Abstract
BackgroundIncreasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression. However, the role of INPP5F in hepatocellular carcinoma (HCC) and its underlying mechanisms is unclear.MethodsThe expression of INPP5F in HCC was analyzed in public databases and our clinical specimens. The biological functions of INPP5F were investigated in vitro and vivo. The molecular mechanism of INPP5F in regulating tumor growth were studied by transcriptome-sequencing analysis, mass spectrometry analysis, immunoprecipitation assay and immunofluorescence assay.ResultsHigh expression of INPP5F was found in HCC tissues and was associated with poor prognosis in HCC patients. Overexpression of INPP5F promoted HCC cell proliferation, and vice versa. Knockdown of INPP5F suppressed tumor growth in vivo. Results from transcriptome-sequencing analysis showed INPP5F not only regulated a series of cell cycle related genes expression (c-MYC and cyclin E1), but also promoted many aerobic glycolysis related genes expression. Further studies confirmed that INPP5F could enhance lactate production and glucose consumption in HCC cell. Mechanistically, INPP5F activated Notch signaling pathway and upregulated c-MYC and cyclin E1 in HCC via interacting with ASPH. Interestingly, INPP5F was commonly nuclear-located in cells of adjacent non-tumor tissues, while in HCC, cytoplasm-located was more common. LMB (nuclear export inhibitor) treatment restricted INPP5F in nucleus and was associated with inhibition of Notch signaling and cell proliferation. Sequence of nuclear localization signals (NLSs) and nuclear export signals (NESs) in INPP5F aminoacidic sequence were then identified. Alteration of the NLSs or NESs influenced the localization of INPP5F and the expression of its downstream molecules. Furthermore, we found INPP5F interacted with both exportin and importin through NESs and NLSs, respectively, but the interaction with exportin was stronger, leading to cytoplasmic localization of INPP5F in HCC.ConclusionThese findings indicate that INPP5F functions as an oncogene in HCC via a translocation mechanism and activating ASPH-mediated Notch signaling pathway. INPP5F may serve as a potential therapeutic target for HCC patients.
Highlights
Increasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression
Increased Inositol polyphosphate-5-phosphatase F (INPP5F) expression predicts poor clinical outcome in hepatocellular carcinoma (HCC) patients To investigate the potential role of INPP5F in human HCC pathogenesis, we firstly employed public databases to evaluate the expression of INPP5F in HCC
Data derived from Oncomine database showed that INPP5F is commonly upregulated in HCC tissues (Fig. 1A)
Summary
Increasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression. The role of INPP5F in hepatocellular carcinoma (HCC) and its underlying mechanisms is unclear. Hepatocellular carcinoma (HCC) is the sixth-most common cancer worldwide and the third-leading cause of cancer-related deaths [1]. Understanding the molecular mechanisms of HCC tumorigenesis and progression may help to improve the therapeutic outcomes for HCC patients. Inositol polyphosphate 5-phosphatases are a large family of enzymes, which are involved in regulating phosphorylation of phosphoinositide and associated with in a series of human pathologies such as the Lowe syndrome, the Joubert and MORM syndromes and several type of cancers [3,4,5,6,7]. Inositol polyphosphate 5-phosphatases contain 10 different isoenzymes and several splice variants in the human genome. While in chronic lymphocytic leukemia, overexpression of INPP5F is associated with chemoresistance [12, 13]
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