Rab8 GTPase regulates Klotho-mediated inhibition of cell growth and progression by directly modulating its surface expression in human non-small cell lung cancer

Chen, Bin; Huang, Shuhong; Pisanic, Thomas R.; Stark, Alejandro; Tao, Yong; Cheng, Bei; Li, Yue; Wei, Yunyan; Zhao, Weihong; Wang, Tza‐Huei; Wu, Jianzhong

doi:10.1016/j.ebiom.2019.10.040

Cited by 17 publications

(16 citation statements)

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“…We also found that DEGs were signi cantly enriched in angiogenesis, which is a core hallmark of advanced cancers, especially in LUAD [18][19][20]. Besides, other signi cant GO terms, such as regulation of cell cycle and regulation of small GTPase mediated signal transduction were also related to cancer progression and chemoresistance reported in many studies [21,22]. As shown in Fig.…”

Section: Functional Enrichment Of Dmgssupporting

confidence: 59%

A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

Wang

Zhou

Xia

et al. 2020

Preprint

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Background DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. Method: The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated expression correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. Result We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47–3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19–3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. Conclusions The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.

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Section: Functional Enrichment Of Dmgssupporting

confidence: 59%

A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

Wang

Zhou

Xia

et al. 2020

Preprint

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“…We also found that DEGs were significantly enriched in angiogenesis, which is a core hallmark of advanced cancers, especially in LUAD [ 18 – 20 ]. Besides, other significant GO terms, such as regulation of cell cycle and regulation of small GTPase mediated signal transduction were also related to cancer progression and chemoresistance reported in many studies [ 21 , 22 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

A methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

et al. 2021

View full text Add to dashboard Cite

Background DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. Method The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. Result We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47–3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19–3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. Conclusions The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.

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“…KL is down-regulated in lung cancer cells and tissues and even more so in chemotherapy-resistant lung cancer ( Chen et al, 2012 , 2016; Chen B. et al, 2018 ). KL inhibits lung cancer cell proliferation, growth, invasiveness, and migration and fosters apoptosis ( Chen et al, 2010 , 2012 , 2016 , 2019 ; Wang X. et al, 2011 ; Wang et al, 2013 ), effects, at least in part, dependent on IGF-1R/AKT ( Chen et al, 2010 ; Wang et al, 2013 ) and Wnt3a/β-catenin signaling ( Chen et al, 2012 , 2019 ) and on reduced interleukin 6 (IL-6) and IL-8 production ( Chen B. et al, 2018 ). MiR-10b lowers, Ras-related GTPase Ras8 up-regulates KL expression in non–small-cell lung cancer cells ( Huang et al, 2015 ).…”

Section: The Role Of αKlotho In Cancermentioning

confidence: 99%

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.

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Rab8 GTPase regulates Klotho-mediated inhibition of cell growth and progression by directly modulating its surface expression in human non-small cell lung cancer

Cited by 17 publications

References 47 publications

A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

A Methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

A methylation-based nomogram for predicting survival in patients with lung adenocarcinoma

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

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