Colon Cancer Tumorigenesis Research Articles

OSI-027 inhibits the tumorigenesis of colon cancer through mediation of c-Myc/FOXO3a/PUMA axis.

Colon cancer is a gastrointestinal malignancy that is one of the leading causes of tumor-associated deaths. It has been reported that the mammalian target of rapamycin (mTOR) can lead to the progression of colon cancer. However, the mechanism by which mTOR inhibitor (OSI-027) mediates the tumorigenesis of colon cancer remains largely unknown. Cell function of colon cancer was investigated by cell counting kit-8 flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, quantitative real-time polymerase chain reaction and Western blot were used to investigate the mechanism underlying the function of OSI-027 in colon cancer. OSI-027 dose-dependently reduced colon cancer cell viability by inducing cell apoptosis. In addition, OSI-027 induced the apoptosis of colon cancer cells via upregulation of PUMA. OSI-027 promoted the expression of PUMA by activation of forkhead box protein O3a (FOXO3a), and c-Myc knockdown partially increased FOXO3a and PUMA levels. Moreover, OSI-027 attenuated the tumor growth of colon cancer through the mediation of the mTOR/c-Myc/FOXO3a axis. OSI-027 attenuates colon cancer progression through the mediation of the c-Myc/FOXO3a/PUMA axis. Thereby, this study might shed new insights on exploring the strategies against colon cancer.

Long non-coding RNA LINC00511 facilitates colon cancer development through regulating microRNA-625-5p to target WEE1

The altered part of long non-coding RNA LINC00511 (LINC00511) is extensively discussed in malignancies. Finitely, the mechanism of LINC00511 in colon cancer (CC) development lacks thorough explorations. Hence, this work is started from the LINC00511-mediated microRNA (miR)-625-5p/WEE1 axis in the CC process. LINC00511, miR-625-5p, and WEE1 levels were tested in CC tissues and cells. Subcellular localization of LINC00511 was clarified. CC cells were transfected with oligonucleotides that altered LINC00511, and miR-625-5p expression to define their performance in CC cell progression. The tumorigenic ability of cells was verified in xenografted tumors. CC tissues and cells highly expressed LINC00511 and WEE1 and lowly expressed miR-625-5p. LINC00511 was mainly localized in the cytoplasm. Deleted LINC00511 or restored miR-625-5p delayed cellular growth in CC. LINC00511 sponged miR-625-5p to target WEE1. Silenced miR-625-5p mitigated the role of depleted LINC00511, while inhibited WEE1 rescued the effect of silenced miR-625-5p on the biological functions of CC cells. It is summarized that down-regulated LINC00511 obstructs tumorigenesis of CC through restoring miR-625-5p and silencing WEE1, consolidating a basal reference for CC-oriented therapy.

A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer

Colon cancer (CC) is the third most common neoplasm and the fourth cause of cancer-related death worldwide in both sexes. It has been established that inflammation plays a critical role in tumorigenesis and progression of CC. Immune, stromal and tumor cells supply the tumor microenvironment with pro-inflammatory cytokines such as interleukin 1β, TNFα, IL-6 and IL-11, to hyperactivate signaling pathways linked to cancerous processes. Recent findings suggest a putative role of microRNAs (miRNAs) in the progression and management of the inflammatory response in intestinal diseases. Moreover, miRNAs are able to regulate expression of molecular mediators that are linking inflammation and cancer. In this work a miRNA panel differentially expressed between healthy, inflammatory bowel disease (IBD) and CC tissue was established. Identified miRNAs regulate signaling pathways related to inflammation and cancer progression. An inflammation associated-miRNA panel composed of 11-miRNAs was found to be overexpressed in CC but not in inflamed or normal tissues (miR-21-5p, miR-304-5p, miR-577, miR-335-5p, miR-21-3p, miR-27b-5p, miR-335-3p, miR-215-5p, miR-30b-5p, miR-192-5p, miR-3065-5p). The association of top hit miRNAs, miR-3065-5p and miR-30b-5p expression with overall survival of CC patients was demonstrated using Kaplan-Meier tests. Finally, differential miRNA expression was validated using an inflammation-associated CC model induced by Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) to compare miRNA expression in normal and inflamed tissue versus CC tissues. Based on these findings we propose the identified inflammatory miRNA panel as a potent diagnostic tool for CC determination.

