Targeting triglyceride metabolism for colorectal cancer prevention and therapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Nagendra Yarla ◽  
Venkateshwar Madka ◽  
Chinthalapally Rao
Keyword(s):  
Colorectal Cancer ◽  
Metabolic Pathways ◽  
Literature Search ◽  
Fatty Acid Synthase ◽  
The Cancer Genome Atlas ◽  
Great Promise ◽  
Triglyceride Metabolism ◽  
Proteomic Data ◽  
Colorectal Cancer Prevention ◽  
Coa Reductase

Background: Triglycerides (TG) are one of the major constituents of body fat and energy reservoir, which consist of an ester derived from glycerol and three free fatty acids. TG lipase, monoacylglycerol lipase, fatty acid synthase, and HMG-CoA reductase are some of the key enzymes related to TG metabolism, and their roles in colorectal cancer (CRC) initiation and progression are under investigation. Methods: The literature search was performed based on various published papers, mostly on triglyceride metabolism relevant to CRC in PubMed, Google Scholar and other search engines. The gene expression profiling of some of the TG metabolic pathway mediators was performed by transcriptomic and/or proteomic data from The Cancer Genome Atlas (TCGA) database using R program and cBioportal software. Results and discussion: Accumulating pieces of evidence suggest that TG profiling may be used as a biomarker for the diagnosis and/or prognosis of CRC. Dysregulation of TG metabolism is associated with the initiation and progression of CRC. Most of the TG anabolic pathway mediators are overexpressed and/or overactivated during CRC tumorigenesis, while most TG catabolic pathway mediators are downregulated and/or inactivated based on literature search and correlated with TCGA data. Metabolic enzymes of TG and FAs metabolic pathways are involved in CRC tumor growth survival and metastasis. Conclusion: Overall studies from the previous literature and our TCGA data analysis demonstrated that the area of research on TG-associated lipid metabolic pathways holds great promise and warranted detailed investigations in this area for the implementation of novel preventive and therapeutic strategies against CRC.

scholarly journals Molecular Targets in Precision Chemoprevention of Colorectal Cancer: An Update from Pre-Clinical to Clinical Trials

2020 ◽  
Vol 21 (24) ◽  
pp. 9609
Author(s):  
Nagendra S. Yarla ◽  
Venkateshwar Madka ◽  
Gopal Pathuri ◽  
Chinthalapally V. Rao
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Fatty Acid Synthase ◽  
Growth Factor Receptor ◽  
Molecular Targets ◽  
Aberrant Crypt Foci ◽  
Current Status ◽  
Prostaglandin E ◽  
Precursor Lesions ◽  
Coa Reductase

Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients.

scholarly journals Fatty Acid Metabolism-Related lncRNAs Are Potential Biomarkers for Predicting the Overall Survival of Patients With Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Yurui Peng ◽  
Chenxin Xu ◽  
Jun Wen ◽  
Yuanchuan Zhang ◽  
Meng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Fatty Acid Synthase ◽  
Acid Metabolism ◽  
Cox Regression ◽  
Clinical Stage ◽  
The Cancer Genome Atlas ◽  
Cox Regression Analysis ◽  
Cerna Network

Abnormal metabolism, including abnormal fatty acid metabolism, is an emerging hallmark of cancer. The current study sought to investigate the potential prognostic value of fatty acid metabolism-related long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). To this end, we obtained the gene expression data and clinical data of patients with CRC from The Cancer Genome Atlas (TCGA) database. Through gene set variation analysis (GSVA), we found that the fatty acid metabolism pathway was related to the clinical stage and prognosis of patients with CRC. After screening differentially expressed RNAs, we constructed a fatty acid metabolism-related competing endogenous RNA (ceRNA) network based on the miRTarBase, miRDB, TargetScan, and StarBase databases. Next, eight fatty acid metabolism-related lncRNAs included in the ceRNA network were identified to build a prognostic signature with Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, and a nomogram was established based on the lncRNA signature and clinical variables. The signature and nomogram were further validated by Kaplan–Meier survival analysis, Cox regression analysis, calibration plots, receiver operating characteristic (ROC) curves, decision curve analysis (DCA). Besides, the TCGA internal and the quantitative real-time polymerase chain reaction (qRT-PCR) external cohorts were applied to successfully validate the robustness of the signature and nomogram. Finally, in vitro assays showed that knockdown of prognostic lncRNA TSPEAR-AS2 decreased the triglyceride (TG) content and the expressions of fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in CRC cells, which indicated the important role of lncRNA TSPEAR-AS2 in modulating fatty acid metabolism of CRC. The result of Oil Red O staining showed that the lipid content in lncRNA TSPEAR-AS2 high expression group was higher than that in lncRNA TSPEAR-AS2 low expression group. Our study may provide helpful information for fatty acid metabolism targeting therapies in CRC.

scholarly journals The roles and prognostic significance of ABI1-TSV-11 expression in patients with left-sided colorectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu Zhang ◽  
Zhaohui Zhong ◽  
Mei Li ◽  
Jingyi Chen ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
The Cancer Genome Atlas ◽  
Actin Dynamics ◽  
Elevated Expression ◽  
Sw480 Cells ◽  
And Migration

