.

DISEASE(S): Liver Transplant Disorder,End Stage Liver Disease,Hepatic Cancer,Liver Neoplasms,Liver Diseases,End-stage Liver Disease

PROVIDER: 10050 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Liver is uniquely capable to repair itself after injury. Multiple molecular and biochemical processes initiated after partial hepatectomy, lead to proliferation of all cells within the liver. MicroRNAs (miRNAs) are a class of highly abundant non-coding RNA molecules that cause post-transcriptional gene repression and are involved in several biological processes including cell cycle regulation and differentiation. We examined the expression levels of miRNAs in liver tissue received from control mice (L0) and compared them with the corresponding levels in liver tissue 12 hours after liver regeneration induced by 2/3 partial hepatectomy (L12). MicroRNA expression was investigated using microRNA profiling. Further qPCR analysis was used for validation of the differentially expressed microRNAs at an early stage of liver regeneration, induced by 2/3 partial hepatectomy. TargetScan and Gene Ontology (GO) analysis was performed in order to identify the possible miRNA target genes and their ontology, respectively. A subset of miRNAs were found to be differentially expressed during liver regeneration. Mmu-miR-21 and mmu-miR-30b* showed the higher levels of up-regulation in liver tissue from the hepatectomized mice at the end of the experiment (L12) compared to the sham operated mice (L0). Mmu-miR-21 up-regulation was further confirmed by qPCR. In situ hybridization (ISH) revealed that mmu-miR-21 exhibited the higher levels of expression at 12 hours post hepatectomy. On the contrary, mmu-miR-34c*, mmu-miR-144, mmu-miR-207, mmu-miR-207, mmu-miR-451, mmu-miR-582-3p and mmu-miR-290-5p exhibited <0.5 down-regulation in liver tissue after partial hepatectomy in L12 vs. L0 mice. Microarrays and qPCR results were in good agreement (Pearson correlation = 0.881). Our results provide important information regarding how microRNAs are deferentially expressed in murine liver tissue before and after partial hepatectomy. The early up-regulation of mmu-miR-21 during the process of liver regeneration suggests a regulatory role in liver regeneration in vivo.

Project description:Phosphorylation is well-known in regulating various biological processes. However, comprehensively phosphoproteomic profiling in the termination of liver regeneration (LR) is still missing. Here, we used TMT labeling coupled with phosphopeptides enrichment and 2D LC-MS/MS analysis to establish a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy. Altogether, 619 phosphorylation sites in 437 proteins were significantly up-regulated and 503 phosphorylation sites in 358 proteins were down-regulated. The differentially phosphorylated proteins were further classified according to their biological process, cellular components, molecular function and subcellular localization. KEGG pathway analysis showed that they mainly participate in metabolic pathways, DNA replication, tight junction and focal adhesion. Motif analysis of the identified phosphorylation sites has revealed a diverse array of consensus sequences, suggesting multiple kinase families such as MAPK, PKA/PKC, CaMK-II, CKII and CDK, may be involved in the termination of LR. Finally, several differentially phosphorylated proteins were validated by Co-immunoprecipitation and Western blot. Taken together, our data unravels the first comprehensive phosphoproteomic map in the termination of liver regeneration in mice, which greatly expands our knowledge in the complicate regulation of this process and provides new directions on the treatment of liver cancer using liver resection and donor liver transplantation. Biological significance: The novelty of this study is that we have established for the first time a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy, which represents the termination of liver regeneration. Altogether, 9,775 phosphorylation sites in 3,458 proteins were identified, among which 7,738 phosphorylation site in 2,971 proteins were quantified. KEGG pathway analysis demonstrates markedly metabolic reprograming in termination of LR, which is further validated by selected validation of several differentially phosphorylated metabolic enzymes such as PDHA, ACACA and FASN. The consistent high phosphorylation of PDHA in the first 4 days and its rapidly decreased phosphorylation at day 5 after PH might be a key signal in controlling the switch between glycolysis and oxidative

Dataset Information

Liver Transplantation With Two-stage Liver Resection in Unresectable Liver Cancer , Metastases or Emd-stage Liver Disease (LTLR-LC)

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