Dataset Information

Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival.

ABSTRACT:

Purpose

Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival.

Methods

We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations.

Results

High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival.

Conclusion

Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.

SUBMITTER: Schmidt A

PROVIDER: S-EPMC8484192 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatoblastoma (HB), hepatocellular carcinoma (HCC), and embryonal sarcoma (ES) are the three main types of liver tumors in children and adolescents. At present, epidemiological knowledge and predictors of these three liver tumor types in multi-ethnic populations are limited. This study aimed to outline the clinical features and construct a prognostic nomogram for these tumors, which can contribute to the prediction of dynamic overall survival probability during the follow-up period.MethodsA total of 1,122 patients liver tumor patients between 2000 to 2019 in Surveillance, Epidemiology, and End Results (SEER) database were enrolled for the current study, and separated into 824 HB, 219 HCC, and 79 ES according to the type of pathology. Independent prognostic factors were screened by univariate and multivariate Cox regression analysis, and a prognostic nomogram was constructed for overall survival. The accuracy and discriminative abilities of the nomogram were evaluated by concordance index as well as time-dependent receiver operating characteristic curves and calibration curves.ResultsRace (P=0.0016), surgery [hazard ratio (HR): 0.1021, P<0.001], and chemotherapy (HR: 0.27, P=0.00018) are independent prognostic factors for hepatoblastoma. Pathological tissue grading (P=0.00043), tumor node metastasis (TNM) staging (P=0.00061), and surgery are independent prognostic factors for hepatocellular carcinoma. Household income and surgery (HR: 0.1906, P<0.001) are independent prognostic factors for embryonal sarcoma. All of these prognostic factors are significantly associated with prognosis. A nomogram consisting of these variables was established, which showed a good concordance index (0.747, 0.775, and 0.828 in hepatoblastoma, hepatocellular carcinoma, and embryonal sarcoma, respectively). Also, the 5-year area under curve (AUC) of the nomogram were 0.738, 0.812, and 0.839 in hepatoblastoma, hepatocellular carcinoma, and embryonal sarcoma, respectively. In the calibration diagram, an optimal agreement between the nomogram-predicted and actual observed survival was evident.ConclusionsWe developed an effective prognostic nomogram for overall survival prediction in hepatoblastoma, hepatocellular carcinoma, and embryonal sarcoma in children and adolescent patients, which will further benefit the assessment of long-term outcomes.