Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Pastore, Mirella; Lori, Giulia; Gentilini, Alessandra; Taddei, Maria Letizia; G, Di Maira; Campani, Claudia; Recalcati, Stefania; Invernizzi, Pietro; Marra, Fabio; Raggi, Chiara

doi:10.3390/cells9030596

Cited by 17 publications

(23 citation statements)

References 206 publications

(285 reference statements)

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“…67 Likewise, CCA also demonstrated reprogrammed metabolism, including classical Warburg effects with glucose dependency, increase in oxidative phosphorylation capacity, enhanced lipid uptake and oxidation with possible dependence on sphingosine, and upregulation of glutaminolysis. 91 Historically, this is thought to be dictated by cell-intrinsic factors, such as genomic alteration and aberrate cell signaling. However, emerging studies have identified the importance of TME, parental tissue architecture, and systemic metabolism as essential contributors to tumor metabolism.…”

Section: Reprogrammed Tumor Metabolismmentioning

confidence: 99%

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations

Osataphan

Mahankasuwan²,

Saengboonmee

2021

J Hepato Biliary Pancreat

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Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelium, and its incidence is increasing globally. Numerous factors are reported associated with an increased risk of CCA and vary among populations across different areas. Obesity is a major, worldwide public health problem that leads to several complications and is associated with increased cancer risk. Although several epidemiological studies have shown that obesity is likely associated with the increased risk of CCA, this association might be limited to Western countries. Multiple hormones, cytokines, and metabolite perturbations in obese states have been shown to enhance tumorigenicity and metastasis potentials. Understanding the biological linkage of obesity to CCA might lead to novel prevention and therapeutic approaches to CCA treatment. This review summarizes the current evidence and highlights the knowledge gaps regarding the relationship between obesity and CCA from epidemiological and molecular perspectives.

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Section: Reprogrammed Tumor Metabolismmentioning

confidence: 99%

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations

Osataphan

Mahankasuwan²,

Saengboonmee

2021

J Hepato Biliary Pancreat

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“…IDH mutation is the most important genetic change in glioma. The mutation is located at the isocitric acid binding site (Arg/R132 of IDH1 and R172 of IDH2) of a single amino acid ( 3 , 4 ). IDH1/2 mutations are common in World Health Organization (WHO) grade II and III gliomas and secondary glioblastoma (GBM; 70–80%), while primary GBM (WHO grade IV) IDH1/2 mutations are rare (<5%) ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

Gao

Zhang

et al. 2021

Mol Med Rep

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Isocitrate dehydrogenase1 (IDH1) mutation is the most important genetic change in glioma. The most common IDH1 mutation results in the amino acid substitution of arginine 132 (Arg/R132), which is located at the active site of the enzyme. IDH1 Arg132His (R132H) mutation can reduce the proliferative rate of glioma cells. Numerous diseases follow circadian rhythms, and there is growing evidence that circadian disruption may be a risk factor for cancer in humans. Dysregulation of the circadian clock serves an important role in the development of malignant tumors, including glioma. Brain-Muscle Arnt-Like protein 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) are the main biological rhythm genes. The present study aimed to further study whether there is an association between IDH1 R132H mutation and biological rhythm in glioma, and whether this affects the occurrence of glioma. The Cancer Genome Atlas (TCGA) database was used to detect the expression levels of the biological rhythm genes BMAL1 and CLOCK in various types of tumor. Additionally, U87-MG cells were infected with wild-type and mutant IDH1 lentiviruses. Colony formation experiments were used to detect cell proliferation in each group, cell cycle distribution was detected by flow cytometry and western blotting was used to detect the expression levels of wild-type and mutant IDH1, cyclins, biological rhythm genes and Smad signaling pathway-associated genes in U87-MG cells. TCGA database results suggested that BMAL1 and CLOCK were abnormally expressed in glioma. Cells were successfully infected with wild-type and mutant IDH1 lentiviruses. Colony formation assay revealed decreased cell proliferation in the IDH1 R132H mutant group. The cell cycle distribution detected by flow cytometry indicated that IDH1 gene mutation increased the G 1 phase ratio and decreased the S phase ratio in U87-MG cells. The western blotting results demonstrated that IDH1 R132H mutation decreased the expression levels of the S phase-associated proteins Cyclin A and CDK2, and increased the expression levels of the G 1 phase-associated proteins Cyclin D3 and CDK4, but did not significantly change the expression levels of the G 2 /M phase-associated protein Cyclin B1. The expression levels of the positive and negative rhythm regulation genes BMAL1, CLOCK, period (PER s (PER1, 2 and 3) and cryptochrom (CRY)s (CRY1 and 2) were significantly decreased, those of the Smad signaling pathway-associated genes Smad2, Smad3 and Smad2-3 were decreased, and those of phosphorylated (p)-Smad2, p-Smad3 and Smad4 were increased. Therefore, the present results suggested that the IDH1 R132H mutation may alter the cell cycle and biological rhythm genes in U87-MG cells through the TGF-β/Smad signaling pathway.

