Colon Adenocarcinoma Tissues Research Articles

Circadian Clock Genes Are Correlated with Prognosis and Immune Cell Infiltration in Colon Adenocarcinoma.

Background Colon adenocarcinoma (COAD) is a malignancy with a high incidence and is associated with poor quality of life. Dysfunction of circadian clock genes and disruption of normal rhythms are associated with the occurrence and progression of many cancer types. However, studies that systematically describe the prognostic value and immune-related functions of circadian clock genes in COAD are lacking. Methods Genomic data obtained from The Cancer Genome Atlas (TCGA) database was analyzed for expression level, mutation status, potential biological functions, and prognostic performance of core circadian clock genes in COAD. Their correlations with immune infiltration and TMB/MSI score were analyzed by Spearman's correlation analysis. Pearson's correlation analysis was performed to analyze their associations with drug sensitivity. Lasso Cox regression analysis was performed to construct a prognosis signature. Moreover, an mRNA-miRNA-lncRNA regulatory axis was also detected by ceRNA network. Results In COAD tissues, the mRNA levels of CLOCK, CRY1, and NR1D1 were increased, while the mRNA levels of ARNTL, CRY2, PER1, PER3, and RORA were decreased. We also summarized the relative genetic mutation variation landscape. GO and KEGG pathway analyses demonstrated that these circadian clock genes were primarily correlated with the regulation of circadian rhythms and glucocorticoid receptor signaling pathways. COAD patients with high CRY2, NR1D1, and PER2 expression had worse prognosis. A prognostic model constructed based on the 9 core circadian clock genes predicted the COAD patients' overall survival with medium to high accuracy. A significant association between prognostic circadian clock genes and immune cell infiltration was found. Moreover, the lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis in COAD was also detected through a mRNA-miRNA-lncRNA network. Conclusion Our results identified CRY2, NR1D1, and PER2 as potential prognostic biomarkers for COAD patients and correlated their expression with immune cell infiltration. The lncRNA KCNQ1OT1/hsa-miRNA-32-5p/PER2/CRY2 regulatory axis was detected in COAD and might play a vital role in the occurrence and progression of COAD.

MicroRNA-323a-3p Negatively Regulates NEK6 in Colon Adenocarcinoma Cells.

Objective The activity of NEK6 is enhanced in several cancer cells, including colon adenocarcinoma (COAD) cells. However, there are few reports on the microRNA (miRNA/miR) regulation of NEK6. In this study, we aimed to investigate the effects of miRNAs targeting NEK6 in COAD cells. Methods Public data and online analysis sites were used to analyze the expression levels of NEK6 and miR-323a-3p in COAD tissues as well as the relationship between NEK6 or miR-323a-3p levels and survival in patients with COAD and to predict miRNAs targeting NEK6. Real-time polymerase chain reaction and western blotting were performed to determine the levels of NEK6 and miR-323a-3p in COAD cells. The targeting of NEK6 by miR-323a-3p was verified using a dual-luciferase reporter assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 5-ethynyl-2′-deoxyuridine assay, propidium iodide (PI) staining, annexin V-fluorescein isothiocyanate/PI staining, and transwell assay were employed to test the proliferation, apoptosis, migration ability, and invasiveness of COAD cells. Results In COAD cells, NEK6 was highly expressed, whereas miR-323a-3p was expressed at low levels and negatively regulated NEK6. Upregulating the level of miR-323a-3p impaired the proliferation, migration, and invasion of COAD cells and promoted apoptosis, whereas supplementing NEK6 alleviated the damage of the proliferation, migration, and invasion of COAD cells caused by miR-323a-3p and inhibited miR-323a-3p-induced apoptosis. These findings indicate that miR-323a-3p regulates the proliferation, migration, invasion, and apoptosis of COAD cells by targeting NEK6. Conclusion miR-323a-3p downregulates NEK6 in COAD cells; this provides a novel basis for further understanding the occurrence and development of COAD.