Establishment and validation of a prognostic model based on HRR-related lncRNAs in colon adenocarcinoma

BackgroundColon cancer (CRC) is the second leading cause of cancer-related death, and its 5-year survival rate is very low. Homologous recombination repair (HRR) is deficient in most colon cancer. Some long non-coding RNAs (lncRNAs) participate in tumorigenesis of colon cancer through the HRR pathway. We aim to establish a prognostic model based on the HRR-related lncRNAs, expecting to provide a new strategy for precision treatment development in colon cancer.MethodsPearson’s correlation was used to identify the HRR-related prognostic lncRNAs in the TCGA-COAD cohort. The TCGA-COAD cohort was randomized into the training set and the testing set. LASSO Cox regression was used to establish the model which was analyzed in the training set and validated in the testing set and the entire TCGA-COAD cohort. Finally, we explored the potential biological function of our model.ResultsA prognostic model was established based on nineteen HRR-related lncRNAs in the training set. COAD patients were scored by the uniform formula and divided into high-risk and low-risk groups based on the median risk score. Patients with high-risk scores indicated poor prognosis in the training set, and the result was confirmed in the testing set and the entire TCGA-COAD cohort (all p < 0.01). Multivariable analysis suggested that our model was an independent factor for overall survival in COAD. The area under the curve (AUC) and C-index indicated that our model had better predictive efficiency than other indicators in the TCGA-COAD cohort. Functional enrichment analysis suggested that our model was associated with the MAPK pathway in COAD. Besides, our model was positively correlated with the HRD scores.ConclusionA new prognostic model was established based on nineteen HRR-related lncRNAs which had excellent predictive efficiency on the prognosis of COAD. This prognostic model may provide a new strategy for prognostic prediction of COAD patients.

Shifting the Focus of Signaling Abnormalities in Colon Cancer.

Simple SummaryThe major signaling pathways in colon cancer are WNT, RAS, and TGF-β. Components of these pathways are mutated in the majority of colon cancers, resulting in aberrantly high or low activity of the pathway. The functional consequences of the mutations reflect the behavior of these signaling pathways in intestinal stem cells. To better understand the roles of each pathway, we cover the basic function as well as points of intersection between the different pathways, to describe how they function individually, as well as together, to regulate cell proliferation.Colon cancer tumorigenesis occurs incrementally. The process involves the acquisition of mutations which typically follow an established pattern: activation of WNT signaling, activation of RAS signaling, and inhibition of TGF-β signaling. This arrangement recapitulates, to some degree, the stem cell niche of the intestinal epithelium, which maintains WNT and EGF activity while suppressing TGF-β. The resemblance between the intestinal stem cell environment and colon cancer suggests that the concerted activity of these pathways generates and maintains a potent growth-inducing stimulus. However, each pathway has a myriad of downstream targets, making it difficult to identify which aspects of these pathways are drivers. To address this, we utilize the cell cycle, the ultimate regulator of cell proliferation, as a foundation for cross-pathway integration. We attempt to generate an overview of colon cancer signaling patterns by integrating the major colon cancer signaling pathways in the context of cell replication, specifically, the entrance from G1 into S-phase.

Epigenetic modifications inhibit the expression of MARVELD1 and in turn tumorigenesis by regulating the Wnt/β-catenin pathway in pan-cancer.

