EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis

Choi, Hyun Ho; Zou, Shaomin; Wu, Jian‐Lin; Wang, Huashe; Phan, Liem; Li, Kai; Zhang, Peng; Chen, Daici; Liu, Qingxin; Qin, Baifu; Nguyen, Thu Anh; Yeung, Sai‐Ching Jim; Fang, Lishan; Lee, Mong Hong

doi:10.1002/advs.202000681

Cited by 27 publications

(15 citation statements)

References 49 publications

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“…After incubation in 70% ethanol overnight, the samples were embedded in paraffin. Paraffin-embedded sections were stained with hematoxylin and eosin according to standard procedures [24,25] and a certified pathologist counted the mitotic cells under high-power fields (40 × magnification).…”

Section: Histologic Staining and Mitosis Countmentioning

confidence: 99%

Impact of diabetes on promoting the growth of breast cancer

Chou

Choi

Huang

et al. 2021

Cancer Communications

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Background Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well‐established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. Methods We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+) mice with MMTV‐ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. Results Treatment with metformin/rosiglitazone in MMTV‐ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti‐insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13C pyruvate‐to‐lactate reaction. The tumor cells from MMTV‐ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. Conclusions MMTV‐ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti‐insulin resistance therapy.

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Section: Histologic Staining and Mitosis Countmentioning

confidence: 99%

Impact of diabetes on promoting the growth of breast cancer

Chou

Choi

Huang

et al. 2021

Cancer Communications

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“…FOXO4 is a suppressor in cancers. Nevertheless, recent studies have shown that FOXO4 is also a tumor promoter ( Li et al, 2016 ; Choi et al, 2020 ; Wang et al, 2021 ); for example, the upregulated FOXO4 could inhibit the invasive and metastatic characteristics of cholangiocarcinoma cells by regulating focal adhesion kinase and F-actin dynamics. FOXO4 upregulation was in response to chemotherapeutic treatment in B-cell lymphoma, which is associated with a poor prognosis ( Lee et al, 2009 ; Ryu et al, 2017 ; Jiang et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis

Sun

Wang

et al. 2021

Front. Cell Dev. Biol.

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Objective: Adenomatous polyposis coli 2 (APC2) is a colorectal cancer (CRC) tumor-suppressor gene. The progression of several kinds of cancer is closely associated with Forkhead box O4 (FOXO4). However, the function of FOXO4 in CRC is unclear. This study focused on the role of FOXO4 and the relationship between FOXO4 and APC2 in CRC migration and metastasis.Methods: The expressions of FOXO4, APC2, and p(S37)-β-catenin were detected in CRC tissues by immunohistochemistry, and their correlation was analyzed using the Spearman coefficient. Chromatin immunoprecipitation was used to test whether FOXO4 binds and regulates APC2 as a transcription factor. Either FOXO4 overexpression or APC2 knockdown was performed in CRC cell lines. The roles of FOXO4 and APC2 were investigated in CRC migration and metastasis.Results: FOXO4 was downregulated in CRC tissues compared with normal tissues and positively correlated with APC2 and p(S37)-β-catenin. FOXO4 could combine the promoter region of APC2 to upregulate its expression and increase the phosphorylated degradation of β-catenin. Stemness genes (CD133, ABCG1, and SOX2) were inhibited by FOXO4 overexpression in SW620 and HCT116 cell lines. Overexpressed FOXO4 suppressed epithelial–mesenchymal transition and the migration of CRC cell lines and metastasis of HCT116 in both the spleen and liver of nude mice, which was reversed by APC2 knockdown.Conclusion: This research demonstrates that overexpressed FOXO4 inhibits the migration and metastasis of CRC cells by enhancing the APC2/β-catenin axis, suggesting that FOXO4 is a potential therapeutic target of CRC.

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“…The metabolomics progress was performed based on a standard method as described previously [ 15 , 16 ]. In short, standards were diluted at a concentration of 5.0 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

High‐Fat Diet‐Induced Fatty Liver Is Associated with Immunosuppressive Response during Sepsis in Mice

Wang

Cen

Liu

et al. 2021

Oxidative Medicine and Cellular Longevity

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High-fat diet-induced fatty liver is an indolent and chronic disease accompanied by immune dysfunction and metabolic disturbances involving numerous biological pathways. This study investigated how this abnormal metabolic disorder influences sepsis in mice. Mice were fed with normal chow (NC) or high-fat diet (HFD), and palmitic acid (PA) was used to treat hepatocytes to mimic fat accumulation in vitro. Lipopolysaccharide (LPS) was used to induce sepsis and related immune responses. Mice fed on a high-fat diet displayed higher mortality and more severe liver damage but compromised immunoreaction. The supernatant from PA-treated primary hepatocytes markedly diminished the inflammatory cytokine expression of macrophages after LPS stimulation, which showed a state of immunosuppression. Metabolomics analysis indicated the level of many key metabolites with possible roles in immunoreaction was altered in the HFD and PA groups compared with corresponding controls; specifically, β-hydroxybutyric acid (BHB) showed an immunosuppressive effect on Raw264.7 cells during the LPS stimulation. Transcriptomic analysis suggested that several differential signaling pathways may be associated with the alteration of immune function between the NC and HFD groups, as well as in the in vitro model. Our study suggests that the consumption of HFD may alter the hepatic metabolic profile, and that certain metabolites may remold the immune system to immunosuppressive state in the context of sepsis.

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EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis

Cited by 27 publications

References 49 publications

Impact of diabetes on promoting the growth of breast cancer

Impact of diabetes on promoting the growth of breast cancer

FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis

High‐Fat Diet‐Induced Fatty Liver Is Associated with Immunosuppressive Response during Sepsis in Mice

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