scholarly journals Na+/H+-Exchanger Family as Novel Prognostic Biomarkers in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Xin Zhou ◽  
Manman Jiang ◽  
Zhihong Liu ◽  
Mengmeng Xu ◽  
Nannan Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ph Value ◽  
Critical Role ◽  
Family Members ◽  
Enrichment Analysis ◽  
Key Factors ◽  
Study Results ◽  
Tumor Immune Microenvironment ◽  
Erbb Signaling ◽  
Patient Prognosis

Background. The acidic characteristics of the tumor microenvironment (TME) are attributed to cancer cells’ needs of metabolism which produce a large amount of H+. In order not to affect its own life activities, it needs to release H+ into the intercellular space through an efficient Na+/H+ exchanger. On account of the intestine whose physiological function is highly dependent on intestinal pH value, NHE family members may play a critical role in the occurrence and development of colorectal cancer (CRC). Methods. TCGA, GEPIA2, ONCOMINE, UALCAN, STRING, TIMER, Cytoscape, TargetScan, ENCORI, LncBase v.2, DNMIVD, HPA, and CellMinerTM databases were used in our study. Results. The mRNA expressions of SLC9A1, SLC9A2, SLC9A3, and SLC9A9 were evidently lower in COAD than in normal samples; however, the mRNA expressions of SLC9A5, SLC9A8, and SLC9B2 were higher. Besides, mRNA expressions of NHE family were extremely associated with clinicopathological features, tumor immune microenvironment and stemness score, DNA methylation, and patient prognosis in COAD. Moreover, we conjectured that NHE family may play a role through MAPK or ErbB signaling pathway according to the results of GO/KEGG enrichment analysis. At last, we found that NHE family members were key factors of various kinds of cancers. Conclusion. Our study indicated that NHE family represented new diagnostic and therapeutic targets for CRC, which could have important significance for the clinical treatment of CRC.

scholarly journals Na+/H+-Exchanger Family As Novel Prognostic Biomarkers In Colorectal Cancer

2021 ◽  
Author(s):  
Xin Zhou ◽  
Manman Jiang ◽  
Zhihong Liu ◽  
Mengmeng Xu ◽  
Nannan Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Ph Value ◽  
Critical Role ◽  
Family Members ◽  
Enrichment Analysis ◽  
Key Factors ◽  
Tumor Immune Microenvironment ◽  
Erbb Signaling ◽  
Patient Prognosis

Abstract Background: The acidic characteristics of the tumor microenvironment (TME) are attributed to cancer cells’ needs of metabolism that produce a large amount of H+. In order not to affect its own life activities, it needs to release H+ into the intercellular space through an efficient Na+/H+ exchanger. On account of the intestine whose physiological function is highly dependent on intestinal pH value, NHE family members may play a critical role in the occurrence and development of colorectal cancer (CRC).Methods: TCGA, GEPIA2, ONCOMINE, UALCAN, STRING, TIMER, Cytoscape, TargetScan, ENCORI, LncBase v.2, DNMIVD, HPA and CellMinerTM databases were used in our study.Results: The mRNA expression of SLC9A1, SLC9A2, SLC9A3 and SLC9A9 were evidently lower in COAD compared to normal samples, however, mRNA expression of SLC9A5, SLC9A8 and SLC9B2 were higher. Besides, mRNA expression of NHE family were extremely associated with clinicopathological features, tumor immune microenvironment and stemness score, DNA methylation and patient prognosis in COAD. Moreover, we conjectured that NHE family may play a role through MAPK or ErbB signaling pathway according to the results of GO/KEGG enrichment analysis. At last, we found that NHE family members were key factors of various kinds of cancers.Conclusion: Our study indicated that NHE family was new diagnostic and therapeutic targets for CRC, which could have important significance for the clinical treatment of CRC.

scholarly journals Identification of 6 Hub Proteins and Protein Risk Signature of Colorectal Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Taohua Yue ◽  
Cheng Liu ◽  
Jing Zhu ◽  
Zhihao Huang ◽  
Shihao Guo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Kinase Inhibitor ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Clinical Information ◽  
The United States ◽  
Resistance Pathway ◽  
Study Results ◽  
Hub Proteins