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“…The 522 genes from turquoise module signi cantly correlated with risk score model were mainly enriched in metabolic-related biological pathways and PPAR signaling pathway. These pathways are well documented as participating in the carcinogenesis and progression of CCA [36]. Various studies based on multiple CCA independent cohorts [37][38][39] also detected that metabolic-related biological processes including small molecule and lipid metabolic processes relate to energy metabolism were pivotal for CCA development.…”

Section: Discussionmentioning

confidence: 93%

An Integrated mRNA-lncRNA Signature for Overall Survival Prediction in Cholangiocarcinoma

Zeng

Mukiibi

et al. 2020

Preprint

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BackgroundThe incidence and mortality rate of cholangiocarcinoma (CCA) have been rising globally. Patients with CCA have extremely poor prognosis, partly due to the silent clinical character and hence diagnosed at advantage stage without effective treatments. There is growing evidence showing that aberrant expression of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) are involved in tumorigenesis and development of CCA. It is essential to establish an integrated mRNA-lncRNA signature to improve the ability of prognostic prediction in CCA patients.MethodsWe collected a training dataset of 45 patients from The Cancer Genome Atlas dataset and a validation cohort (GSE107943) of 57 patients from Gene Expression Omnibus. An integrated mRNA-lncRNA risk score was established by a univariate and a multivariate Cox regression analyses. Time-dependent receiver operating characteristic (ROC) analysis was used to evaluate prognostic performance. Moreover, we conducted a correlation analysis between the signature and different clinical characteristics, and preformed weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis to investigate functional roles of the integrated signature.ResultsA total of two mRNAs (CFHR3 and PIWIL4) and two lncRNAs (AC007285.1 and AC134682.1) were identified to construct the integrated signature through a univariate Cox regression (P-value = 1.35E-02) and a multivariable Cox analysis (P-value = 1.12E-02). The ROC curve suggested the integrated mRNA-lncRNA signature possessed a high specificity and sensitivity of prognostic prediction with an area under the curve (AUC) of 0.872 and 0.790 at 1-year and 3-years, respectively. Subsequently, the signature was validated in GSE107943 cohort and combined dataset, and an area under the ROC curve reached up to 0.750 and 0.819 at 1-year. The signature was not only independent from different clinical features (P-value= 1.12E-02), but also outperformed other clinical characteristics as prognostic biomarkers with AUC of 0.781 at 3 years. These molecules in the integrated signature may associated with metabolic-related biological process and lipid metabolism pathway, which was highly involved in CCA carcinogenesis. ConclusionThese results showed that the integrated mRNA-lncRNA signature had an independent prognostic value for risk stratification, and further facilitated personalized treatment for CCA patients.

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Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

Cited by 17 publications

References 206 publications

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations

IDH1 gene mutation activates Smad signaling molecules to regulate the expression levels of cell cycle and biological rhythm genes in human glioma U87‑MG cells

An Integrated mRNA-lncRNA Signature for Overall Survival Prediction in Cholangiocarcinoma

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