scholarly journals Restoring HOXD10 Exhibits Therapeutic Potential for Ameliorating Malignant Progression and 5-Fluorouracil Resistance in Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Weijie Pan ◽  
Kaijing Wang ◽  
Jiayong Li ◽  
Hanhua Li ◽  
Yuchan Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Therapeutic Potential ◽  
Methylation Status ◽  
Suppressor Gene ◽  
Resistant Cell ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Normal Tissues

Emerging evidence suggests that hypermethylation of HOXD10 plays an important role in human cancers. However, the biological and clinical impacts of HOXD10 overmethylation and its downstream targets in colorectal cancer remain unknown. We evaluated the methylation level of HOXD10 in paired cancer and normal tissues (n = 42) by using pyrosequencing, followed by validation of the methylation status of HOXD10 from The Cancer Genome Atlas (TCGA) datasets with 302 cancer tissues and 38 normal tissues. The biological function of HOXD10 was characterized in cell lines. We further evaluated the effects of HOXD10 and its targets on chemoresistance in our established resistant cell lines and clinical cohort (n = 66). HOXD10 was found frequently methylated in colorectal cancer, and its hypermethylation correlates with its low expression level, advanced disease, and lymph node metastasis. Functionally, HOXD10 acts as a tumor suppressor gene, in which HOXD10-expressing cells showed suppressed cell proliferation, colony formation ability, and migration and invasion capacity. Mechanistically, DNMT1, DNMT3B, and MeCP2 were recruited in the HOXD10 promoter, and demethylation by 5-Aza-2′-deoxycytidine (5-Aza-CdR) treatment or MeCP2 knockdown can sufficiently induce HOXD10 expression. HOXD10 regulates the expressions of miR-7 and IGFBP3 in a promoter-dependent manner. Restoration of the expression of HOXD10 in 5-fluorouracil (5-FU)-resistant cells significantly upregulates the expressions of miR-7 and IGFBP3 and enhances chemosensitivity to 5-FU. In conclusion, we provide novel evidence that HOXD10 is frequently methylated, silenced, and contributes to the development of colorectal cancers. Restoration of HOXD10 activates the expressions of miR-7 and IGFBP3 and results in an inhibited phenotype biologically, suggesting its potential therapeutic relevance in colorectal cancer (CRC).

scholarly journals SNORA71A Promotes Colorectal Cancer Cell Proliferation, Migration, and Invasion

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhengxiang Zhang ◽  
Yunxiang Tao ◽  
Qingling Hua ◽  
Juan Cai ◽  
Xiaobing Ye ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Sensory Perception ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion ◽  
Integrated Analysis ◽  
Small Rna Sequencing ◽  
Chemical Stimulus ◽  
Normal Tissues

Small nucleolar RNAs (snoRNAs) play a crucial role during colorectal cancer (CRC) development. The study of SNORA71A is few, and its role in CRC is unknown. This study focused on screening abnormal snoRNAs in CRC and exploring the role of key snoRNA in CRC. The expression pattern of snoRNAs in 3 CRC and 3 normal colon tissues was detected via small RNA sequencing. The six candidate snoRNAs were identified by quantitative PCR (qPCR). Subsequently, the expression level of SNORA71A was further verified through the Cancer Genome Atlas (TCGA) data analysis and qPCR. The CCK8 and transwell assays were used to detect the functional role of SNORA71A in CRC cells. The integrated analysis of snoRNA expression profile indicated that a total 107 snoRNAs were significantly differentially expressed (DE) in CRC tissues compared with normal tissues, including 45 upregulated and 62 downregulated snoRNAs. Bioinformatics analysis revealed that the DE snoRNAs were mainly implicated in “detection of chemical stimulus involved in sensory perception of smell” and “sensory perception of smell” in the biological process. The DE snoRNAs were preferentially enriched in “olfactory transduction” and “glycosphingolipid biosynthesis-ganglio series pathway.” The expression of SNORA71A was upregulated in CRC tissues and cells. SNORA71A expression showed statistically significant correlations with TNM stage ( P = 0.0196 ) and lymph node metastasis ( P = 0.0189 ) and can serve as biomarkers for CRC. Importantly, SNORA71A significantly facilitated the CRC cell proliferation, migration, and invasion. Our findings indicate that SNORA71A screened by sequencing acted as an oncogene and promoted proliferation, migration, and invasion ability of CRC cells.

