PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2

Chen, Qiongfeng; Jin, Jingguang; Guo, Wenyue; Tang, Zhimin; Luo, Yunfei; Ying, Ying; Lin, Hui; Luo, Zhijun

doi:10.3390/ijms23158798

Cited by 5 publications

(7 citation statements)

References 45 publications

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“…In molecular pathways, we observed that 10 cancer Hallmark pathways including glycolysis, hypoxia, IL2-STAT5-signaling, ILl6-JAK-STAT5 signaling, MTORC1 signaling, notch signaling, peroxisome, reactive oxygen species pathway, spermatogenesis, and unfolded protein response were actively enriched in Cluster1 subtype. More intriguingly, these pathways are reported to be associated with malignant transformation [35][36][37]. For example, the previous findings in melanoma revealed that unfolded protein response is positively linked with tumor development, size, and patient prognosis [38,39].…”

Section: Discussionmentioning

confidence: 96%

Deep learning classification of uveal melanoma based on histopathological images and identification of a novel indicator for prognosis of patients

et al. 2023

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Background Deep learning has been extensively used in digital histopathology. The purpose of this study was to test deep learning (DL) algorithms for predicting the vital status of whole-slide image (WSI) of uveal melanoma (UM). Methods We developed a deep learning model (Google-net) to predict the vital status of UM patients from histopathological images in TCGA-UVM cohort and validated it in an internal cohort. The histopathological DL features extracted from the model and then were applied to classify UM patients into two subtypes. The differences between two subtypes in clinical outcomes, tumor mutation, and microenvironment, and probability of drug therapeutic response were investigated further. Results We observed that the developed DL model can achieve a high accuracy of > = 90% for patches and WSIs prediction. Using 14 histopathological DL features, we successfully classified UM patients into Cluster1 and Cluster2 subtypes. Compared to Cluster2, patients in the Cluster1 subtype have a poor survival outcome, increased expression levels of immune-checkpoint genes, higher immune-infiltration of CD8 + T cell and CD4 + T cells, and more sensitivity to anti-PD-1 therapy. Besides, we established and verified prognostic histopathological DL-signature and gene-signature which outperformed the traditional clinical features. Finally, a well-performed nomogram combining the DL-signature and gene-signature was constructed to predict the mortality of UM patients. Conclusions Our findings suggest that DL model can accurately predict vital status in UM patents just using histopathological images. We found out two subgroups based on histopathological DL features, which may in favor of immunotherapy and chemotherapy. Finally, a well-performing nomogram that combines DL-signature and gene-signature was constructed to give a more straightforward and reliable prognosis for UM patients in treatment and management.

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Section: Discussionmentioning

confidence: 96%

Deep learning classification of uveal melanoma based on histopathological images and identification of a novel indicator for prognosis of patients

et al. 2023

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“…Coincidentally, a few studies have demonstrated PEBP4 has a tightly connection with PI3K/AKT pathway. On the one hand, PEBP4 was confirmed to be as a scaffold protein for AKT and mTOR to enhance their interaction and to promote the activation of AKT and mTOR [ 16 ]. On the other hand, PEBP4 was found to positively regulate the phosphorylation of AKT in various cancer models [ 8 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, several recent research have revealed the relationship between PEBP4 and the PI3K/AKT pathway. PEBP4 is found to act as a scaffold protein for AKT/mammalian target of rapamycin (mTOR) signal transduction, and PEBP4 knock-down disturbs the interaction between AKT and mTOR [ 16 ]. In lung cancer cells, overexpression of PEBP4 promotes the AKT and mTOR phosphorylation, while PEBP4 knock-down shows the opposite result [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Shi,

Huang,

et al. 2024

Cell. Mol. Life Sci.

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Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase β1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.

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“…Aberrant expression of PEBP4 has been investigated in several types of cancers [27,28]. PEBP4 overexpression exacerbates the malignant behavior of hepatocellular carcinoma cells through the combined action of mTORC1 and mTORC2 [29]. In breast cancer, PEBP4 promotes cell migration and invasion by regulating the PI3K/AKT signaling pathway, whereas AKT downregulates calmodulin expression, contributes to the epithelial mesenchymal transition (EMT), and reduces intercellular adhesion [11].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of the prognostic value of PEBP4 in pan-cancers

Wang

Luo

2023

Preprint

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Background PEBP4, a member of the protein family containing a binding motif for phosphatidylethanolamine, is involved in the development, progression, metastasis, and invasion of many cancers. However, a complete analysis of the predictive value of PEBP4 in diagnosis, prognosis, and immunotherapy has not been conducted. Therefore, this study aimed to evaluate the relationship between PEBP4 expression and pan-cancer prognosis, progression of multiple cancers, and immune cell infiltration into the tumor microenvironment.Methods In this study, transcriptomic data on PEBP4 expression in tumor tissues and normal or paraneoplastic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Based on various analysis tools such as " Gene set variation analysis (GSVA)" and "CIBERSORT," we comprehensively analyzed PEBP4 expression differences, clinical features, survival prognosis, immune-related characteristics, and potential interaction targets in various tumors.Results The analysis of the expression of PEBP4 in 33 human cancers showed that PEBP4 expression was downregulated in most cancers and correlated with the pathological stage, grade, and prognosis of multiple cancers, suggesting that PEBP4 may play a role in regulating tumorigenesis and progression in multiple cancers. In addition, PEBP4 gene expression is associated with the infiltration of several immune cells and immune-related genes, and is related to Tumor Mutation Burden (TMB)/ Microsatellite Instability (MSI) in various cancers. These results indicated that PEBP4 is involved in the immune response of tumor cells to immunotherapy and could be a potential target for immunotherapy in various cancers.Conclusion This study identified PEBP4 as a potential biomarker for the diagnosis and prognosis of multiple cancers. It is closely associated with the regulation of the tumor immune microenvironment, which lays the groundwork for further functional and mechanistic experiments.

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PEBP4 Directs the Malignant Behavior of Hepatocellular Carcinoma Cells via Regulating mTORC1 and mTORC2

Cited by 5 publications

References 45 publications

Deep learning classification of uveal melanoma based on histopathological images and identification of a novel indicator for prognosis of patients

Deep learning classification of uveal melanoma based on histopathological images and identification of a novel indicator for prognosis of patients

PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway

Comprehensive analysis of the prognostic value of PEBP4 in pan-cancers

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