MARVEL domain-containing 1 (MARVELD1) is one of the MARVEL domain-containing proteins. Expression of MARVELD1 in tumor and non-tumor tissues, the relationship between its expression and cancer prognosis, and upstream regulation of MARVELD1 were examined using pan-cancer data from The Cancer Genome Atlas. MARVELD1 expression was significantly downregulated in tissues used for pan-cancer analysis compared to that in normal tissues. Low expression of MARVELD1 was associated with poor disease outcomes in pan-cancer. Colon cancer patients with low expression of MARVELD1 had worse progression free survival and overall survival than those with high expression levels in our cohort. Hypermethylation and histone modification in the MARVELD1 promoter locus synergistically affected its expression in pan-cancer. The function of MARVELD1 in colon cancer remains to be studied. Gene Ontology enrichment analysis revealed that MARVELD1 may modulate processes associated with inhibition of tumorigenesis in colon cancer. Both upstream transcription factors and downstream functional enrichment of MARVELD1 were related to the Wnt/β-catenin signaling pathway. Overexpression of MARVELD1 inhibited the expression of β-catenin and its entry into the nucleus. MARVELD1 also inhibited the proliferation, migration, and invasion of colon cancer cells. With Wnt/β-catenin activator LiCl treatment, rescue experiments demonstrated that the role of MARVELD1 in colon cancer progression was dependent on the Wnt/β-catenin pathway. These results indicate that MARVELD1 acts as a tumor suppressor and inhibits tumorigenesis via the Wnt/β-catenin pathway.

DHOK Exerts Anti-Cancer Effect Through Autophagy Inhibition in Colorectal Cancer.

DHOK (14,15β-dihydroxyklaineanone) is a novel diterpene isolated from roots of Eurycoma longifolia Jack, a traditional herb widely applied in Southeast Asia. It is reported that DHOK has cytotoxic effect on cancer cells, but its anti-cancer mechanism has still been not clear. In our study, we first observed that DHOK inhibits cell proliferation of colorectal cancer cells in a time- and dose-dependent manner. Next, we performed transcriptome sequencing to identify the targets of DHOK and found that autophagy-related signaling pathways are involved under DHOK treatment. Indeed, in DHOK-treated cells, the level of autophagosome marker LC3 and the formation of GFP-LC3 puncta were decreased, indicating the reduction of autophagy. Moreover, confocal microscopy results revealed the lysosomal activity and the formation of autolysosomes are also inhibited. Our western blotting results demonstrated the activation of mammalian target of rapamycin (mTOR) signaling pathway by DHOK, which may be attributed to the enhancement of ERK and AKT activity. Functionally, activation of autophagy attenuated DHOK-caused cell death, indicating that autophagy serves as cell survival. In xenograft mouse model, our results also showed that DHOK activates the mTOR signaling pathway, decreases autophagy level and inhibits the tumorigenesis of colon cancer. Taken together, we revealed the molecular mechanism of DHOK against cancer and our results also demonstrate great potential of DHOK in the treatment of colorectal cancer.

Comprehensive Analysis of Subtype-Specific Molecular Characteristics of Colon Cancer: Specific Genes, Driver Genes, Signaling Pathways, and Immunotherapy Responses.

Colon cancer is a complex, heterogeneous disease. The Colorectal Cancer Subtyping Consortium reported a novel classification system for colon cancer in 2015 to better understand its heterogeneity. This molecular classification system divided colon cancer into four distinct consensus molecular subtypes (CMS 1, 2, 3, and 4). However, the characteristics of different colon cancer molecular subtypes have not been fully elucidated. This study comprehensively analyzed the molecular characteristics of varying colon cancer subtypes using multiple databases and algorithms, including The Cancer Genome Atlas (TCGA) database, DriverDBv3 database, CIBERSORT, and MCP-counter algorithms. We analyzed the alterations in the subtype-specific genes of different colon cancer subtypes, such as the RNA levels and DNA alterations, and showed that specific subtype-specific genes significantly affected prognosis. We also explored the changes in colon cancer driver genes and representative genes of 10 signaling pathways in different subtypes. We identified genes that were altered in specific subtypes. We further detected the infiltration of 22 immune cell types in four colon cancer subtypes and the infiltration level of primary immune cells among these subtypes. Additionally, we explored changes in immune checkpoint genes (ICGs) and immunotherapy responses among different colon cancer subtypes. This study may provide clues for the molecular mechanism of tumorigenesis and progression in colon cancer. It also offers potential biomarkers and targets for the clinical diagnosis and treatment of different colon cancer subtypes.

