Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis

Oaks, Zachary; Patel, A.; Huang, Nick; Choudhary, G.; Winans, Thomas; Faludi, T.; Krakkó, Dániel; Duarte, Maria F.; Lewis, Jacqueline S.; Beckford, Miguel; Blair, Sampson Lee; Kelly, Ryan L.; Landas, Steve K.; Middleton, Frank A.; Asara, John M.; Chung, Sookja K.; Fernández, Marcel; Bánki, Katalin; Perl, András

doi:10.1038/s42255-022-00711-9

Cited by 23 publications

(8 citation statements)

References 62 publications

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“…Secondly, risk factors from common laboratory tests in hospitals were fully analyzed in this study. Transaldolase and aldolase B regulated the reprogramming of pentose phosphate pathway to have a deep effect on hepatocellular carcinogenesis (35)(36)(37). Thus, the novel metabolic markers should be comprehensively evaluated as risk variables that might improve predictive performance.…”

Section: Discussionmentioning

confidence: 99%

The hepatocellular carcinoma risk in patients with HBV-related cirrhosis: a competing risk nomogram based on a 4-year retrospective cohort study

Guo,

Li,

Zhao

et al. 2024

Front. Oncol.

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ObjectiveThe study aimed to build and validate a competitive risk nomogram to predict the cumulative incidence of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV)-related cirrhosis.MethodsA total of 1401 HBV-related cirrhosis patients were retrospectively enrolled from January 1, 2011 to December 31, 2014. Application of 20 times imputation dealt with missing data using multiple imputation by chained equations (MICE). The patients were randomly divided into a training set (n = 1017) and a validation set (n = 384) at a ratio of 3:1. A prediction study was carried out using a competing risk model, where the event of interest was HCC and the competing events were death and liver transplantation, and subdistribution hazard ratios (sHRs) with 95% CIs were reported. The multivariate competing risk model was constructed and validated.ResultsThere was a negligible difference between the original database and the 20 imputed datasets. At the end of follow-up, the median follow-up time was 69.9 months (interquartile range: 43.8–86.6). There were 31.5% (442/1401) of the patients who developed HCC, with a 5-year cumulative incidence of 22.9 (95%CI, 20.8%–25.2%). The univariate and multivariate competing risk regression and construction of the nomogram were performed in 20 imputed training datasets. Age, sex, antiviral therapy history, hepatitis B e antigen, alcohol drinking history, and alpha-fetoprotein levels were included in the nomogram. The area under receiver operating characteristic curve values at 12, 24, 36, 60, and 96 months were 0.68, 0.69, 0.70, 0.68, and 0.80, and the Brier scores were 0.30, 0.25, 0.23, 0.21, and 0.20 in the validation set. According to the cumulative incidence function, the nomogram effectively screened out high-risk HCC patients from low-risk patients in the presence of competing events (Fine–Gray test p < 0.001).ConclusionThe competitive risk nomogram was allowed to be used for predicting HCC risk in individual patients with liver cirrhosis, taking into account both the association between risk factors and HCC and the modifying effect of competition events on this association.

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Section: Discussionmentioning

confidence: 99%

The hepatocellular carcinoma risk in patients with HBV-related cirrhosis: a competing risk nomogram based on a 4-year retrospective cohort study

Guo,

Li,

Zhao

et al. 2024

Front. Oncol.

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“…Smads are downstream targets of the TGF-β signaling pathway, TGF-β1/Smad3 signaling has been demonstrated to promote hepatic gluconeogenesis [ 45 ]. ZMIZ2 enhances the transcriptional activity of androgen receptor(AR) [ 46 ], which is highly expressed in HCC and is associated with increased tumor recurrence and decreased overall survival [ 47 – 50 ]. These findings suggest that ZMIZ2 plays an important role in HCC development.…”

Section: Discussionmentioning

confidence: 99%

ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/β-catenin pathway

Ding,

Ning,

Kang

et al. 2024

Exp Hematol Oncol

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Background Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high lethality rate. ZMIZ2 is a transcriptional co-activator implicated in various human diseases. However, the role and molecular mechanism of ZMIZ2 in HCC remains to be elucidated. Methods The expression and prognostic value of ZMIZ2 in HCC was excavated from public databases and explored by bioinformatic analysis. Then the expression of ZMIZ2 and related genes was further validated by quantitative RT-PCR, western blotting, and immunohistochemistry. Loss and gain-of-function experiments were performed in vitro and in vivo to investigate the function of ZMIZ2 in HCC. In addition, transcriptome sequencing and immunoprecipitation was conducted to explore the potential molecular mechanisms of ZMIZ2. Results ZMIZ2 was highly expressed in HCC and associated with poor prognosis. Silencing ZMIZ2 significantly inhibited HCC cell proliferation, cell cycle process, migration, and invasion in vitro, and also inhibited the progression of HCC in vivo. Additionally, ZMIZ2 expression was correlated with immune cell infiltration in HCC samples. Somatic mutation analysis showed that ZMIZ2 and TP53 mutations jointly affected the progression of HCC. Mechanistically, ZMIZ2 interacted with LEF1 to regulate malignant progression of HCC by activating the Wnt/β-catenin pathway. Conclusion ZMIZ2 was overexpressed in HCC and associated with poor prognosis. The overexpression of ZMIZ2 was corelated with malignant phenotype, and it facilitated HCC progression via LEF1-mediated activation of the Wnt/β-catenin pathway. Furthermore, ZMIZ2 could be served as a prognostic biomarker and a new therapeutic target for HCC.

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“…A plausible hypothesis is that rapamycin modifies the metabolic and protein synthesis of cancer cells to a greater extent than Tregs' function (119)(120)(121). It's also important to remember that rapamycin-mediated mTOR blockage may be particularly effective in certain forms of cancer that are preceded by autoimmune inflammation, such as mTORdependent cirrhosis that precedes hepatocarcinogenesis in patients with transaldolase deficiency (122,123).…”

Section: Pi3k-akt-mtorc1 Axismentioning

confidence: 99%

Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?

Liu,

Zhang,

Zhang

et al. 2024

Front. Immunol.

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Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.

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Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis

Cited by 23 publications

References 62 publications

The hepatocellular carcinoma risk in patients with HBV-related cirrhosis: a competing risk nomogram based on a 4-year retrospective cohort study

The hepatocellular carcinoma risk in patients with HBV-related cirrhosis: a competing risk nomogram based on a 4-year retrospective cohort study

ZMIZ2 facilitates hepatocellular carcinoma progression via LEF1 mediated activation of Wnt/β-catenin pathway

Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?

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