LncRNA ubiquitin-binding protein domain protein 10 antisense RNA 1 inhibits colon adenocarcinoma progression via the miR-515-5p/slit guidance ligand 3 axis

ABSTRACT Dysregulated long non-coding RNAs (lncRNAs) play an important role in cancer progression. However, there have been limited reports to date of the involvement of ubiquitin-binding protein domain protein 10 antisense RNA 1 (UBXN10-AS1) in cancer. Our aim was to explore the role and underlying mechanism of UBXN10-AS1 in the occurrence of colon adenocarcinoma (COAD). Real-time quantitative PCR and Western blotting were performed to determine the expression of UBXN10-AS1, miR-515-5p, and Slit guidance ligand 3 (SLIT3). Cell Counting Kit-8 and wound healing scratch assays were performed to measure COAD cell proliferation and migration. A xenograft assay was performed to examine tumor growth in vivo. Luciferase reporter and RNA immunoprecipitation (RIP) assays were used to determine the binding interaction among miR-515-5p, UBXN10-AS1, and SLIT3. The results showed that UBXN10-AS1 and SLIT3 were expressed at low levels in COAD tissues, while miR-515-5p was expressed at high levels. UBXN10-AS1 overexpression suppressed tumor growth in vitro and in vivo. The luciferase reporter and RNA RIP assays demonstrated that UBXN10-AS1 targeted miR-515-5p, which in turn targeted SLIT3. Functionally, miR-515-5p overexpression reversed the inhibition of COAD cell proliferation and migration by UBXN10-AS1 overexpression, and SLIT3 overexpression counteracted the oncogenicity of miR-515-5p. Our study shows that UBXN10-AS1 modulates the miR-515-5p/SLIT3 axis, thereby resulting in the inhibition of COAD cell proliferation and migration.

Prognostic significance of Notch3 immunoreactivity patterns in Caucasian colon adenocarcinoma patients

IntroductionColon cancer is traditionally regarded as the most commonly diagnosed gastrointestinal malignant disease. Nevertheless, despite advances in diagnosis and novel therapeutic options, the clinical outcomes of patients are still not satisfactory.AimTo investigate the prognostic role of Notch3, an immunohistochemical study was performed on samples of colon adenocarcinoma tissues and adjacent non-pathological mucosa in Caucasian patients.Material and methodsParaffin-embedded colon adenocarcinoma samples were assessed immunohistochemically for Notch3 protein. Connections between Notch3 immunoexpression and clinicopathological factors including the 5-year overall survival (OS) were evaluated.ResultsThe level of the Notch3 immunohistochemical reactivity was correlated with the grade of the histological differentiation (p < 0.001). A strong expression of Notch3 protein was detected more frequently in patients with G3 tumours than in patients with G1 tumours. Moreover, the significant difference was also detected between the patients with G1 tumour and those with G2. In the G2 patients a strong reactivity was described more frequently. The Kaplan-Meier survival analysis showed that the overall survival rate in the group of patients with a low expression level of Notch3 was significantly greater than that for patients with a moderate or strong level of Notch3 immunoreactivity (p < 0.001). A multivariate analysis demonstrated that the grade of tumour differentiation (p = 0.001) and Notch3 expression (p < 0.001) were independent risk factors for worse survival.ConclusionsThe high level of Notch3 immunoexpression was demonstrated to be associated with malignancy-related clinicopathological factors and 5-year overall survival of patients.

HIG1 domain family member 1A disrupts proliferation, migration, and invasion of colon adenocarcinoma cells