Evaluation of Visceral Adiposity Index and Vitamin D Status in Colon Cancer: Is Visceral Obesity the Missing Link?

Background: We aimed to evaluate the effect of visceral obesity and vitamin D status on colon cancer and to investigate the possible link between visceral obesity and vitamin D in those patients. Methods: This case-control study included 60 colon cancer patients and 40 subjects as control. Clinical, anthropometric, and pathological data were collected. Calculation of visceral adiposity index (VAI) and detection of vitamin D (25(OH)D) levels were performed and compared between groups. Results: There were significant differences in VAI and level of 25(OH)D between both groups. Moreover, we found a significantly higher prevalence of vitamin D deficiency in the patient’ group (53.3%) versus the control group (32.5%). There was a significant different mean of VAI in vitamin D deficient patients versus non-deficient patients (P = 0.024). We found a significantly different means of VAI and vitamin D in the patients’ group with different TNM stages, as higher stages are associated with a lower level of vitamin D and higher VAI. Conclusions: VAI and 25(OH)D were different in colon cancer patients compared with control. Likewise, they had different means with different TNM stages. Vitamin D may augment the inflammatory status in visceral obesity which is involved in tumorigenesis of colon cancer. J Endocrinol Metab. 2021;11(5):115-122 doi: https://doi.org/10.14740/jem762

Evaluation of Visceral Adiposity Index and Vitamin D Status in Colon Cancer: Is Visceral Obesity the Missing Link?

Background: We aimed to evaluate the effect of visceral obesity and vitamin D status on colon cancer and to investigate the possible link between visceral obesity and vitamin D in those patients. Methods: This case-control study included 60 colon cancer patients and 40 subjects as control. Clinical, anthropometric, and pathological data were collected. Calculation of visceral adiposity index (VAI) and detection of vitamin D (25(OH)D) levels were performed and compared between groups. Results: There were significant differences in VAI and level of 25(OH)D between both groups. Moreover, we found a significantly higher prevalence of vitamin D deficiency in the patient’ group (53.3%) versus the control group (32.5%). There was a significant different mean of VAI in vitamin D deficient patients versus non-deficient patients (P = 0.024). We found a significantly different means of VAI and vitamin D in the patients’ group with different TNM stages, as higher stages are associated with a lower level of vitamin D and higher VAI. Conclusions: VAI and 25(OH)D were different in colon cancer patients compared with control. Likewise, they had different means with different TNM stages. Vitamin D may augment the inflammatory status in visceral obesity which is involved in tumorigenesis of colon cancer. J Endocrinol Metab. 2021;11(5):115-122 doi: https://doi.org/10.14740/jem762

Identification of Prognostic Genes for Colon Cancer through Gene Co-expression Network Analysis.

The present study was aimed to identify novel key genes, prognostic biomarkers and molecular pathways implicated in tumorigenesis of colon cancer. The microarray data GSE41328 containing 10 colon cancer samples and 10 adjacent normal tissues was analyzed to identify 4763 differentially expressed genes. Meanwhile, another microarray data GSE17536 was performed for weighted gene co-expression network analysis (WGCNA). In present study, 12 co-expressed gene modules associated with tumor progression were identified for further studies. The red module showed the highest association with pathological stage by Pearson's correlation analysis. Functional enrichment analysis revealed that genes in red module focused on cell division, cell proliferation, cell cycle and metabolic related pathway. Then, a total of 26 key hub genes were identified, and GEPIA database was subsequently selected for validation. Holliday junction-recognizing protein (HJURP) and cell division cycle 25 homolog C (CDC25C) were identified as effective prognosis biomarkers, which were all detrimental to prognosis. Gene set enrichment analyses (GSEA) found the two hub genes were enriched in "oocyte meiosis", "oocyte maturation that are progesterone-mediated", "p53 signaling pathway", and "cell cycle". Furthermore, the immunohistochemistry and western blotting showed that HJURP was highly expressed in colon cancer tissue. HJURP was identified as a key gene associated with colon cancer progression and prognosis by WGCNA, which might influence the prognosis by regulating cell cycle pathways.