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 Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

2020 ◽  
Author(s):  
Liang Jing ◽  
Junhui Wu ◽  
Xiaocheng Tang ◽  
Min Ma ◽  
Fei Long ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Tumor Stage ◽  
Circular Rna ◽  
Gene Expression Omnibus ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Normal Tissues ◽  
Node Metastasis

Abstract Background: Circular RNAs (circRNAs) are a novel class of noncoding RNAs. Increasing evidence indicates that circRNAs play an important role in the occurrence and development of tumors. However, the role of circRNA hsa_circ_0044556 in the progression of colorectal cancer (CRC) remains unclear. Methods: First, we searched for differentially expressed circRNAs using a circRNA microarray in paired CRC and adjacent normal tissues. The circRNA hsa_circ_0044556 was screened out from the existing CRC circRNA microarray in the Gene Expression Omnibus database and our microarray. The clinical significance of hsa_circ_0044556 expression level in CRC patients was then investigated. Finally, the functions of the targets of this circRNA were determined in CRC cell lines.Results:Hsa_circ_0044556 was highly expressed in CRC patients and was positively correlated with tumor stage and lymph node metastasis. In CRC cell lines, the proliferation, migration, and invasion of cancer cells were inhibited by knocking down hsa_circ_0044556 expression.Conclusion: Hsa_circ_0044556 promoted the progression of CRC. It is possible that hsa_circ_0044556 will become a novel biomarker or therapeutic target for CRC.

scholarly journals Epigenetic Inactivation of Protocadherin 10 by Methylation in Colorectal Cancer

2020 ◽  
Author(s):  
Mohammad Amin Kerachian ◽  
Sahar Tavakolian ◽  
Matineh Barati Bagherabad ◽  
Dor Mohammad Kordi-Tamandani ◽  
Mohammad Reza Abbaszadegan
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
High Specificity ◽  
Suppressor Gene ◽  
Potential Candidate ◽  
Critical Function ◽  
Normal Tissues

Aberrant promoter methylation of CpG islands of tumor-suppressor genes has been recognized as one of the important tumor markers for cancer detection. The aim of this study was to investigate the promoter methylation status of protocadherin 10 (PCDH10), a tumor suppressor gene, in Iranian colorectal cancer (CRC) patients. Cancerous and the adjacent normal tissues obtained from 38 CRC patients were used to assess the methylation status of PCDH10 with Methylation Specific PCR, in addition, to study the expression level of this gene by quantitative PCR. The relationship between hypermethylation and the demographic characteristics of these patients was analyzed. The promoter methylation level of PCDH10 was statistically different between tumoral and normal tissues in CRC patients. Twenty-seven out of 38 patients showed hypermethylation with a sensitivity of 73% and a specificity of 97%. PCDH10 expression decreased in 15 cases (46%) as 16 cases (50 %) showed overexpression and 1 case (4%) had no changes. Not a significant association was reported between PCDH10 hypermethylation and the clinicopathological characteristics (P>0.05). Our results indicated that PCDH10 methylation has a critical function in CRC, with a nearly elevated sensitivity and a high specificity in the Iranian population, qualify it as a potential candidate biomarker. © 2019 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran 2019;57(8):472-477.

scholarly journals MicroRNA-188-5p targeting Forkhead Box L1 promotes colorectal cancer progression via activating Wnt/β-catenin signaling

2020 ◽  
Author(s):  
Jialin Wu ◽  
Zehong Chen ◽  
Wenwei Liu ◽  
Yongxin Zhang ◽  
Wei Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Beta Catenin ◽  
Advanced Tumor Stage ◽  
Normal Tissues ◽  
Advanced Tumor

MicroRNA-188-5p (miR-188) enhances oncologic progression in various human malignancies. This study aimed to explore its role in colorectal cancer (CRC). Human CRC tissues paired with normal tissues, and several CRC cell lines were utilized. Real-time quantitative PCR was applied to measure the expression of miR-188. Overexpression and knockdown were used to access the function of miR-188 and to investigate whether FOXL1/Wnt signaling mediates such function. The proliferation, migration and invasion of cancer cells were evaluated by CCK8, wound-healing and transwell assays, respectively. Whether FOXL1 acted as a direct target of miR-188 was verified by dual-luciferase reporter assays. Levels of miR-188 were upregulated in CRC tissues than in paired-normal tissues, as well as in various CRC cell lines. High expression of miR-188 was strongly associated with advanced tumor stage, accompanied with significant tumor cell proliferation, invasion and migration. It was confirmed that FOXL1 played positive crosstalk between miR-188 regulation and downstream Wnt/&beta;-catenin signaling activation. All findings indicate that miR-188 promotes CRC cell proliferation and invasion through targeting FOXL1/Wnt signaling and could be served as a potential therapeutic target for human CRC in the future.

