scholarly journals Hypermethylation of APC2 Is a Predictive Epigenetic Biomarker for Chinese Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yuan He ◽  
Li-Yue Sun ◽  
Jing Wang ◽  
Rui Gong ◽  
Qiong Shao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Sequencing Analysis ◽  
Primary Tumors ◽  
Protein Levels ◽  
Normal Tissues ◽  
Ffpe Tissues ◽  
Epigenetic Biomarker

Objective. To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods. The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n=66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n=44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results. Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p<0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p<0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p<0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p<0.05). Conclusion. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.

scholarly journals Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuhui Wu ◽  
Xiaojing Liang ◽  
Junjie Ni ◽  
Rongjie Zhao ◽  
Shengpeng Shao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Normal Tissues

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

scholarly journals RACK1 Acts as a Potential Tumor Promoter in Colorectal Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Xue-Yang Li ◽  
Yi Hu ◽  
Nian-Shuang Li ◽  
Jian-Hua Wan ◽  
Yin Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
The Cancer Genome Atlas ◽  
Biological Role ◽  
Tumor Promoter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Normal Tissues ◽  
Geo Dataset

Background. The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. Materials and Methods. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. Results. RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P<0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P<0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. Conclusions. Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

scholarly journals Downregulated SPINK4 is associated with poor survival in colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaojie Wang ◽  
Qian Yu ◽  
Waleed M. Ghareeb ◽  
Yiyi Zhang ◽  
Xingrong Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Poor Survival ◽  
Protein Levels ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Cancer Genome Atlas ◽  
Independent Indicator

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

scholarly journals Vacuolar Membrane ATPase Activity 21 Predicts a Favorable Outcome and Acts as a Suppressor in Colorectal Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Fan Zhang ◽  
Hao Shen ◽  
Yating Fu ◽  
Guanyu Yu ◽  
Fuao Cao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Independent Predictor ◽  
Vacuolar Membrane ◽  
Ph Homeostasis ◽  
Protein Levels ◽  
Normal Tissues ◽  
Membrane Atpase ◽  
Assembly Factor

Extracellular and/or intracellular manipulation of pH in tumor may have noticeable potential in cancer treatment. Although the assembly factor genes of V0 domain of the V-ATPase complex are required for intracellular pH homeostasis, their significance in colorectal cancer (CRC) remains largely unknown. Here, we used bioinformatics to identify the candidates from known assembly factor genes of the V0 domain, which were further evaluated by immunohistochemistry (IHC) in CRC and adjacent normal specimens from 661 patients. Univariate and multivariate Cox analyses were used to evaluate factors contributing to prognosis. The effects of variations in the expression of VMA21 on tumor growth were assessed in vitro and in vivo. Of five known assembly factors, only VMA21 showed differential expression between CRC and adjacent normal tissues at both mRNA and protein levels. Patients with high VMA21 expression had higher differentiation grade and longer disease-specific survival (DSS) at stages I–III disease. High VMA21 expression in tumors was also an independent predictor of DSS (hazard ratio, 0.345; 95% confidence interval, 0.123–0.976), with covariates included TNM stage and differentiation grade. VMA21 overexpression decreased CRC growth, whereas VMA21 knockdown increased CRC growth in vitro and in vivo. VMA21 expression suppresses CRC growth and predicts a favorable DSS in patients with stage I-III disease.

scholarly journals Coiled-Coil Domain-Containing 68 Downregulation Promotes Colorectal Cancer Cell Growth by Inhibiting ITCH-Mediated CDK4 Degradation

2021 ◽  
Vol 11 ◽  
Author(s):  
Cong Wang ◽  
Hongyan Li ◽  
Lei Wu ◽  
Xueli Jiao ◽  
Zihui Jin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ectopic Expression ◽  
Coiled Coil ◽  
Disease Free Survival ◽  
Cancer Cell Growth ◽  
Protein Levels ◽  
Normal Tissues ◽  
Coiled Coil Domain

Coiled-coil domain-containing 68 (CCDC68) plays different roles in cancer and is predicted as a tumor suppressor in human colorectal cancer (CRC). However, the specific role of CCDC68 in CRC and the underlying mechanisms remain unknown. Here, we showed that CCDC68 expression was lower in CRC than that in corresponding normal tissues, and CCDC68 level was positively correlated with disease-free survival. Ectopic expression of CCDC68 decreased CRC cell proliferation in vitro and suppressed the growth of CRC xenograft tumors in vivo. CCDC68 caused G0/G1 cell cycle arrest, downregulated CDK4, and upregulated ITCH, the E3 ubiquitin ligase responsible for CDK4 protein degradation. This increased CDK4 degradation, which decreased CDK4 protein levels and inhibited CRC tumor growth. Collectively, the present results identify a novel CDK4 regulatory axis consisting of CCDC68 and ITCH, which suggest that CCDC68 is a promising target for the treatment of 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 Identification of novel cell glycolysis related gene signature predicting survival in patients with breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Feng Jiang ◽  
Chuyan Wu ◽  
Ming Wang ◽  
Ke Wei ◽  
Jimei Wang
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
Single Gene ◽  
Prediction Method ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Cox Models ◽  
Normal Tissues ◽  
Predictive Risk