A micro-peptide encoded by HOXB-AS3 promotes the proliferation and viability of oral squamous cell carcinoma cell lines by directly binding with IGF2BP2 to stabilize c-Myc.

HOXB-AS3 is a long non-coding RNA and recent studies have shown that the HOXB-AS3-encoded micro-peptide was associated with the progression of colon cancer tumorigenesis; however, the biofunction of HOXB-AS3 varies in different types of cancer and the potential function in oral squamous cell carcinoma (OSCC) is still unknown. The Cancer Genome Atlas (TCGA) database was searched and the expression patterns of HOXB-AS3 in head and neck carcinoma were analyzed. Reverse transcription-quantitative PCR and western blot analysis was used to measure the mRNA and protein expression level of HOXB-AS3 in patients with OSCC, respectively. Next, HOXB-AS3 was knocked down in 2 OSCC cell lines to investigate the biological function of the HOXB-AS3-encoded protein using a Cell Counting Kit-8 and colony formation assays. To further identify the potential mechanism of the HOXB-AS3-encoded protein, co-immunoprecipitation was also used to detect the interaction between HOXB-AS3 and IGF2BP2, while HOXB-AS3 was re-expressed to determine whether the HOXB-AS3-encoded protein and not HOXB-AS3 exerted its function in OSCC. HOXB-AS3 was upregulated in OSCC tissues, in both TCGA database and in patients with OSCC recruited into the present study. HOXB-AS3 was associated with poor prognosis in OSCC. The proliferation and viability decreased in the 2 OSCC cell lines following knock down of HOXB-AS3. HOXB-AS3 was also found to encode a protein that directly interacted with IGF2BP2 and thereby promoted the stability of c-myc. Taken together, the results from the present study indicated that increased HOXB-AS3 expression was associated with poor prognosis in OSCC. This indicated that HOXB-AS3 and its encoded protein promoted OSCC cell proliferation and viability by maintaining c-Myc mRNA stability by directly binding to IGF2BP2.

LINC01287 facilitates proliferation, migration, invasion and EMT of colon cancer cells via miR-4500/MAP3K13 pathway

BackgroundAccumulated studies indicate that aberrant expression of long noncoding RNAs (lncRNAs) is associated with tumorigenesis and progression of colon cancer. In the present study, long intergenic non-protein coding RNA 1287 (LINC01287) was identified to up-regulate in colon cancer by transcriptome RNA-sequencing, but the exact function remained unclear.MethodsTranscriptome RNA-sequencing was conducted to identify dysregulated lncRNAs. Expression of LINC01287 was evaluated by real-time quantitative PCR. The downstream targets of LINC01287 and miR-4500 were verified by luciferase reporter assay, pull down assay and western blot. The potential functions of LINC01287 were evaluated by cell viability assay, colony formation assay, soft agar assay, flow cytometry, transwell migration and invasion assay, and tumor xenograft growth in colon cancer cells.ResultsOur results indicated that LINC01287 was up-regulated in colon cancer patients. High LINC01287 expression was associated with advanced TNM stage, lymph node metastasis, distant metastasis and shorter overall survival. Knockdown of LINC01287 inhibited cell growth, colony formation in plates and soft agar, transwell cell migration and invasion, and epithelial-mesenchymal transition (EMT) of colon cancer cells, while LINC01287 overexpression had contrary effects. In addition, LINC01287 mediated MAP3K13 expression by sponging miR-4500, thus promoted NF-κB p65 phosphorylation. Restored MAP3K13 expression or miR-4500 knockdown partially abrogated the effects of silencing LINC01287 in colon cancer cells.ConclusionOur findings demonstrated that the LINC01287/miR-4500/MAP3K13 axis promoted progression of colon cancer. Therefore, LINC01287 might be a potential therapeutic target and prognostic marker for colon cancer patients.