ABSTRACT HIG1 domain family member 1A (Higd-1a) interacts with dynamin-like 120 kDa protein to maintain the morphological and functional integrity of the mitochondria and thus plays an important role in the progression of malignant tumors. Higd-1a promotes the proliferation of pancreatic cancer cells and the growth of pancreatic cancer; however, no similar observations have been reported for colorectal cancer (CRC). This study, therefore, aimed to verify the role of Higd-1a in CRC. We downloaded data from the Genotype-Tissue Expression (GTEX) and The Cancer Genome Atlas (TCGA) databases and identified an association between Higd-1a levels in colon adenocarcinoma (COAD) tissues and poor survival using Kaplan–Meier curves. Subsequently, we overexpressed Higd-1a in the human COAD cell line HCT-8, knocked down Higd-1a expression in SW480 cells, and evaluated the effects via quantitative PCR (qPCR) and western blotting. MTT assays, colony formation assay, cell cycle analysis, annexin V-FITC/PI, wound-healing analysis, and transwell assay were used to test cell proliferation, formation of cell colonies, cell cycle progression, migration, invasiveness, and apoptosis. Higd-1a has low transcription levels in COAD tissue and suggests a poor prognosis. Higd-1a overexpression in HCT-8 cells weakened cell proliferation, formation of cell colonies, cell cycle progression, migration ability, and invasiveness, and increased apoptosis. Moreover, the decrease of Higd-1a in SW480 cells induced cell proliferation, formation of cell colonies, cell cycle progression, migration, and invasion, and inhibited apoptosis. Higd-1a is underexpressed in COAD cells and its overexpression impaired the proliferation, migration, and invasiveness of COAD cells.

Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma

ABSTRACT Colon adenocarcinoma (COAD), having high malignancy and poor prognosis, is the main pathological type of colon cancer. Previous studies show that Keratin 17 (KRT17) plays an important role in the development of many malignant tumors. However, its role and the molecular mechanism underlying COAD remain unclear. Using TCGA and ONCOMINE databases, as well as immunohistochemistry, we found that the expression of KRT17 was higher in COAD tissues as compared to that in the adjacent normal tissues. Cell- and animal-based experiments showed that overexpression of KRT17 promoted the invasion and metastasis of colon cancer cells while knocking down KRT17 reversed these processes both in vitro and in vivo. In addition, we also showed that KRT17 promoted the formation of new blood vessels. Mechanistically, KRT17 could regulate the WNT/β-catenin signaling pathway, and APC may be involved in this process by interacting with KRT17. In summary, these findings suggested that high expression of KRT17 could promote cell metastasis and angiogenesis of colon cancer cells by regulating the WNT/β-catenin signaling pathway. Thus, KRT17 could be a potential therapeutic target for COAD treatment.

Prognostic role of oxytocin receptor in colon adenocarcinoma.

The oxytocin receptor (OXTR) is directly involved in the pathological mechanisms of multiple cancers, including breast cancer, prostate cancer, and ovarian cancer; however, the role of OXTR in the modulation of colon adenocarcinoma (COAD) growth, metastasis, and clinical prognosis remains to be elucidated. This study used systematic bioinformatics analysis to explore the effects of OXTR on modulating COAD growth and prognosis in patients with COAD. Compared with normal tissues, OXTR mRNA level was higher in COAD tissues, which was associated with tumor progression. Elevated mRNA level of OXTR also indicated a poor prognosis in COAD patients. Furthermore, high mRNA level of OXTR was significantly associated with pathways involved in cell cycle regulation and signal transduction pathways, including the hedgehog, mTOR, TGF-β, and Wnt signaling pathways. OXTR expression was significantly correlated with the infiltration level of type 2T helper cell, central memory CD8 T cell, CD56 bright natural killer cell, activated CD8 T cell, activated B cell, and Type 1T helper cell. Moreover, silencing OXTR inhibited cell proliferation, migration, and invasion, and arrested the cell cycle. In conclusion, high mRNA level of OXTR indicates poor prognosis.

Comprehensive Pan-Cancer Analysis of Heat Shock Protein 110, 90, 70, and 60 Families.