Background. Colorectal cancer (CRC) is the second most common cause of cancer death in the United States and the third most common cancer globally. The incidence of CRC tends to be younger, and we urgently need a reliable prognostic assessment strategy. Methods. Protein expression profile and clinical information of 390 CRC patients/samples were downloaded from the TCPA and TCGA database, respectively. The Kaplan-Meier, Cox regression, and Pearson correlation analysis were applied in this study. Results. Based on the TCPA and TCGA database, we screened 6 hub proteins and first constructed protein risk signature, all of which were significantly associated with CRC patients’ overall survival (OS). The risk score was an independent prognostic factor and significantly related with the size of the tumor in situ ( T ). 6 hub proteins were differentially expressed in cancer and normal tissues and in different CRC stages, which were validated at the ONCOMINE database. Next, 40 coexpressed proteins of 6 hub proteins were extracted from the TCPA database. In the protein-protein interaction (PPI) network, HER1, HER2, and CTNNB1 were at the center. Function enrichment analysis illustrated that 46 proteins were mainly involved in the EGFR (HER1) tyrosine kinase inhibitor resistance pathway. Conclusion. Studies indicated that 6 hub proteins might be considered as new targets for CRC therapies, and the protein risk signature can be used to predict the OS of CRC patients.

scholarly journals Protein-Protein Interaction Analysis Reveals A Novel Cancer Stem Cell Related Target TMEM17 in Colorectal Cancer

2020 ◽  
Author(s):  
Zhaoliang Yu ◽  
Yu-feng Chen ◽  
Bin Zheng ◽  
Ze-rong Cai ◽  
Yi-feng Zou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Protein Interaction ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Study ◽  
Clinical Samples ◽  
Stem Cell Markers ◽  
Protein Protein Interaction

Abstract Background Cancer stem cells (CSCs) have been increasingly reported for tumour recurrence and chemoresistance in colorectal cancer (CRC). However, it is still lack of effective therapy on CSCs. Methods Here we describe a two-step strategy to generate CSC targets with high selectivity for colon stem cell markers, consisting in first step to generate specific proteins interacted CSC markers and second step to validate in survival analysis. TMEM17 was found and further investigated its biological functions in CRC cells. Finally, we utilized the Gene Set Enrichment Analysis (GSEA) to dig the potential mechanisms of TMEM17 in CRC.Results By combining protein-protein interaction (PPI) database and high-throughput gene profiles, network analysis revealed a cluster of colon CSCs related genes. In the cluster, TMEM17 was identified as a novel CSCs related gene. In vitro functional study, our results show that TMEM17 depletion can suppress cell proliferation and sensitize chemotherapy drugs to CRC cells. Enrichment analysis of differentially expressed genes was conducted using GSEA algorithm, Wnt/β-catenin pathway was found to be associated with TMEM17 expression. Further validation in clinical samples revealed TMEM17 expression was much higher in tumour than normal tissue and it was associated with poor survival in CRC patients. Conclusion Collectively, our finding unveils the critical role of TMEM17 in CRC and targeting TMEM17 is potential effective therapeutic for CRC patients.

scholarly journals A novel identified pyroptosis-related prognostic signature of colorectal cancer

2021 ◽  
Vol 18 (6) ◽  
pp. 8783-8796
Author(s):  
Chen Zheng ◽  
◽  
Zhaobang Tan ◽  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Cox Regression ◽  
Critical Role ◽  
Enrichment Analysis ◽  
R Package ◽  
Gene Set Enrichment Analysis ◽  
Risk Scores ◽  
Prognostic Signature ◽  
Cox Regression Analysis