Abstract 2430: HOXC6 promotes tumorigenesis of right-sided colon cancer

Abstract Colorectal cancer (CRC) is a common malignant tumor of the digestive tract, with high heterogeneity. The significant difference in prognosis and therapeutic response of left and right colon cancer is a hot spot in the field of colorectal cancer (CRC) in recent years. The prognosis and drug response of right-sided colon cancer were significantly worse than that of the left-sided colon cancer. Clinical trials have proved that MSI-H colon cancer is mainly seen in the right-sided colon cancer, and the prognosis is better than that of MSS. Because MSS and MSI-H patients have different molecular characteristics and prognosis, we searched for key genes of RCC and LCC in MSS and MSI-H groups respectively. The difference between the prognosis and the curative effect of the left and right-sided colon cancer is essentially the difference between the molecular pathology and the immune environment. Therefore, the aim of this study is to explore the molecular mechanism related to the prognosis of left and right-sided colon cancer in order to provide a molecular target for accurate treatment of left and right-sided colon cancer. First of all, bioinformatics methods were used to screen the right and left-sided CRC differentially expressed genes in MSS and MSI-H. The expression levels of these key genes in clinical samples and cell lines were detected by RT-qPCR and IHC, and their correlation with survival prognosis was analyzed. Homeobox C6(HOXC6)were selected. First, HOXC6 stable overexpressed and knockout colorectal cancer cell lines were established and its biological function was preliminarily studied, including transwell, wound-healing assay and CCK-8 tests. Finally, the ChIP-seq data were used to analyze the carcinogenic mechanism of HOXC6. Bioinformatics methods were used to screen 30 differentially expressed genes in MSS right and left CRC, of which HOXC6 in the right colon cancer was significantly higher than that in the left-sided colon cancer, which was positively correlated with TNM staging and lymph node metastasis. Kaplan-Meier survival analysis showed that the expression of HOXC6 was negatively correlated with the total survival of CRC patients (p=0.002). RT-qPCR and IHC showed that the expression of HOXC6 in the right-sided colon cancer was higher than that in the left, P&amp;lt;0.05. Functional experiments showed that Hoxc6 promoted the growth, invasion and migration. ChIP-seq data and real-time PCR results showed that SPOCD1 and S100A1 were the target genes of HOXC6. Citation Format: Xin li, Jinhong Xia, Dengbo Ji, Jin Gu. HOXC6 promotes tumorigenesis of right-sided colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2430.

Identification and Verification of a 17 Immune-Related Gene Pair Prognostic Signature for Colon Cancer.

Background Colon cancer (CC) is a malignant tumor with a high incidence and poor prognosis. Accumulating evidence shows that the immune signature plays an important role in the tumorigenesis, progression, and prognosis of CC. Our study is aimed at establishing a novel robust immune-related gene pair signature for predicting the prognosis of CC. Methods Gene expression profiles and corresponding clinical information are obtained from two public data sets: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, GSE39582). We screened out immune-related gene pairs (IRGPs) associated with prognosis in the discovery cohort. Lasso-Cox proportional hazard regression was used to develop the best prognostic signature model. According to this, the patients in the validation cohort were divided into high immune-risk group and low immune-risk group, and the prediction ability of the signature model was verified by survival analysis and independent prognostic analysis. Results A total of 17 IRGPs composed of 26 IRGs were used to construct a prognostic-related risk scoring model. This model accurately predicted the prognosis of CC patients, and the patients in the high immune-risk group indicated poor prognosis in the discovery cohort and validation cohort. Besides, whether in univariate or multivariate analysis, the IRGP signature was an independent prognostic factor. T cell CD4 memory resting in the low-risk group was significantly higher than that in the high-risk group. Functional analysis showed that the biological processes of the low-risk group included “TCA cycle” and “RNA degradation,” while the high-risk group was enriched in the “CAMs” and “focal adhesion” pathways. Conclusion We have successfully established a signature model composed of 17 IRGPs, which provides a novel idea to predict the prognosis of CC patients.