Background: Here we carried out a panoramic analysis of the expression and prognosis of HSP110, HSP90, HSP70, and HSP60 families in 33 types of cancer, with the aim of deepening the systematic understanding of heat shock proteins (HSPs) in cancer. Materials and Methods: Next-generation sequencing data of multiple tumors were downloaded from TCGA, CCLE and Oncomine databases. RStudio 3.6.1 was used to analyze HSP110, HSP90, HSP70 and HSP60 families based on their expression in 33 types of cancer. The validations in vivo (stomach adenocarcinoma and colon adenocarcinoma tissues) were performed by qRT-PCR. Results: HSPs were differentially expressed in different cancers. The results revealed mainly positive correlations among the expressions of HSPs in different cancers. Expressions of HSP family members were generally associated with poor prognosis in respiratory, digestive, urinary and reproductive system tumors and associated with good prognosis in cholangiocarcinoma, pheochromocytoma and paraganglioma. TCGA mutation analysis showed that HSP gene mutation rate in cancers was 0–23%. CCLE mutation analysis indicated that HSP gene mutation rate in 828 cell lines from 15 tumors was 0–17%. CNV analysis revealed that HSPs have different degrees of gene amplifications and deletions in cancers. Gene mutations of 15 HSPs influenced their protein expressions in different cancers. Copy number amplifications and deletions of 22 HSPs also impacted protein expression levels in pan-cancer. HSP gene mutation was generally a poor prognosis factor in cancers, except for uterine corpus endometrial carcinoma. CNVs in 14 HSPs showed varying influences on survival status in different cancers. HSPs may be involved in the activation and inhibition of multiple cancer-related pathways. HSP expressions were closely correlated with 22 immune cell infiltrations in different cancers. The qRT-PCR validation results in vivo showed that HSPA2 was down-regulated in stomach adenocarcinoma and colon adenocarcinoma; HSPA7 and HSPA1A also were down-regulated in colon adenocarcinoma. HSPA2-HSPA7 (r = 0.031, p = 0.009) and HSPA1A-HSPA7 (r = 0.516, p < 0.001) were positive correlation in colon adenocarcinoma. Conclusion: These analysis and validation results show that HSP families play an important role in the occurrence and development of various tumors and are potential tumor diagnostic and prognostic biomarkers as well as anti-cancer therapeutic targets.

Development and Validation of a Prognostic Model of RNA-Binding Proteins in Colon Adenocarcinoma: A Study Based on TCGA and GEO Databases.

BackgroundPrevious studies reported that dysregulation of RNA-binding proteins (RBPs) is significantly associated with the development of cancer. However, there are few studies to date on the role of RBPs in colon adenocarcinoma (COAD).MethodsRNA sequencing and clinical data for COAD patients were downloaded from The Cancer Genome Atlas (TCGA) database to identify differentially expressed (DE) RBPs between COAD tissue and normal colon tissue, and then the expression and prognostic significance of these RBPs were investigated in detail by systematic bioinformatics analysis. qRT-PCR was used to validate the expressions of prognosis-related RBP-encoding genes.ResultsSeven RBPs (RPL10L, ERI1, POP1, CAPRIN2, TDRD7, SNIP1 and PPARGC1A) were identified as hub genes associated with prognosis by a series of regression analyses, and were then used to construct a prognostic model. Further analysis based on this model indicated that the overall survival (OS) of the high-risk groups was lower than that of the low-risk groups. In this prognostic model, the area under the ROC curve (AUC) was 0.694, 0.709 and 0.665 for the TCGA cohort at 1, 3 and 5 years, respectively, while the AUC was 0.671, 0.633 and 0.601 for the GEO combined cohort at 1, 3 and 5 years, respectively, indicating the good predictive ability of the model. We also built a nomogram based on the 7 RBPs in the TCGA cohort, and the model showed good discriminatory ability for COAD.ConclusionWe screened seven prognosis-related genes in COAD patients based on RBP-related genes, validated the expressions of the seven prognosis-related RBP-encoding genes by qRT-PCR and constructed a prognosis-related nomogram for patients with COAD.

Upregulation of ADAM12 Is Associated With a Poor Survival and Immune Cell Infiltration in Colon Adenocarcinoma.

