Abstract
Hepatoblastoma (HB) is the most common hepatic neoplasm in childhood and the therapeutic outcomes remain undesirable due to its recurrence and metastasis. Increasing evidence shows that dipeptidase 1 (DPEP1) has pivotal function in tumorigenesis in multiple tumors. However, the expression pattern, biological function, and underlying mechanism of DPEP1 in HB have not been reported. Here we showed that DPEP1 was significantly upregulated and was associated with poor prognosis in HB patients. In vitro and in vivo assays indicated that silencing DPEP1 significantly suppressed HB cell proliferation, migration, and invasion, while DPEP1 overexpression exhibited the opposite effect. In addition, we identified that DPEP1 was a direct target of microRNA-193a-5p (miR-193a-5p). Functional experiments demonstrated that overexpression of miR-193a-5p significantly inhibited cell proliferation and invasion of HB cells, while the inhibitory effect could be reversed by DPEP1 overexpression. Moreover, miR-193a-5p was decreased in HB tumor tissues and associated with a poor clinical prognosis. Mechanistically, our results indicated that the miR-193a-5p/DPEP1 axis participated to the progression of HB via regulating the PI3K/Akt/mTOR (phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin) signaling. In conclusion, our findings suggest that the miR-193a-5p /DPEP1 axis might be a good prognostic predictor and therapeutic target in HB.
Highlights
Hepatoblastoma (HB) is one of the most highly invasive malignant carcinoma in children, which accounts for ~50% of pediatric liver cancers[1,2]
dipeptidase 1 (DPEP1) is upregulated in HB tissues and high DPEP1 expression correlates with poor prognosis in HB patients To explore DPEP1 expression pattern in different cancers, we analyzed the expression levels of DPEP1 messenger RNAs (mRNAs) in various types of cancers using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEX) database
(see figure on previous page) Fig. 2 Knockdown of DPEP1 suppresses HB cell proliferation, migration, and invasion. a Western blot analysis of DPEP1 expression in normal liver cell lines (L02 and Chang Liver) and HB cell lines (HepG2 and HuH-6). b Western blot analysis of DPEP1 expression in HepG2 or HuH-6 cells transfected with negative control (NC), or different concentration of DPEP1 small interfering RNA (siRNA). c Confirmation of DPEP1 knockdown in HB cell lines by immunofluorescence. d Cell proliferation of HepG2 or HuH-6 cells transfected with NC or DPEP1 siRNA was analyzed by Cell Counting Kit-8 (CCK-8) assay. e Cell proliferation of HepG2 or Huh-6 cells transfected with NC or DPEP1 siRNA was analyzed by EDU staining assay
Summary
DPEP1 is upregulated in HB tissues and high DPEP1 expression correlates with poor prognosis in HB patients To explore DPEP1 expression pattern in different cancers, we analyzed the expression levels of DPEP1 mRNA in various types of cancers using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEX) database. Gene Set Enrichment Analysis (GSEA) suggested that high expression level of DPEP1 was correlated with poor prognosis (Fig. 1j). Univariate and multivariate Cox regression analysis revealed that vascular invasion, distant metastasis, recurrence, and high DPEP1 expression were independent risk factors for survival in children with HB (Fig. 1k and Table 2). Taken together, these findings suggest that DPEP1 might play a vital function in the tumorigenesis of HB. We demonstrated that upregulation of DPEP1 promoted HB cell proliferation, migration, and invasion in vitro (Supplementary Fig. S2). IHC staining of DPEP1 was inversely associated with the IHC scores of mTOR and Akt in HB tissues (Fig. 4g, h).To a
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