Role of ZBTB7A zinc finger in tumorigenesis and metastasis.

The zinc finger and BTB (broad-complex, tramtrack and bric a brac) domain containing protein 7A (ZBTB7A) is a pleiotropic transcription factor that plays an important role in various stages of cell proliferation, differentiation, and other developmental processes. ZBTB7A is a member of the POK family that directly and specifically binds to short DNA recognition sites located near their target genes thereby acting as transcriptional activator or repressor. ZBTB7A overexpression has been associated with tumorigenesis and metastasis in various human cancer types, including breast, prostate, lung, ovarian, and colon cancer. However in some instances downregulation of ZBTB7A results in tumor progression, suggesting its role as a tumor suppressor. ZBTB7A is involved with complicated regulatory networks which include protein-protein and protein-nucleic acid interactions. ZBTB7A involvement in cancer progression and metastasis is perhaps enabled through the regulation of various signaling pathways depending on the type and genetic context of cancer. The association of ZBTB7A with other proteins affects cancer aggressiveness, therapeutic resistance and clinical outcome. This review focuses on the involvement of ZBTB7A in various signaling pathways and its role in cancer progression. We will also review the literature on ZBTB7A and cancer which could be potentially explored for its therapeutic implications.

Construction of competing endogenous RNA network and identification of novel molecular biomarkers in colon cancer: A bioinformatic analysis.

Colon cancer patients suffer from high incidence and mortality rates worldwide. More novel molecular biomarkers should be used for the diagnosis and treatment of colon cancer. Long noncoding RNAs (lncRNAs) are found to be involved in colon cancer tumorigenesis and metastasis. This study aimed to identify novel lncRNAs in colon cancer.Two independent datasets (GSE70880 and GSE110715) were downloaded from the Gene Expression Omnibus database and merged with the sva package. R software was used to distinguish differentially expressed lncRNAs and mRNAs in the merged dataset. The competing endogenous RNA (ceRNA) network was constructed using differentially expressed lncRNAs and mRNAs with Cytoscape. Differentially expressed RNAs in the ceRNA network were further verified using the Cancer Genome Atlas database. Gene oncology analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment and survival analysis were also performed to identify hub genes.A total of 99 differentially expressed lncRNAs and 95 differentially expressed mRNAs were identified in the merged database. Ten lncRNAs, 8 miRNAs, and 6 mRNAs were involved in the ceRNA network, in which LINC00114 and UCA1 were highly expressed in colon cancer. They were both associated with early tumor stages and might be used for the early diagnosis of colon cancer. High expression of LINC00114 can lead to poor overall survival of colon cancer patients. Furthermore, new pathways such as LINC00114/miR-107/PCKS5, UCA1/miR-107/PCKS5, and UCA1/miR-129-5p/SEMA6A were identified.Two novel lncRNAs (LINC00114 and UCA1) in colon cancer were identified by bioinformatics analysis. They might contribute to the occurrence and development of colon cancer. In addition, LINC00114 may be involved in the overall survival of colon cancer patients.

MicroRNA-4284 inhibits colon cancer epithelial-mesenchymal transition by down-regulating Perilipin 5