BackgroundA disintegrin and metalloprotease 12 (ADAM12) is a member of the multidomain protein family, but the mechanisms by which it affects prognosis and immune cell infiltration in patients with colon adenocarcinoma (COAD) remain unclear. Here, our study aimed to analyze the prognostic value of ADAM12 and investigate the correlation between ADAM12 expression and immune cell infiltration in patients with COAD.MethodsDifferential expression analyses were performed using the Oncomine and UALCAN databases, and prognostic analyses were conducted using PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan–Meier Plotter. Then, the cBioPortal database was used to analyze alterations in the ADAM12 gene, and the STRING and Metascape websites were used to conduct Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Additionally, relationships between ADAM12 and the immune microenvironment were evaluated based on the TIMER, GEPIA, and TISIDB databases.ResultsADAM12 was overexpressed in COAD tissues, and higher ADAM12 expression correlated with a worse prognosis for patients with COAD. The gene regulatory network suggested that ADAM12 was mainly enriched in extracellular matrix (ECM) organization, ECM proteoglycans, skeletal system development, and ossification, among other pathways. Moreover, ADAM12 expression significantly correlated with the abundance of CD4+ T cells, B cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, and their markers, as well as lymphocytes, immunomodulators, and chemokines.ConclusionsIn colorectal tumors, ADAM12 may play vital roles in regulating the ECM and the recruitment of immune cells, and we suggest that ADAM12 will become a reliable biomarker for determining response to immunotherapy and the prognosis of patients with COAD.

HOXC11 positively regulates the long non-coding RNA HOTAIR and is associated with poor prognosis in colon adenocarcinoma.

Colorectal cancer ranks third in terms of incidence and second in terms of mortality worldwide. The homeobox transcript antisense intergenic RNA (HOTAIR), which was found to be located on the antisense chain of the homeobox C (HOXC) gene cluster, is a long non-coding RNA involved in multiple types of tumors. The role of HOXC11 in tumors remains unclear. Reverse transcription-quantitative PCR was performed to detect the expression level of HOXC11 in colon adenocarcinoma. Cell proliferation and invasion were assessed. RNase protection assay was used to test the possibility of RNA duplex formation. The increased expression and co-expression trend of HOXC11 and HOTAIR were identified in multiple types of cancer from The Cancer Genome Atlas and the results were validated in 12 colon adenocarcinoma and paired non-tumor tissue samples. The expression of HOXC11 and HOTAIR was found to be associated with poor prognosis in colon adenocarcinoma and kidney renal clear cell carcinoma. Furthermore, HOXC11 was found to positively regulate HOTAIR by RNA duplex formation and promoted the proliferation and invasion of colon adenocarcinoma cells.

Long non-coding RNA VPS9D1-AS1 promotes growth of colon adenocarcinoma by sponging miR-1301-3p and CLDN1.

Colon adenocarcinoma is a frequent malignancy among all colon cancer types. Long non-coding RNAs (lncRNAs) are involved in the progression of colon adenocarcinoma. This study aimed to uncover the molecular mechanism of VPS9D1-AS1 in regulating colon adenocarcinoma development. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) revealed that VPS9D1-AS1 expression was markedly upregulated in colon adenocarcinoma tissues and cell lines. Cell functional experiments showed that knockdown of VPS9D1-AS1 repressed the growth and invasion of colon adenocarcinoma cells but upregulated cell apoptosis. In addition, we confirmed the interaction of VPS9D1-AS1-miR-1301-3p-CLDN1 using a luciferase assay. Downregulation of miR-1301-3p promoted the progression of colon adenocarcinoma cells. In conclusion, VPS9D1-AS1 facilitated cell growth and suppressed apoptosis of colon adenocarcinoma cells by sponging miR-1301-3p and upregulating CLDN1, which may be effective therapeutic strategies for patients with colon adenocarcinoma.

Gene Expression Profiling of Tricarboxylic Acid Cycle and One Carbon Metabolism Related Genes for Prognostic Risk Signature of Colon Carcinoma.

Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide. Colon adenocarcinoma (COAD) is the most common pathological type of CRC and several biomarkers related to survival have been confirmed. Yet, the predictive effect of a single gene biomarker is not enough. The tricarboxylic acid (TCA) cycle and carbon metabolism play an important role in tumors. Thus, we aimed to identify new gene signatures from the TCA cycle and carbon metabolism to better predict the survival of COAD. This study performed mRNA expression profiling in large COAD cohorts (n = 417) from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and multivariate Cox regression analysis were performed, and receiver operating characteristic (ROC) curve was used to screen the variable combinations model which is most relevant to patient prognosis survival mostly. Univariable or multivariate analysis results showed that SUCLG2, SUCLG1, ACLY, SUCLG2P2, ATIC and ACO2 have associations with survival in COAD. Combined with clinical variables, we confirmed model 1 (AUC = 0.82505), most relevant to patient prognosis survival. Model 1 contains three genes: SUCLG2P2, SUCLG2 and ATIC, in which SUCLG2P2 and SUCLG2 were low-expressed in COAD, however, ATIC was highly expressed, and the expressions above are related to stages of CRC. Pearson analysis showed that SUCLG2P2, SUCLG2 and ATIC were correlated in normal COAD tissues, while only SUCLG2P2 and SUCLG2 were correlated in tumor tissues. Finally, we verified the expressions of these three genes in COAD samples. Our study revealed a possible connection between the TCA cycle and carbon metabolism and prognosis and showed a TCA cycle and carbon metabolism related gene signature which could better predict survival in COAD patients.

MicroRNA-148a-3p Directly Targets SERPINE1 to Suppress EMT-Mediated Colon Adenocarcinoma Progression.

AimThis research aimed at clarifying the intracellular effect of SERPINE1 in the progression of colon adenocarcinoma (COAD) and the underlying mechanism.MethodsWe obtained the expression profile of SERPINE1 in COAD via the Starbase database and verified it on COAD tissue samples through qRT-PCR and immunoblotting, respectively. Also, miRWalk, TargetScan and miRDB databases were adopted to generate the miRNA prediction that might target SERPINE1, and the gene target miR-148a-3p was confirmed using dual-luciferase assays. The effect of SERPINE1 and miR-148a-3p on COAD was further evaluated by cell experiments. MTT assay was used to detect the change of cell proliferation ability. The invasive and migratory capability of COAD cells was examined using transwell and would healing assays. Cell apoptosis was determined through flow cytometry. The expressions of genes and EMT-associated proteins were evaluated by qRT-PCR and immunoblotting. Further lucubration of the biological relevance of SERPINE1 and miR-148a-3p was conducted using rescue experiments.ResultsWe found that the expression quantities of SERPINE1 in COAD tissues and cell lines were higher than those in corresponding non-cancerous tissues and normal cells. When SERPINE1 expression is reduced, EMT process is inhibited, invasion and proliferation ability of COAD cells are obviously reduced, and apoptosis level is increased. Moreover, SERPINE1 was identified as the target gene of miR-148a-3p. When the expression of miR-148a-3p was enhanced, it was found that the expression of SERPINE1 was reduced. miR-148a-3p played the similar effect of si-SERPINE1 that suppressed the COAD progression. Additionally, we found out that SERPINE1 is validated in hindering the tumor healing effect of miR148a-3p in COAD, including cell growth and invasion.ConclusionOur study suggests that SERPINE1/miR-148a-3p axis has potential as prognostic markers of COAD and provides reference for the development of new therapies.

LncRNA IGFL2-AS1 Promotes the Proliferation, Migration, and Invasion of Colon Cancer Cells and is Associated with Patient Prognosis.

BackgroundLncRNAs play an important role in tumor initiation and development. However, the underlying involvement of lncRNA expression in colorectal carcinoma remains to be clarified.MethodsAll analyses were performed in R software v4.0, SPSS v13.0, and GraphPad Prism 8. The “limma” package was used to identify differentially expressed lncRNAs between two groups with the threshold of |logFC| >1 and P <0.05. The “Survival” package was used to conduct survival analysis. HCT8 and SE480 cell lines were used to conduct further phenotype experiments, including transwell, wound-healing, CCK8 and colony formation assay. Gene set enrichment analysis was used to explore the biological pathway difference in high and low IGFL2-AS1 patients.ResultsThe lncRNA IGFL2-AS1 was highly expressed in colon adenocarcinoma (COAD) tissue and cell lines (HCT116, HCT8, HCT129, and SW480). The COAD patients with high IGFL2-AS1 were associated with a worse prognosis. Meanwhile, the knockdown of IGFL2-AS1 could significantly suppress the proliferation and invasion of COAD cells. Gene set enrichment analysis showed that the top five biological pathways involving IGFL2-AS1 were angiogenesis, epithelial–mesenchymal transition, KRAS signaling, myogenesis, and coagulation. Western blot results showed that the inhibition of IGFL2-AS1 could significantly reduce the N-cadherin, HIF1A and KRAS protein expression, yet increase the E-cadherin protein level. IGFL2-AS1 was also positively correlated with M0 macrophages, M2 macrophages, and neutrophils but negatively correlated with CD4+ memory T cells and CD8+ T cells.ConclusionIGFL1-AS1 could seriously worsen patient outcomes and facilitate COAD progression, thus serving as an independent tumor marker.