<abstract> <p>Colorectal cancer (CRC), one of the most common malignancies worldwide, leads to abundant cancer-related mortalities annually. Pyroptosis, a new kind of programmed cell death, plays a critical role in immune response and tumor progression. Our study aimed to identify a prognostic signature for CRC based on pyroptosis-related genes (PRGs). The difference in PRGs between CRC tissues and normal tissues deposited in the TCGA database was calculated by "limma" R package. The tumor microenvironment (TME) of CRC cases was accessed by the ESTIMATE algorithm. The prognostic PRGs were identified using Cox regression analysis. A least absolute shrinkage and selector operation (LASSO) algorithm was used to calculate the risk scores and construct a clinical predictive model of CRC. Gene Set Enrichment Analysis (GSEA) was performed for understanding the function annotation of the signature in the tumor microenvironment. We found that most PRGs were significantly dysregulated in CRC. Through the LASSO method, three key PRGs were selected to calculate the risk scores and construct the prognostic model for CRC. The risk score was an independent indicator of patient's prognosis. In addition, we classified the CRC patients into two clusters based on risk scores and discovered that CRC patients in cluster 2 underwent worse overall survival and owned higher expression levels of immune checkpoint genes in tumor tissues. In conclusion, our study identified a PRG-related prognostic signature for CRC, according to which we classified the CRC patients into two clusters with distinct prognosis and immunotherapy potential.</p> </abstract>

scholarly journals Transcription levels and prognostic significance of the NFI family members in human cancers

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8816 ◽  
Author(s):  
Yuexian Li ◽  
Cheng Sun ◽  
Yonggang Tan ◽  
Lin Li ◽  
Heying Zhang ◽  
...  
Keyword(s):  
Head And Neck ◽  
Mrna Expression ◽  
Critical Role ◽  
Prognostic Significance ◽  
Family Members ◽  
Survival Outcomes ◽  
Expression Levels ◽  
Human Cancers ◽  
Study Results ◽  
Km Plotter

Background The nuclear factor I (NFI) is a family of transcription factors consisting of four distinct but closely related genes, NFIA, NFIB, NFIC and NFIX, which are important in the development of various tissues and organs in mammals. Recent study results have shown that NFI family may play a critical role in the progression of various human tumors and have been identified as key tumor suppressors and oncogenes for many cancers. However, the expression levels and distinctive prognostic values of the NFI family remain poorly explored in most cancers. Materials and Methods In the present study, the differences in mRNA expression of the NFI family in various cancers were investigated using the Oncomine and TCGA databases, and the mRNA expression, genetic alteration and DNA methylation of the NFI family members in various cancers were examined using cBioPortal for Cancer Genomics. In addition, the prognostic significance of the NFI family was assessed in multiple cancers using the Kaplan–Meier plotter (KM plotter) and SurvExpress databases. Results The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression. Although NFIX expression was not downregulated in kidney, colorectal and prostate cancers. Furthermore, NFIB expression was upregulated in gastric cancer. Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers. Decreased expression levels of NFIA, NFIB and NFIC were associated with poor overall survival (OS) in head and neck cancer. Low mRNA expression of NFIA and NFIB was significantly associated with OS and first progression in lung adenocarcinoma, but not in lung squamous cell carcinoma. In addition, potential correlations between NFI family members and survival outcomes were also observed in liver, esophageal, kidney and cervical cancer. Conclusion The results from the present study indicated certain members of the NFI family could be promising therapeutic targets and novel prognostic biomarkers for human cancers.

The Critical Role of the miR-21-MEG2 Axis in Colorectal Cancer

2020 ◽  
Vol 30 (6) ◽  
pp. 509-518
Author(s):  
Zengtao Bao ◽  
Shanting Gao ◽  
Baoming Zhang ◽  
Wenchao Shi ◽  
Aimin Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Critical Role

scholarly journals Transglutaminases and Obesity in Humans: Association of F13A1 to Adipocyte Hypertrophy and Adipose Tissue Immune Response

2020 ◽  
Vol 21 (21) ◽  
pp. 8289
Author(s):  
Mari T. Kaartinen ◽  
Mansi Arora ◽  
Sini Heinonen ◽  
Aila Rissanen ◽  
Jaakko Kaprio ◽  
...  
Keyword(s):  
Immune Response ◽  
Adipose Tissue ◽  
Family Members ◽  
Enrichment Analysis ◽  
Human Adipose Tissue ◽  
Adipocyte Size ◽  
Gene Enrichment ◽  
Adipocyte Hypertrophy ◽  
Mz Twins