scholarly journals Identification of circular RNA hsa_circ_0044556 and its effect on the development and progression of colorectal cancer

2020 ◽  
Author(s):  
Liang Jing ◽  
Junhui Wu ◽  
Xiaocheng Tang ◽  
Min Ma ◽  
Fei Long ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Tumor Stage ◽  
Circular Rna ◽  
Gene Expression Omnibus ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Normal Tissues ◽  
Node Metastasis

Abstract Background Circular RNAs (circRNAs) are a novel class of noncoding RNAs. Increasing evidence indicates that circRNAs play an important role in the occurrence and development of tumors. However, the role of circRNAs in the development and progression of colorectal cancer (CRC) remains unclear. Methods First, we searched for differentially expressed circRNAs using a circRNA microarray in paired CRC and adjacent normal tissues. The circRNA hsa_circ_0044556 was screened out from the existing CRC circRNA microarray in the Gene Expression Omnibus database and our microarray. The clinical significance of hsa_circ_0044556 expression level in CRC patients was then investigated. Finally, the functions of the targets of this circRNA were determined in CRC cell lines. Results hsa_circ_0044556 was highly expressed in CRC patients and was positively correlated with tumor stage and lymph node metastasis. In CRC cell lines, the proliferation, migration, and invasion of cancer cells were inhibited by knocking down hsa_circ_0044556 expression. Conclusion hsa_circ_0044556 promoted the development and progression of CRC. It is possible that hsa_circ_0044556 will become a novel biomarker or therapeutic target for CRC.

scholarly journals The miR-106b/NR2F2-AS1/PLEKHO2 Axis Regulates Migration and Invasion of Colorectal Cancer through the MAPK Pathway

2021 ◽  
Vol 22 (11) ◽  
pp. 5877
Author(s):  
Shuzhen Liu ◽  
Guoyan An ◽  
Qing Cao ◽  
Tong Li ◽  
Xinyu Jia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mapk Signaling ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Normal Tissues

Increasing numbers of miRNAs have been observed as oncogenes or tumor suppressors in colorectal cancer (CRC). It was recently reported that hsa-miR-106b-5p (miR-106b) promoted CRC cell migration and invasion. However, there were also studies showing contradictory results. Therefore, in the present study, we further explore the role of miR-106b and its downstream networks in the carcinogenesis of CRC. We observed that the expression of miR-106b is significantly increased in Pan-Cancer and CRC tissues compared with normal tissues from The Cancer Genome Atlas (TCGA) database. Furthermore, we used Transwell, Cell Counting Kit-8, and colony formation assays to clarify that miR-106b promotes the migratory, invasive, and proliferative abilities of CRC cells. For the first time, we systematically screened the target mRNAs and lncRNAs of miR-106b using TCGA database and the bioinformatics algorithms. Dual-luciferase reporter assay confirmed that NR2F2-AS1 and PLEKHO2 are the direct targets of miR-106b. Furthermore, NR2F2-AS1 acts as a competing endogenous RNA (ceRNA) to regulate PLEKHO2 expression by sponging miR-106b. The results of Gene set enrichment analysis (GSEA) and Western blot indicated that they play important roles in CRC progression by regulating MAPK pathway. Thus, miR-106b/NR2F2-AS1/PLEKHO2/MAPK signaling axis may suggest the potential usage in CRC treatment.

scholarly journals FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Sun ◽  
Lin Wang ◽  
Xuehu Xu ◽  
Puqing Han ◽  
Jinghao Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Hct116 Cell ◽  
Suppressor Gene ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Forkhead Box ◽  
The Relationship

Objective: Adenomatous polyposis coli 2 (APC2) is a colorectal cancer (CRC) tumor-suppressor gene. The progression of several kinds of cancer is closely associated with Forkhead box O4 (FOXO4). However, the function of FOXO4 in CRC is unclear. This study focused on the role of FOXO4 and the relationship between FOXO4 and APC2 in CRC migration and metastasis.Methods: The expressions of FOXO4, APC2, and p(S37)-β-catenin were detected in CRC tissues by immunohistochemistry, and their correlation was analyzed using the Spearman coefficient. Chromatin immunoprecipitation was used to test whether FOXO4 binds and regulates APC2 as a transcription factor. Either FOXO4 overexpression or APC2 knockdown was performed in CRC cell lines. The roles of FOXO4 and APC2 were investigated in CRC migration and metastasis.Results: FOXO4 was downregulated in CRC tissues compared with normal tissues and positively correlated with APC2 and p(S37)-β-catenin. FOXO4 could combine the promoter region of APC2 to upregulate its expression and increase the phosphorylated degradation of β-catenin. Stemness genes (CD133, ABCG1, and SOX2) were inhibited by FOXO4 overexpression in SW620 and HCT116 cell lines. Overexpressed FOXO4 suppressed epithelial–mesenchymal transition and the migration of CRC cell lines and metastasis of HCT116 in both the spleen and liver of nude mice, which was reversed by APC2 knockdown.Conclusion: This research demonstrates that overexpressed FOXO4 inhibits the migration and metastasis of CRC cells by enhancing the APC2/β-catenin axis, suggesting that FOXO4 is a potential therapeutic target of CRC.