ETV4 transcriptionally activates HES1 and promotes Stat3 phosphorylation to promote malignant behaviors of colon adenocarcinoma.

Colon adenocarcinoma (COAD) is the commonest type of colorectal cancer with high morbidity and mortality worldwide. ETS variant 4 (ETV4) is a member of the ETS transcription factors and is frequently involved in the progression of many cancers. This study focused on the relevance of ETV4 to the progression of COAD. ETV4 was highly expressed in the collected COAD tissues and acquired cells and indicated advanced Dukes staging in patients. Knockdown of ETV4 in COAD cells weakened proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) activity of cells. The downstream genes of ETV4 were predicted, and a Gene Ontology (GO) analysis was conducted to identify the key molecule involved. ETV4 bound to the promoter sequence of HES1 and activated its transcription. Further overexpression of HES1 restored the malignant behaviors of COAD cells. HES1 was also found to promote phosphorylation of Stat3. Similar results were reproduced in vivo where downregulation of ETV4 blocked the growth of xenograft tumors in nude mice. This study demonstrated that ETV4 encourages malignant development of COAD through activating HES1 transcription and Stat3 phosphorylation. This study may offer novel insights into COAD therapy.

Weighted Gene Co-expression Network Analysis Identified a Novel Thirteen-Gene Signature Associated With Progression, Prognosis, and Immune Microenvironment of Colon Adenocarcinoma Patients.

Colon adenocarcinoma (COAD) is one of the most common malignant tumors and has high migration and invasion capacity. In this study, we attempted to establish a multigene signature for predicting the prognosis of COAD patients. Weighted gene co-expression network analysis and differential gene expression analysis methods were first applied to identify differentially co-expressed genes between COAD tissues and normal tissues from the Cancer Genome Atlas (TCGA)-COAD dataset and GSE39582 dataset, and a total of 309 overlapping genes were screened out. Then, our study employed TCGA-COAD cohort as the training dataset and an independent cohort by merging the GES39582 and GSE17536 datasets as the testing dataset. After univariate and multivariate Cox regression analyses were performed for these overlapping genes and overall survival (OS) of COAD patients in the training dataset, a 13-gene signature was constructed to divide COAD patients into high- and low-risk subgroups with significantly different OS. The testing dataset exhibited the same results utilizing the same predictive signature. The area under the curve of receiver operating characteristic analysis for predicting OS in the training and testing datasets were 0.789 and 0.868, respectively, which revealed the enhanced predictive power of the signature. Multivariate Cox regression analysis further suggested that the 13-gene signature could independently predict OS. Among the 13 prognostic genes, NAT1 and NAT2 were downregulated with deep deletions in tumor tissues in multiple COAD cohorts and exhibited significant correlations with poorer OS based on the GEPIA database. Notably, NAT1 and NAT2 expression levels were positively correlated with infiltrating levels of CD8+ T cells and dendritic cells, exhibiting a foundation for further research investigating the antitumor immune roles played by NAT1 and NAT2 in COAD. Taken together, the results of our study showed that the 13-gene signature could efficiently predict OS and that NAT1 and NAT2 could function as biomarkers for prognosis and the immune response in COAD.

