Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation

Grąt, Michał; Krawczyk, Marek; Wronka, Karolina Maria; Stypułkowski, Jan; Lewandowski, Zbigniew; Wasilewicz, Michał; Krawczyk, Piotr; Grąt, Karolina; Patkowski, Waldemar; Zieniewicz, Krzysztof

doi:10.1038/s41598-018-27319-y

Cited by 43 publications

(42 citation statements)

References 36 publications

(38 reference statements)

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“…Although surgery, transcatheter arterial chemoembolization (TACE), radiofrequency ablation, radiotherapy and other therapeutic approaches can control the progress of HCC, generally speaking, HCC is still under exploration in the areas of molecular typing, molecular diagnosis and gene target selection. Although CDH 21 , LDH 22 , NCOR1 23 and other mutant genes are new biomarkers in HCC subtype classification 24,25 , identification of gene mutations that affect recurrence is complex but will have clinical significance. Meanwhile, various probability theories and linear algebra algorithms can be used for comprehensive analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Shen

Liang

Zou

et al. 2020

Sci Rep

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Hepatocellular carcinoma (HCC) is a common malignant tumor in China. In the present study, we aimed to construct and verify a prediction model of recurrence in HCC patients using databases (TCGA, AMC and Inserm) and machine learning methods and obtain the gene signature that could predict early relapse of HCC. Statistical methods, such as feature selection, survival analysis and Chi-Square test in R software, were used to analyze and select mutant genes related to disease free survival (DFS), race and vascular invasion. In addition, whole-exome sequencing was performed on 10 HCC patients recruited from our center, and the sequencing results were compared with the databases. Using the databases and machine learning methods, the prediction model of recurrence was constructed and optimized, and the selected mutant genes were verified in the test group. The accuracy of prediction was 74.19%. Moreover, these 10 patients from our center were used to verify these mutant genes and the prediction model, and a success rate of 80% was achieved. Collectively, we discovered recurrence-related genes and established recurrence prediction model of recurrence for HCC patients, which could provide significant guidance for clinical prediction of recurrence. Hepatocellular carcinoma (HCC) is a common malignant tumor in China, which ranks the third in morbidity and the second in mortality. Its morbidity is usually associated with specific risk factors, including infections with HBV and HCV, high alcohol intake, obesity and consumption of aflatoxin-containing food 1. With the development of the second-generation sequencing techniques increasing research on HCC has been conducted on the molecular level. In 2014, Totoki et al. 2 have reported the whole-genome sequencing of 608 HCC patients from Asia and Europe. In 2015, Schulze et al. 3 have reported the whole-genome sequencing of 243 HCC patients from Europe and America. In 2016, Fujimoto et al. 4 have reported the whole-genome sequencing of 300 HCC patients from Japan. The molecular blueprint of HCC including somatic mutation, mRNA expression, methylation and miRNA regulation has been gradually outlined, which could be used for the diagnosis, treatment, and prediction of recurrence and survival of liver cancer patients. In 2017, TCGA working group 5 has systematically analyzed the sequencing results of the whole exome of more than 360 HCC patients in TCGA database and compared these data with other published HCC sequencing samples. Various statistical methods, related classification and clustering algorithms of machine learning have been used. TERT, TP53, CTNNB1, AXIN1, ARID1A, ARID2, RB1, ALB, APOB, PTEN, CDKN2A, DOCK2 6-15 and other somatic cells with significantly mutant genes (SMGs) and driver mutation have been identified. These findings have been rapidly applied as potential therapeutic targets and prognostic indicators in clinical practice. However, the high cost of whole-exome sequencing and whole-genome sequencing limits its use in clinical practice. Actually, patients often ...