scholarly journals Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer

2018 ◽  
Vol 46 (6) ◽  
pp. 2197-2214 ◽  
Author(s):  
Zhonghua Ma ◽  
Peng Peng ◽  
Jing Zhou ◽  
Bingqing Hui ◽  
Hao Ji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
The Cancer Genome Atlas ◽  
Current Evidence ◽  
Migration And Invasion ◽  
Mice Model ◽  
Tissue Samples

Background/Aims: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. Current evidence has revealed the key roles of long non-coding RNAs (IncRNAs) in multiple cancers, including CRC. In this study we identified the lncRNA SH3PXD2A-AS1 as a novel molecule associated with CRC progression by analyzing the publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to examine the expression levels of SH3PXD2A-AS1 in CRC tissue samples and CRC cell lines. Cell viability examination, colony-formation experiments, ethynyl deoxyuridine (Edu) assays and flow cytometry were performed to investigate the roles of SH3PXD2A-AS1 in CRC proliferation, cell cycle regulation, and apoptosis. Transwell assays were used to explore the effects of SH3PXD2A-AS1 on CRC cells migration and invasion. A nude mice model was used to assess the effects of SH3PXD2A-AS1 on tumorigenesis in vivo. Subcellular fractionation, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to detect the molecular mechanisms of SH3PXD2A-ASl-mediated gene expression. Rescue assays were used to determine whether P57 and Kruppel-like factor 2 (KLF2) were involved in SH3PXD2A-ASl-dependent CRC proliferation. Results: We firstly found that SH3PXD2A-AS1 was significantly upregulated in CRC tissues and cell lines, and overexpression of SH3PXD2A-AS1 was correlated with tumor size, TNM stage, and lymph node metastasis in patients with CRC. Furthermore, SH3PXD2A-AS1 knockdown inhibited CRC cells proliferation, migration and invasion in vitro, and suppressed tumorigenesis in vivo. Mechanistic studies indicated that SH3PXD2A-AS1 could epiqenetically repress P57 and KLF2 expression through interaction with EZH2. Rescue experiments suggested that SH3PXD2A-ASl-mediated oncogenesis was impaired by overexpression of P57 or KLF2. Interestingly, the expression of SH3PXD2A-AS1 was inversely correlated with the expression of P57 and KLF2 in CRC tissue samples. Conclusion: Our research presents the first evidence that SH3PXD2A-AS1 acts as an oncogene in CRC, and may be a promising diagnostic or therapeutic target in patients with CRC.

scholarly journals Identification of circular RNA hsa_circ_0044556 and its effect on the progression of colorectal cancer

2020 ◽  
Author(s):  
Liang Jing ◽  
Junhui Wu ◽  
Xiaocheng Tang ◽  
Min Ma ◽  
Fei Long ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Tumor Stage ◽  
Circular Rna ◽  
Gene Expression Omnibus ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Normal Tissues ◽  
Node Metastasis

Abstract Background: Circular RNAs (circRNAs) are a novel class of noncoding RNAs. Increasing evidence indicates that circRNAs play an important role in the occurrence and development of tumors. However, the role of circRNA hsa_circ_0044556 in the progression of colorectal cancer (CRC) remains unclear. Methods: First, we searched for differentially expressed circRNAs using a circRNA microarray in paired CRC and adjacent normal tissues. The circRNA hsa_circ_0044556 was screened out from the existing CRC circRNA microarray in the Gene Expression Omnibus database and our microarray. The clinical significance of hsa_circ_0044556 expression level in CRC patients was then investigated. Finally, the functions of the targets of this circRNA were determined in CRC cell lines.Results:Hsa_circ_0044556 was highly expressed in CRC patients and was positively correlated with tumor stage and lymph node metastasis. In CRC cell lines, the proliferation, migration, and invasion of cancer cells were inhibited by knocking down hsa_circ_0044556 expression.Conclusion: Hsa_circ_0044556 promoted the progression of CRC. It is possible that hsa_circ_0044556 will become a novel biomarker or therapeutic target for CRC.

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