Background: MicroRNA (miR) has been suggested in the development of several types of cancer; yet, the exact function of miR-4284 in colon cancer remains elusive.&#x0D; Methods: MiR-4284 expression was assessed in normal colon cell line CCD-18Co, and HT-29 and SW480 cell lines representing human colon cancer. Potential target gene of miR-4284 was predicted using TargetScanHuman, and experimentally verified using luciferase report assay. Wound-healing, cell invasion and attachment were evaluated to determine the effect of miR-4284 on the migration, invasion, and metastatic properties of colon cancer cell lines. Expression of epithelial-mesenchymal transition (EMT) phenotypic protein hallmarks, including N-cadherin, E-cadherin, as well as Vimentin, was also evaluated.&#x0D; Results: MiR-4284 was significantly decreased in colon cancer cell lines, and Perilipin 5 (PLIN5) was found to be directly targeted by miR-4284. Ectopic expression of miR-4284 significantly reduced endogenous expression level of PLIN5 in colon cancer cell lines, suppressing migration, invasion, and metastatic phenotypes. In addition, re-introducing miR-4284 reversed the expression profile of EMT markers.&#x0D; Conclusion: Our findings for the first time identify miR-4284 as an anti-tumor miRNA in colon cancer, which acts to reduce PLIN5 and inhibit EMT, leading to inhibited colon cancer tumorigenesis. These results highlight the potential of miR-4284 as a therapeutic target in metastatic colon cancer.

RETRACTED: MicroRNA-498 disturbs the occurrence and aggression of colon cancer through targeting MDM2 to mediate PPARγ ubiquitination

MicroRNA (miR)-498 is indicative of diagnostic and prognostic significance in colon cancer (CC). On the basis of that, this study is initiated from miR-498, combined with mouse double minute 2 (MDM2)/peroxisome proliferator-activated receptor γ (PPARγ) ubiquitination axis to have an insight into CC progression. CC tissues and their adjacent tissues were harvested to determine miR-498, MDM2 and PPARγ expression. The interactions among these three factors were identified. The screened human CC cells were transfected with miR-498/MDM2-related sequences, followed by detection of the biological behaviors of CC cells. Xenografted tumors were taken to validate cell experimental outcomes. Bioinformatics and dual-luciferase report analysis verified the targeting relationship between miR-498 and MDM2. The relation between MDM2 and PPARγ was identified by immunoprecipitation and in vivo deubiquitination. Down-regulated miR-498 and PPARγ and up-regulated MDM2 were exhibited in CC. miR-498 targeted MDM2 while MDM2 mediated PPARγ ubiquitination. Elevated miR-498 or reduced MDM2 impaired cell viability, colony-forming, migratory and invasive activities and enhanced apoptosis in CC. Elevated MDM2 abolished the effects of up-regulated miR-498 on the biological behaviors of CC cells. Elevated miR-498 or reduced MDM2 depressed tumorigenic ability of CC cells in mice. It is conclusive that restoring miR-498 depresses MDM2 to modify PPARγ ubiquitination, thereby disturbing the tumorigenesis of CC. This work constructs the base for exploring novel agents in treating CC.

EHD2 Overexpression Suppresses the Proliferation, Migration, and Invasion in Human Colon Cancer

Background: To investigate how EHD2 influences the development of colon cancer. Methods: Immunohistochemistry of 90 colon cancer tissue specimens were determined the expression of EHD2. The lentivirus-EHD2-transfected colon cancer cells were conducted to evaluate the biological behaviors. Results: EHD2 was closely associated with clinic pathological parameters (p < 0.001). EHD2 upregulation was relative with a longer overall survival. The results of the univariate and multivariate analyses indicated that EHD2 could be an independent prognosis marker. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest. Conclusions: EHD2 might represent a therapeutic target of colon cancer. IMPACT STATEMENT What is already known on this subject? Membrane trafficking is crucial for cell proliferation, differentiation and apoptosis, especially tumorigenesis and development. EHD2 proteins play an important role in the regulation of membrane trafficking in endocytosis. EHD2 has been suggested to participate in the occurrence of some malignancies. What are the new findings? EHD2 could be an independent prognosis marker in colon cancer. EHD2 overexpression suppressed cell invasion and proliferation, but enhanced cell apoptosis and cell cycle arrest in vitro. EHD2 overexpression markedly increased the expression of EMT marker E-cadherin in colon cancer. How might it impact on clinical practice in the foreseeable future? EHD2 overexpression may inhibit tumorigenesis in colon cancer through the modulation of E-cadherin, the critical marker of EMT which is closely related to invasion and distant metastasis of tumor cells.