Hepatocellular
carcinoma (HCC) causes more than half a million
annual deaths worldwide. Understanding the mechanisms contributing
to HCC development is highly desirable for improved surveillance,
diagnosis, and treatment. Liver tissue metabolomics has the potential
to reflect the physiological changes behind HCC development. Also,
it allows identification of biomarker candidates for future evaluation
in biofluids and investigation of racial disparities in HCC. Tumor
and nontumor tissues from 40 patients were analyzed by both gas chromatography–mass
spectrometry (GC–MS) and liquid chromatography–mass
spectrometry (LC–MS) platforms to increase the metabolome coverage.
The levels of the metabolites extracted from solid liver tissue of
the HCC area and adjacent non-HCC area were compared. Among the analytes
detected by GC–MS and LC–MS with significant alterations,
18 were selected based on biological relevance and confirmed metabolite
identification. These metabolites belong to TCA cycle, glycolysis,
purines, and lipid metabolism and have been previously reported in
liver metabolomic studies where high correlation with HCC progression
is implied. We demonstrated that metabolites related to HCC pathogenesis
can be identified through liver tissue metabolomic analysis. Additionally,
this study has enabled us to identify race-specific metabolites associated
with HCC.
Testicular germ cell tumors (TGCTs) are a diverse group of neoplasms that are derived from dysfunctional fetal germ cells and can also present in extragonadal sites. The genetic drivers underlying malignant transformation of TGCTs have not been fully elucidated so far. The aim of the present study is to clarify the functional role and regulatory mechanism of miR‐196a‐5p in TGCTs. We demonstrated that miR‐196a‐5p was downregulated in TGCTs. It can inhibit the proliferation, migration, and invasion of testicular tumor cell lines including NT‐2 and NCCIT through targeting the
NR6A1
gene, which we proved its role in promotion of cell proliferation and repression of cellular junction and aggregation. Mechanistically, NR6A1 inhibited E‐cadherin through binding with DR0 sites in the
CDH1
gene promoter and recruiting methyltransferases Dnmt1. Further, NR6A1 promoted neuronal marker protein MAP2 expression in RA‐induced neurodifferentiation of NT‐2 cells and testicular tumor xenografts. Clinical histopathologically, NR6A1 was positively correlated with MAP2, and negatively correlated with E‐cadherin in TGCTs. These findings revealed that the miR‐196a‐5p represses cell proliferation, migration, invasion, and tumor neurogenesis by inhibition of NR6A1/E‐cadherin signaling axis, which may be a potential target for diagnosis and therapy of TGCTs.
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