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Section: Discussionmentioning

confidence: 99%

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Shen

Liang

Zou

et al. 2020

Sci Rep

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“…Upregulation of HIF and NETs formation are major responses to vascular injury during surgery, and tumor cells exposed to acute, perioperative hypoxia followed by normoxia (ischemia/reperfusion injury [I/R injury]) show increased proliferation . Also, murine models of CRC clearly demonstrated that the I/R injury accelerated the outgrowth of liver metastases …”

Section: Hypoxiamentioning

confidence: 99%

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Raskov

Orhan

Salanti

et al. 2020

Intl Journal of Cancer

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The physiological stress response to surgery promotes wound healing and functional recovery and includes the activation of neural, inflammatory and proangiogenic signaling pathways. Paradoxically, the same pathways also promote metastatic spread and growth of residual cancer. Human and animal studies show that cancer surgery can increase survival, migration and proliferation of residual tumor cells. To secure the survival and growth of disseminated tumor cells, the formation of premetastatic niches in target organs involves a complex interplay between microenvironment, immune system, circulating tumor cells, as well as chemical mediators and exosomes secreted by the primary tumor. This review describes the current understanding of the early mechanisms of dissemination, as well as how surgery may facilitate disease progression.

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“…Ischemia-reperfusion (I/R) injury is an unavoidable consequence after liver transplantation especially at the early phase. Several lines of clinical and experimental studies have pointed out that I/R injury is a signi cant risk factor of HCC recurrence after liver transplantation (6)(7)(8). Our previous research studies have also demonstrated a positive correlation between early phase hepatic injury and late phase HCC recurrence after liver transplantation.…”

Section: Introductionmentioning

confidence: 56%

“…Despite of employing selection strategies to minimize the potential high-risk HCC patients, deciphering its underlying risk factors becomes a critical task in developing effective strategies to predict and prevent HCC recurrence (34,35). Increasing evidences from clinical and experimental research have demonstrated a positive correlation between post-transplant early phase I/R injury and late phase tumor recurrence (7,36,37). Studies have pointed out that elevated systemic and regional in ammatory responses during the early phase can increase the likelihood of late phase tumor recurrence (7,10,37,38).…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

Yeung

Lam

et al. 2020

Preprint

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BackgroundAn inevitable hepatic injury at the early phase after liver transplantation vitally affects the late phase hepatocellular carcinoma (HCC) recurrence. However, their linkage and underlying risk factors of HCC recurrence are unclear. This study aimed to clarify the clinical impact and functional roles of glutathione S-transferase A2 (GSTA2) in affecting HCC recurrence after liver transplantation.MethodsExpression significance and prognostic value of hepatic and circulating GSTA2 in HCC recipients were examined. The polymorphism of GSTA2 transcript was analysed by Sanger sequencing. The functions and molecular mechanisms of GSTA2 in the proliferation and metastasis of HCC were characterized by molecular, cellular and animal experiments. ResultsThe GSTA2 expression was significantly correlated with the early phase hepatic and systemic injury and reactive oxygen species (ROS) level after liver transplantation. Importantly, the level of the early phase circulating GSTA2 protein was a significant predictor of HCC recurrence and survival of HCC recipients. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. The GSTA2 expression was positively correlated with the aggressiveness of HCCs. Overexpression of GSTA2, by endogenous or exogenous approaches, could enhance the proliferation and invasion of HCCs through activating epithelial-mesenchymal-transition promoting proteins. Targeted inhibition of GSTA2 remarkably suppressed the proliferation and metastasis of HCCs. Increased level of GSTA2 could compensate the H2O2-induced ROS stress and therefore protect the HCC cells from damage. Alteration of GSTA2 expression in HCC cells could influence the activation of ROS-associated JNK and AKT signaling pathways and the expression of ROS-associated genes in responding to the H2O2 condition. ConclusionsOur research discovered GSTA2 to be the significant risk factor of HCC recurrence via providing a favorable ROS environment for HCC to survival and progress. This study presents a novel functional biomarker for combating HCC recurrence after liver transplantation.

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Ischemia-reperfusion injury and the risk of hepatocellular carcinoma recurrence after deceased donor liver transplantation

Cited by 43 publications

References 36 publications

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Premetastatic niches, exosomes and circulating tumor cells: Early mechanisms of tumor dissemination and the relation to surgery

Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

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