AbstractAbnormally expressed and/or phosphorylated Abelson interactor 1 (ABI1) participates in the metastasis and progression of colorectal cancer (CRC). ABI1 presents as at least 12 transcript variants (TSVs) by mRNA alternative splicing, but it is unknown which of them is involved in CRC metastasis and prognosis. Here, we firstly identified ABI1-TSV-11 as a key TSV affecting the metastasis and prognosis of left-sided colorectal cancer (LsCC) and its elevated expression is related to lymph node metastasis and shorter overall survival (OS) in LsCC by analyzing data from The Cancer Genome Atlas and TSVdb. Secondly, ABI1-TSV-11 overexpression promoted LoVo and SW480 cells adhesion and migration in vitro, and accelerated LoVo and SW480 cells lung metastasis in vivo. Finally, mechanism investigations revealed that ABI1-isoform-11 interacted with epidermal growth factor receptor pathway substrate 8 (ESP8) and regulated actin dynamics to affect LoVo and SW480 cells biological behaviors. Taken together, our data demonstrated that ABI1-TSV-11 plays an oncogenic role in LsCC, it is an independent risk factor of prognosis and may be a potential molecular marker and therapeutic target in LsCC.

scholarly journals Computed Tomography Colonography as a Sensible Option for Colorectal Cancer Screening: Evidence Based on Metanalysis

2021 ◽  
Vol 41 (01) ◽  
pp. 087-095
Author(s):  
Ingrid Chaves de Souza Borges ◽  
Natália Costa Resende Cunha ◽  
Amanda Marsiaj Rassi ◽  
Marcela Garcia de Oliveira ◽  
Jacqueline Andréia Bernardes Leão-Cordeiro ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Computed Tomography ◽  
Cancer Screening ◽  
Literature Search ◽  
Web Of Science ◽  
Screening Method ◽  
Colorectal Polyp ◽  
Evidence Based ◽  
Polyp Detection ◽  
Computed Tomography Colonography

Abstract Objective This metanalysis aimed to evaluate the sensitivity and specificity of computed tomography colonography in colorectal polyp detection. Methods A literature search was performed in the PubMed and Web of Science databases. Results A total of 1,872 patients (males 57.2%, females 42.8%) aged 49 to 82 years old (mean age 59.7 ± 5.3 years) were included in this metanalysis. The estimated sensitivity of computed tomography colonography was 88.4% (46.3–95.7%, coefficient of variation [CV] = 28.5%) and the estimated specificity was 73.6% (47.4–100.0%, CV = 37.5%). For lesions up to 9 mm, the sensitivity was 82.5% (62.0–99.9%, CV = 25.1%) and the specificity was 79.2% (32.0–98.0%, CV = 22.9%). For lesions > 9 mm, the sensitivity was 90.2% (64.0–100.0%, CV = 7.4%) and the specificity was 94.7% (80.0–100.0%, CV = 6.2%). No statistically significant differences in sensitivity according to the size of the lesion were found (p = 0.0958); however, the specificity was higher for lesions > 9 mm (p < 0.0001). Conclusions Most of the studies analyzed in the present work were conducted before 2010, which is about a decade after computed tomography colonography started being indicated as a screening method by European and American guidelines. Therefore, more studies aimed at analyzing the technique after further technological advancements are necessary, which could lead to the development of more modern devices.

scholarly journals Physiological and Proteomic Responses of Pitaya to PEG-Induced Drought Stress

Agriculture ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 632
Author(s):  
Aihua Wang ◽  
Chao Ma ◽  
Hongye Ma ◽  
Zhilang Qiu ◽  
Xiaopeng Wen
Keyword(s):  
Drought Stress ◽  
Energy Metabolism ◽  
Metabolic Pathways ◽  
Treatment Time ◽  
Soluble Sugar ◽  
Antioxidant Systems ◽  
Antioxidant Enzyme Activities ◽  
Proteomic Data ◽  
Proteome Profile ◽  
Proteomic Responses

Pitaya (Hylocereus polyrhizus L.) is highly tolerant to drought stress. Elucidating the response mechanism of pitaya to drought will substantially contribute to improving crop drought tolerance. In the present study, the physiological and proteomic responses of the pitaya cultivar ‘Zihonglong’ were compared between control seedlings and seedlings exposed to drought stress (−4.9 MPa) induced by polyethylene glycol for 7 days. Drought stress obviously enhanced osmolyte accumulation, lipid peroxidation, and antioxidant enzyme activities. Proteomic data revealed drought stress activated several pathways in pitaya, including carbohydrate and energy metabolism at two drought stress treatment time-points (6 h and 3 days). Other metabolic pathways, including those related to aspartate, glutamate, glutathione, and secondary metabolites, were induced more at 3 days than at 6 h, whereas photosynthesis and arginine metabolism were induced exclusively at 6 h. Overall, protein expression changes were consistent with the physiological responses, although there were some differences in the timing. The increases in soluble sugar contents mainly resulted from the degradation and transformation of insoluble carbohydrates. Differentially accumulated proteins in amino acid metabolism may be important for the conversion and accumulation of amino acids. GSH and AsA metabolism and secondary metabolism may play important roles in pitaya as enzymatic and nonenzymatic antioxidant systems. The enhanced carbohydrate and energy metabolism may provide the energy necessary for initiating the above metabolic pathways. The current study provided the first proteome profile of this species exposed to drought stress, and may clarify the mechanisms underlying the considerable tolerance of pitaya to drought stress.