Expression and Clinical Significance of Lactate Dehydrogenase A in Colon Adenocarcinoma

Lactate dehydrogenase A (LDHA) is an important glycolytic enzyme that promotes glycolysis and plays a crucial role in cancer cell invasion and immune infiltration. However, the relevance of LDHA in colon adenocarcinoma (COAD) remains unclear. In this study, we analyzed the correlation between the expression of LDHA and clinicopathological characteristics in COAD using immunohistochemistry analysis, and then used integrative bioinformatics analyses to further study the function and role of LDHA in COAD. We found that LDHA was highly expressed in COAD tissues compared with adjacent normal tissues, and that COAD patients with high LDHA expression levels showed poor survival. In addition, LDHA expression was closely associated with the immune infiltrating levels of CD8+ T cells, neutrophils, and dendritic cells. Our findings highlight the potential role of LDHA in the tumorigenesis and prognosis of COAD. Furthermore, our results indicate that COAD is a novel immune checkpoint in the diagnosis and treatment of COAD.

Classification with respect to colon adenocarcinoma and colon benign tissue of colon histopathological images with a new CNN model: MA_ColonNET

AbstractColon cancer is a common type of carcinoma that occurs in the large intestine. This type of cancer affects millions of people around the world each year. Early and accurate diagnosis is very important in the treatment of colon cancer as in other types of cancer. Thanks to early and accurate diagnosis, many people can get rid of this disease with less damage. Medical imaging techniques are widely used in the early diagnosis, follow‐up, and after the treatment process of colon cancer. Therefore, manually controlling a large number of medical images and their interpretation is a difficult process and consumes more time. In addition, the interpretation of data with traditional methods in this process can cause misdiagnosis due to human errors. For this reason, computer‐aided systems can be used in the diagnosis of colon cancer in order to both help experts and carry out the process more quickly and successfully. In this study, a novel method named by us, CNN‐based, MA_ColonNET is developed for detecting colon cancer image data. A 45‐layer model in MA_ColonNET has been used to classify. A success (accuracy) rate of 99.75% has been achieved by means of the new model. It is shown that the proposed model can detect colon cancer earlier. In this way, the treatment process can be carried out more successfully.

CBX4 Provides an Alternate Mode of Colon Cancer Development via Potential Influences on Circadian Rhythm and Immune Infiltration.

The circadian machinery is critical for the normal physiological functions and cellular processes. Circadian rhythm disruption has been associated with immune suppression which leads to higher cancer risk, suggesting a putative tumor protective role of circadian clock homeostasis. CBX4, as an epigenetic regulator, has been explored for its involvement in tumorigenesis. However, little is known about the correlation between CBX4 and circadian rhythm disruption in colon cancer as well as the potential impact on the tumor immunity. A significant upregulation of CBX4 was identified in the TCGA colon adenocarcinoma (COAD) samples when compared with the normal controls (p < 0.001). This differential expression was confirmed at the protein level using colon adenocarcinoma tissue array (p < 0.01). CBX4 was up-regulated in the recurred/progressed colon cancer cases compared with the disease-free samples (p < 0.01), suggesting CBX4 as a potential predictor for poor prognosis. With regard to nodular metastasis, CBX4 was found to be associated with early onset of metastatic diseases but not late progression. The circadian rhythm is orchestrated by the alternating activation and suppression of the CLOCK/ARNTL-driven positive loop and the PER/CRY-controlled negative loop. In COAD, CBX4 was negatively correlated with CLOCK (p < 0.001), and positively correlated with PER1 (p < 0.001), PER3 (p < 0.01), and CRY2 (p < 0.001) as well as NR1D1 (p < 0.001), a critical negative regulator of the circadian clock. These interactions consistently impacted on patient survival based on the colorectal cancer cohorts GSE17536 and GSE14333 of PrognoScan. CBX4 showed significant negative correlations with infiltrating B cells (p < 0.05) and CD4+ T cells (p < 0.01), and positive correlations with myeloid derived suppressor cells (MDSCs) (p < 0.05) and cancer associated fibroblast (CAFs) (p < 0.001), as well as a low immunoscore. Moreover, CBX4 displayed significant correlations with diverse immune metagenes. PER1 and PER3, consistent with their coordinated expression with CBX4, also had strong correlations with these gene representatives in COAD, suggesting a potential interaction of CBX4 with the circadian machinery. Our studies implicate that CBX4 may contribute to colon cancer development via potential influence on circadian rhythm and immune infiltration. These findings provide new insights into deciphering the function of CBX4, and may contribute to the development of new targeting strategies.