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The protein kinase activity of NME7 activates one-carbon metabolism through positively regulating wnt/β-catenin signaling

ABSTRACT: Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/β-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the molecular mechanisms linked to hyperactivation of Wnt/β-catenin signaling and the strategy for targeting this pathway in HCC are incompletely understood. In this study, a screen of the potential kinases regulating Wnt/β-catenin signaling revealed that NME7 is a positive regulator of this pathway. NME7 was upregulated in HCC, and its expression was positively correlated with the clinical features of patients with HCC. Knockdown of NME7 inhibited the growth and tumorigenesis of HCC cells, while overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model of HCC established by hydrodynamic injection and promote the growth of tumor-derived organoids. Mechanistically, GSK3β was identified as the substrate of NME7, and their interaction was strengthened upon Wnt3a stimulation. NME7 exerts protein kinase activity and phosphorylates serine 9 of GSK3β in vitro and in vivo. Through further study, MTHFD2, the key enzyme in one-carbon metabolism, was found to be the target gene of β-catenin and to mediate the biological functions of NME7. Moreover, mouse tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to the MTHFD2 inhibitor LY345899. Additionally, the expression levels of NME7, β-catenin and MTHFD2 correlated well in HCC, and higher expression of all three predicted poor prognosis. Taken together, the results of this study emphasize the crucial roles of NME7 protein kinase activity in activating one-carbon metabolism and Wnt/β-catenin signaling, suggesting that NME7 and MTHFD2 are therapeutic targets for HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165985 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:Background & Aims: Extracellular vesicles (EVs) play a pivotal role in connecting tumor cells and their local and distant microenvironment. Here, we aimed to understand the role and molecular basis of patient-derived EVs in modulating cancer stemness and tumorigenesis in the context of hepatocellular carcinoma (HCC). Methods: EVs were isolated, quantified and characterized from patients’ sera. EVs were tested vigorously, both in vitro and in vivo, by various functional assays. Proteomic analysis was performed to identify the functional components of EVs. The expression level of polymeric immunoglobulin receptor (pIgR) in circulating EVs, tumor and non-tumorous tissues of HCC patients was determined by ELISA, immunoblotting, immunohistochemistry and quantitative PCR. The functional role and underlying mechanism of EVs with an enhanced pIgR expression was elucidated. Blockage of EV-pIgR with neutralizing antibody was performed in nude mice implanted with patient-derived tumor xenograft (PDTX). Results: Circulating EVs of late-stage HCC (L-HCC) patient had significantly elevated pIgR expression when compared to the EVs released by control individuals. The augmenting effect of L-HCC patient in cancer stemness and tumorigenesis was hindered by anti-pIgR antibody. EVs enriched with pIgR consistently promoted cancer stemness and cancerous phenotypes in the recipient cells. Mechanistically, EV-pIgR-induced cancer aggressiveness was abrogated by Akt and β-catenin inhibitors, ascertaining the role of EV-pIgR through the activation of PDK1/Akt/GSK3β/β-catenin signaling axis. Furthermore, anti-pIgR neutralizing antibody attenuated the tumor growth in mice implanted with PDTX. Conclusion: The study illustrates an unrevealed role of EV-pIgR in regulating cancer stemness and aggressiveness, in which EV-pIgR activates PDK1/Akt/GSK3β/β-catenin signaling cascades. The blockage of intercellular communications mediated by EV-pIgR in the tumor microenvironment may provide a new therapeutic strategy for cancer patients.

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The protein kinase activity of NME7 activates one-carbon metabolism through positively regulating wnt/β-catenin signaling

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