Transglutaminases TG2 and FXIII-A have recently been linked to adipose tissue biology and obesity, however, human studies for TG family members in adipocytes have not been conducted. In this study, we investigated the association of TGM family members to acquired weight gain in a rare set of monozygotic (MZ) twins discordant for body weight, i.e., heavy–lean twin pairs. We report that F13A1 is the only TGM family member showing significantly altered, higher expression in adipose tissue of the heavier twin. Our previous work linked adipocyte F13A1 to increased weight, body fat mass, adipocyte size, and pro-inflammatory pathways. Here, we explored further the link of F13A1 to adipocyte size in the MZ twins via a previously conducted TWA study that was further mined for genes that specifically associate to hypertrophic adipocytes. We report that differential expression of F13A1 (ΔHeavy–Lean) associated with 47 genes which were linked via gene enrichment analysis to immune response, leucocyte and neutrophil activation, as well as cytokine response and signaling. Our work brings further support to the role of F13A1 in the human adipose tissue pathology, suggesting a role in the cascade that links hypertrophic adipocytes with inflammation.

scholarly journals RNF141 interacts with KRAS to promote colorectal cancer progression

Oncogene ◽  
2021 ◽  
Author(s):  
Jiuna Zhang ◽  
Xiaoyu Jiang ◽  
Jie Yin ◽  
Shiying Dou ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Critical Role ◽  
Ring Finger ◽  
Immunohistochemical Analysis ◽  
Bimolecular Fluorescence Complementation

AbstractRING finger proteins (RNFs) play a critical role in cancer initiation and progression. RNF141 is a member of RNFs family; however, its clinical significance, roles, and mechanism in colorectal cancer (CRC) remain poorly understood. Here, we examined the expression of RNF141 in 64 pairs of CRC and adjacent normal tissues by real-time PCR, Western blot, and immunohistochemical analysis. We found that there was more expression of RNF141 in CRC tissue compared with its adjacent normal tissue and high RNF141 expression associated with T stage. In vivo and in vitro functional experiments were conducted and revealed the oncogenic role of RNF141 in CRC. RNF141 knockdown suppressed proliferation, arrested the cell cycle in the G1 phase, inhibited migration, invasion and HUVEC tube formation but promoted apoptosis, whereas RNF141 overexpression exerted the opposite effects in CRC cells. The subcutaneous xenograft models showed that RNF141 knockdown reduced tumor growth, but its overexpression promoted tumor growth. Mechanistically, liquid chromatography-tandem mass spectrometry indicated RNF141 interacted with KRAS, which was confirmed by Co-immunoprecipitation, Immunofluorescence assay. Further analysis with bimolecular fluorescence complementation (BiFC) and Glutathione-S-transferase (GST) pull-down assays showed that RNF141 could directly bind to KRAS. Importantly, the upregulation of RNF141 increased GTP-bound KRAS, but its knockdown resulted in a reduction accordingly. Next, we demonstrated that RNF141 induced KRAS activation via increasing its enrichment on the plasma membrane not altering total KRAS expression, which was facilitated by the interaction with LYPLA1. Moreover, KRAS silencing partially abolished the effect of RNF141 on cell proliferation and apoptosis. In addition, our findings presented that RNF141 functioned as an oncogene by upregulating KRAS activity in a manner of promoting KRAS enrichment on the plasma membrane in CRC.

scholarly journals Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

2021 ◽  
Vol 22 (15) ◽  
pp. 8117
Author(s):  
Nunzia D’Onofrio ◽  
Elisa Martino ◽  
Luigi Mele ◽  
Antonino Colloca ◽  
Martina Maione ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Dependent Manner ◽  
Colon Cancer Cells ◽  
Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

scholarly journals MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer

2021 ◽  
Author(s):  
Andrea Lampis ◽  
Jens C. Hahne ◽  
Pierluigi Gasparini ◽  
Luciano Cascione ◽  
Somaieh Hedayat ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Critical Role ◽  
Tumour Volume ◽  
Cell Permeability ◽  
Oncogenic Pathways ◽  
Morphogenetic Protein ◽  
Cancer Phenotype ◽  
And Migration ◽  
2D And 3D

AbstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.

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