AbstractOne of the most frequently identified tumors and a contributing cause of death in women is breast cancer (BC). Many biomarkers associated with survival and prognosis were identified in previous studies through database mining. Nevertheless, the predictive capabilities of single-gene biomarkers are not accurate enough. Genetic signatures can be an enhanced prediction method. This research analyzed data from The Cancer Genome Atlas (TCGA) for the detection of a new genetic signature to predict BC prognosis. Profiling of mRNA expression was carried out in samples of patients with TCGA BC (n = 1222). Gene set enrichment research has been undertaken to classify gene sets that vary greatly between BC tissues and normal tissues. Cox models for additive hazards regression were used to classify genes that were strongly linked to overall survival. A subsequent Cox regression multivariate analysis was used to construct a predictive risk parameter model. Kaplan–Meier survival predictions and log-rank validation have been used to verify the value of risk prediction parameters. Seven genes (PGK1, CACNA1H, IL13RA1, SDC1, AK3, NUP43, SDC3) correlated with glycolysis were shown to be strongly linked to overall survival. Depending on the 7-gene-signature, 1222 BC patients were classified into subgroups of high/low-risk. Certain variables have not impaired the prognostic potential of the seven-gene signature. A seven-gene signature correlated with cellular glycolysis was developed to predict the survival of BC patients. The results include insight into cellular glycolysis mechanisms and the detection of patients with poor BC prognosis.

scholarly journals TRIM27 interacts with Iκbα to promote the growth of human renal cancer cells through regulating the NF-κB pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chengwu Xiao ◽  
Wei Zhang ◽  
Meimian Hua ◽  
Huan Chen ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Protein Levels ◽  
Kaplan Meier ◽  
Cancer Genome Atlas

Abstract Background The tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC. Methods The mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression. Results We discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation. Conclusions Our results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

scholarly journals A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linbang Wang ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Nian Zhou ◽  
Tianji Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Pearson Correlation ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Mcf7 Cells ◽  
Tumour Immunity ◽  
Immune Genes ◽  
Normal Tissues

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

scholarly journals DPP3/CDK1 contributes to the progression of colorectal cancer through regulating cell proliferation, cell apoptosis, and cell migration

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Yixin Tong ◽  
Yuan Huang ◽  
Yuchao Zhang ◽  
Xiangtai Zeng ◽  
Mei Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Apoptosis ◽  
Downstream Target ◽  
Normal Tissues ◽  
Physiological Processes ◽  
Mutual Regulation

AbstractAt present, colorectal cancer (CRC) has become a serious threat to human health in the world. Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase that may be involved in several physiological processes. However, whether DPP3 affects the development and progression of CRC remains a mystery. This study is the first to demonstrate the role of DPP3 in CRC. Firstly, the results of immunohistochemistry analysis showed the upregulation of DPP3 in CRC tissues compared with normal tissues, which is statistically analyzed to be positively correlated with lymphatic metastasis, pathological stage, positive number of lymph nodes. Moreover, the high expression of DPP3 predicts poor prognosis in CRC patients. In addition, the results of cell dysfunction experiments clarified that the downregulation of DPP3 significantly inhibited cell proliferation, colony formation, cell migration, and promoted apoptosis in vitro. DPP3 depletion could induce cell apoptosis by upregulating the expression of BID, BIM, Caspase3, Caspase8, HSP60, p21, p27, p53, and SMAC. In addition, downregulation of DPP3 can reduce tumorigenicity of CRC cells in vivo. Furthermore, CDK1 is determined to be a downstream target of DPP3-mediated regulation of CRC by RNA-seq, qPCR, and WB. The interaction between DPP3 and CDK1 shows mutual regulation. Specifically, downregulation of DPP3 can accentuate the effects of CDK1 knockdown on the function of CRC cells. Overexpression of CDK1 alleviates the inhibitory effects of DPP3 knockdown in CRC cells. In summary, DPP3 has oncogene-like functions in the development and progression of CRC by targeting CDK1, which may be an effective molecular target for the prognosis and treatment of CRC.

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