High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma

Song, Shushu; Ying, Jia-Fu; Zhang, You‐Ni; Pan, Hongying; He, Xianglei; Hu, Zhiming; Wang, Hui‐Ju; Dou, Xiaobing; Mou, Xiaozhou

doi:10.3892/ol.2020.11430

Cited by 16 publications

(23 citation statements)

References 57 publications

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“…Additionally, Lallemand et al (32) demonstrated that overexpression of FOXO6 activated breast cancer cell proliferation and inhibited the endogenous expression of FOXO6 to induce accumulation of cells in the G 0 / G 1 phase but did not cause apoptosis. Moreover, FOXO3 promotes cell proliferation and inhibits apoptosis in HCC cells, suggesting an association with poor prognosis (20,33). Furthermore, the upregulation of miR-421 expression elicits carcinogenic effects in nasopharyngeal carcinoma by inhibiting FOXO4 expression, resulting in the inhibition of cell proliferation and resistance to apoptosis (34).…”

Section: Roles Of Foxo Proteins In Cancer Cell Proliferationmentioning

confidence: 99%

“…Lu et al (112) reported that FOXO3 was significantly activated in pathological specimens from patients with HCC. In addition, FOXO3 activated positive feedback pathways, such as the PI3K/AKT and mTOR complex 2 signaling pathways, in the hepatocytes from a transgenic mouse model with high FOXO3 expression, thereby promoting oxidative stress and DNA damage to regulate ROS (20). Alternatively, FOXO3 can activate the pentose phosphate pathway to form ROS-eliminating systems.…”

Section: Foxo3 In Hccmentioning

confidence: 99%

“…Further, FOXO3 expression is significantly associated with metastasis, TNM stage, Edmondson grade, AFP level, overall survival, and small vessel invasion. Moreover, high FOXO3 expression predicts poor prognosis in patients with HCC, indicating its potential as a therapeutic target for HCC (20,21). FOXO6 is highly expressed in HCC cells compared with normal human hepatocytes, and FOXO6 knockdown inhibits the proliferation and invasion and induced apoptosis of HCC cells (15,41).…”

Section: Prospects Foxo Proteins As Hcc Tumor Markersmentioning

confidence: 99%

“…Both FOXO3 and FOXO4 are widely distributed in tissues, including those of lymph nodes, liver, kidney, heart, and skeletal muscles (16,17), whereas FOXO6 is prominently expressed in the brain and nervous system (18). Previous studies have shown that FOXO subtypes exhibit differential expression in primary tumor tissues and cells (19)(20)(21). Thus, these proteins may function as tumor suppressors or carcinogenic factors, affecting tumor cell function.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, these proteins may function as tumor suppressors or carcinogenic factors, affecting tumor cell function. For example, patients with primary gastric adenocarcinoma exhibit low expression of FOXO3 (19), which is highly expressed in patients with HCC (20,21). Moreover, the FIGURE 1 | Patterns of post-translational modification of FOXO proteins via phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

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Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

et al. 2021

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Hepatocellular carcinoma (HCC), the most common type of malignant tumor of the digestive system, is associated with high morbidity and mortality. The main treatment for HCC is surgical resection. Advanced disease, recurrence, and metastasis are the main factors affecting prognosis. Chemotherapy and radiotherapy are not sufficiently efficacious for the treatment of primary and metastatic HCC; therefore, optimizing targeted therapy is essential for improving outcomes. Forkhead box O (FOXO) proteins are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals, thereby inducing the specific expression of downstream signal factors and regulation of the cell cycle, senescence, apoptosis, oxidative stress, HCC development, and chemotherapy sensitivity. Accordingly, FOXO proteins are considered multifunctional targets of cancer treatment. The current review discusses the roles of FOXO proteins, particularly FOXO1, FOXO3, FOXO4, and FOXO6, in HCC and establishes a theoretical basis for the potential targeted therapy of HCC.

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Section: Roles Of Foxo Proteins In Cancer Cell Proliferationmentioning

confidence: 99%

Section: Foxo3 In Hccmentioning

confidence: 99%

Section: Prospects Foxo Proteins As Hcc Tumor Markersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

et al. 2021

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Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma

Jagosky

Anderson²,

Symanowski

et al. 2022

Cancer Medicine

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Purpose Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. Experimental Design Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. Results Thirty‐eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow‐up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%–29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease‐specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). Conclusions This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.

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Targeting the PI3K/pAKT/mTOR/NF‐κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk

Abdel‐Bakky,

Mohammed,

Mahmoud

et al. 2024

Environmental Toxicology

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Liver malignancy is well recognized as a prominent health concern, with numerous treatment options available. Natural products are considered a renewable source, providing inspiring chemical moieties that could be used for cancer treatment. Suaeda vermiculata Forssk has traditionally been employed for management of hepatic conditions, including liver inflammation, and liver cirrhosis, as well as to improve general liver function. The findings of our earlier study demonstrated encouraging in vivo hepatoprotective benefits against liver injury generated by paracetamol and carbon tetrachloride. Additionally, Suaeda vermiculata Forssk exhibited cytotoxic activities in vitro against Hep‐G2 cell lines and cell lines resistant to doxorubicin. The present investigation aimed to examine the potential in vivo hepatoprotective efficacy of Suaeda vermiculata Forssk extract (SVE) against hepatocellular carcinoma induced by diethylnitrosamine (DENA) in rats. The potential involvement of the PI3K/AKT/mTOR/NF‐κB pathway was addressed. Sixty adult male albino rats were allocated into five groups randomly (n = 10). First group received a buffer, whereas second group received SVE only, third group received DENA only, and fourth and fifth groups received high and low doses of SVE, respectively, in the presence of DENA. Liver toxicity and tumor markers (HGFR, p‐AKT, PI3K, mTOR, NF‐κB, FOXO3a), apoptosis markers, and histopathological changes were analyzed. The current results demonstrated that SVE inhibited PI3K/AKT/mTOR/NF‐κB pathway as well as increased expression of apoptotic parameters and FOXO3a levels, which were deteriorated by DENA treatment. Furthermore, SVE improved liver toxicity markers and histopathological changes induced by DENA administration. This study provided evidence for the conventional hepatoprotective properties attributed to SV and investigated the underlying mechanism by which its extract, SVE, could potentially serve as a novel option for hepatocellular carcinoma (HCC) treatment derived from a natural source.

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High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma

Cited by 16 publications

References 57 publications

Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

Role of Forkhead Box O Proteins in Hepatocellular Carcinoma Biology and Progression (Review)

Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma

Targeting the PI3K/pAKT/mTOR/NF‐κB/FOXO3a signaling pathway for suppressing the development of hepatocellular carcinoma in rats: Role of the natural remedic Suaeda vermiculata forssk

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