scholarly journals Circulating let-7e-5p, miR-106a-5p, miR-28-3p, and miR-542-5p as a Promising microRNA Signature for the Detection of Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1493
Author(s):  
Camila Meirelles S. Silva ◽  
Mateus C. Barros-Filho ◽  
Deysi Viviana T. Wong ◽  
Julia Bette H. Mello ◽  
Livia Maria S. Nobre ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Unmet Need ◽  
Area Under The Curve ◽  
Discrimination Performance ◽  
Colorectal Carcinogenesis ◽  
The Cancer Genome Atlas ◽  
Colon Perforation ◽  
Data Series ◽  
Predictive Tool ◽  
Incidence And Mortality

Colorectal cancer (CRC) is a disease with high incidence and mortality. Colonoscopy is a gold standard among tests used for CRC traceability. However, serious complications, such as colon perforation, may occur. Non-invasive diagnostic procedures are an unmet need. We aimed to identify a plasma microRNA (miRNA) signature for CRC detection. Plasma samples were obtained from subjects (n = 109) at different stages of colorectal carcinogenesis. The patients were stratified into a non-cancer (27 healthy volunteers, 17 patients with hyperplastic polyps, 24 with adenomas), and a cancer group (20 CRC and 21 metastatic CRC). miRNAs (381) were screened by TaqMan Low-Density Array. A classifier based on four differentially expressed miRNAs (miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p) was able to discriminate cancer versus non-cancer cases. The overexpression of these miRNAs was confirmed by RT-qPCR, and a cross-study validation step was implemented using eight data series retrieved from Gene Expression Omnibus (GEO). In addition, another external data validation using CRC surgical specimens from The Cancer Genome Atlas (TCGA) was carried out. The predictive model’s performance in the validation set was 76.5% accuracy, 59.4% sensitivity, and 86.8% specificity (area under the curve, AUC = 0.716). The employment of our model in the independent publicly available datasets confirmed a good discrimination performance in five of eight datasets (median AUC = 0.823). Applying this algorithm to the TCGA cohort, we found 99.5% accuracy, 99.7% sensitivity, and 90.9% specificity (AUC = 0.998) when the model was applied to solid colorectal tissues. Overall, we suggest a novel signature of four circulating miRNAs, i.e., miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p, as a predictive tool for the detection of CRC.

scholarly journals Fucoxanthin and Colorectal Cancer Prevention

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2379
Author(s):  
Masaru Terasaki ◽  
Atsuhito Kubota ◽  
Hiroyuki Kojima ◽  
Hayato Maeda ◽  
Kazuo Miyashita ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Brown Algae ◽  
Lifestyle Modification ◽  
Signal Pathways ◽  
Potential Candidate ◽  
Anticancer Effects ◽  
Cancer Models ◽  
Candidate Drug ◽  
Colorectal Cancer Prevention ◽  
Dietary Carotenoid

Colorectal cancer (CRC), which ranks among the top 10 most prevalent cancers, can obtain a good outcome with appropriate surgery and/or chemotherapy. However, the global numbers of both new cancer cases and death from CRC are expected to increase up to 2030. Diet-induced lifestyle modification is suggested to be effective in reducing the risk of human CRC; therefore, interventional studies using diets or diet-derived compounds have been conducted to explore the prevention of CRC. Fucoxanthin (Fx), a dietary carotenoid, is predominantly contained in edible brown algae, such as Undaria pinnatifida (wakame) and Himanthalia elongata (Sea spaghetti), which are consumed particularly frequently in Asian countries but also in some Western countries. Fx is responsible for a majority of the anticancer effects exerted by the lipophilic bioactive compounds in those algae. Interventional human trials have shown that Fx and brown algae mitigate certain risk factors for CRC; however, the direct mechanisms underlying the anti-CRC properties of Fx remain elusive. Fx and its deacetylated type “fucoxanthinol” (FxOH) have been reported to exert potential anticancer effects in preclinical cancer models through the suppression of many cancer-related signal pathways and the tumor microenvironment or alteration of the gut microbiota. We herein review the most recent studies on Fx as a potential candidate drug for CRC prevention.

scholarly journals Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marta Codrich ◽  
Emiliano Dalla ◽  
Catia Mio ◽  
Giulia Antoniali ◽  
Matilde Clarissa Malfatti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Cell Model ◽  
Patient Specific ◽  
Driver Genes ◽  
Proteomic Data ◽  
Whole Exome ◽  
Molecular Stability ◽  
Culturing Conditions ◽  
Colorectal Cancer Progression

Abstract Background Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing. Methods Through integrated multi–omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor. Results Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients’ tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification. Conclusion The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient’s tumor, underlining relevant potentialities of this 3D model.

Sign in / Sign up

Export Citation Format

Share Document