Natural dietary ingredients like flavonoids are important for body improvement against diseases. The flavonol rutin is widely found in fruits and vegetables and shows significant anticancer properties. However, the underlined signaling pathways have not been elucidated yet. In this study, the impacts of various doses of rutin (400–700 mM/ml) have been examined on human colon cancer SW480 cells metabolism, cell cycle, and apoptosis. The transcriptome was analyzed by bioinformatics tools and the interactions between rutin modulated microRNAs (miRNAs), long noncoding RNAs (lncRNAs), messenger RNAs (mRNAs), and transcription factors (TFs) were built, filtered and enriched. A dose of 600 mM of rutin significantly decreased cells metabolic activity, halved the population and arrested the cell cycle at the sub‐G1 phase. The enrichment analysis of miRNAs‐lncRNAs‐mRNAs‐TFs network showed that these effects were mediated through alteration of glucose, lipid, and protein metabolism, modulating endoplasmic reticulum stress responses, negative regulation of cell cycle process, and inducing the extrinsic and intrinsic apoptotic signaling pathways. Additionally, the key parent nodes of each annotation were illustrated. These findings create a detailed image of rutin underlying intracellular signaling pathways in CRC and also help us to better understand the role of dietary natural compounds in cancer treatment.
Like other noncoding RNAs (ncRNAs), dysregulation of long ncRNAs (lncRNAs) has been associated with various clinicopathological features of colorectal cancer (CRC) patients such as lymph node metastasis (LNM). Recently, three aberrant expressed oncogenic lncRNA (onco‐lncRNAs), including HOXA transcript at the distal tip (HOTTIP), plasmacytoma variant translocation 1 (PVT1), and urothelial carcinoma associated 1 (UCA1) have been reported in LNM. Herein, we compared the diagnostic performance of these lncRNAs as individual biomarkers and as a discriminating panel between LNM CRC patients, nonmetastatic lymph nodes (NLN) and normal healthy subjects. The lncRNAs expression level was measured by quantitative real‐time PCR and analyzed by the Mann‐Whitney U test. The receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic power. The Kaplan‐Meier survival analysis was performed to outline the overall survival (OS) of CRC patients with an abnormal level of lncRNAs. The area under the ROC curve (AUC) of the overexpressed HOTTIP (0.7817; 95% CI, 0.6809‐0.8824), PVT1 (0.8559; 95% CI, 0.7737‐0.9382), and UCA1 (0.8135; 95% CI, 0.722‐0.9051) introduced them as individual CRC biomarkers. As a predictive panel, the AUC values of the HOTTIP, PVT1, and UCA1 for training set were 0.9256 (95% CI, 0.8634‐0.9879; all CRCs), 0.8708 (95% CI, 0.7709‐0.9378; NLN) and 0.9804 (95% CI, 0.9585‐0.9998; LNM), and for validation set were 0.9286 (95% CI, 0.8752‐0.9820; all CRCs), 0.8911 (95% CI, 0.8238‐0.9585; NLN), and 0.9833 (95% CI, 0.9642‐1.002; LNM), respectively. Also, HOTTIP/PVT1/UCA1 panel dysregulation had a marked correlation with patient's OS in training set (logrank test P = 0.0121; hazard ratio [HR], 0.1225; 95% confidence interval [CI], 0.02376‐0.6312), and in validation set (logrank test P < 0.0001, HR, 0.2003; 95% CI, 0.08942‐0.4486). These data showed that the combination of HOTTIP, PVT1, and UCA1 as a predictive panel, has a better diagnostic performance than each of these lncRNAs individually, and could be used for the screening of patients with advanced CRC.
Modulation of fatty acids metabolism is an appropriate strategy for starvation‐induced death in tumor cancers. Colon cancer cells express a high level of acyl‐CoA synthetase‐5 (ACSL5), and as yet no therapeutic approach has been achieved. Herein, ACSL5‐related microRNAs (miRNAs) were identified via TargetScan, and their impacts on ACSL5 and lipid content along with metabolic activity, cell cycle, migration, and invasion of colorectal cancer (CRC) cells were examined, and subsequently compared with transcriptome for better visualization of intracellular‐signaling networks. In vivo analysis was performed using BALB/c mice xenograft model of CRC injected with target miRNA. Clinical significances were also evaluated in 80 CRC tumors and matched adjacent normal tissues. There was a reverse correlation between ACSL5 and miR‐497‐5p, which miR‐497‐5p overexpression modulated CRC cell proliferation and development. A similar observation was received from the in vivo examination in which intratumoral injection of miR‐497‐5p reversed the tumor growth in the CRC xenograft model. Downregulation of miR‐497‐5p correlated with tumor differentiation, tumor, node, and metastasis staging, lymph node metastasis, and poor survival in patients with CRC. These results suggested that miR‐497‐5p upregulation could be considered as a therapeutic strategy for modulation of lipid metabolism in colon cancer.
Metastasis is known as a key step in cancer recurrence and could be stimulated by multiple factors. Calumenin (CALU) is one of these factors which has a direct impact on cancer metastasis and yet, its underlined mechanisms have not been completely elucidated. The current study was aimed to identify CALU co-expressed genes, their signaling pathways, and expression status within the human cancers. To this point, CALU associated genes were visualized using the Cytoscape plugin BisoGenet and annotated with the Enrichr webbased application. The list of CALU related diseases was retrieved using the DisGenNet, and cancer datasets were downloaded from The Cancer Genome Atlas (TCGA) and analyzed with the Cufflink software. ROC curve analysis was used to estimate the diagnostic accuracy of DEGs in each cancer, and the Kaplan-Meier survival analysis was performed to plot the overall survival of patients. The protein level of the signature biomarkers was measured in 40 biopsy specimens and matched adjacent normal tissues collected from CRC and lung cancer patients. Analysis of CALU co-expressed genes network in TCGA datasets indicated that the network is markedly altered in human colon (COAD) and lung (LUAD) cancers. Diagnostic accuracy estimation of differentially expressed genes showed that a gene panel consisted of CALU, AURKA, and MCM2 was able to successfully distinguish cancer tumors from healthy samples. Cancer cases with abnormal expression of the signature genes had a significantly lower survival rate than other patients. Additionally, comparison of CALU, AURKA, and MCM2 proteins between healthy samples, early and advanced tumors showed that the level of these proteins was increased through normalcarcinoma transition in both types of cancers. These data indicate that the interactions between CALU, AURKA, and MCM2 has a pivotal role in cancer development, and thereby needs to be explored in the future.
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