scholarly journals XRCC2-Deficient Cells are Highly Sensitive to 5-Fluorouracil in Colorectal Cancer

2017 ◽  
Vol 43 (3) ◽  
pp. 1207-1219 ◽  
Author(s):  
Yong-zhou Zhang ◽  
Ji-Hong An ◽  
Yu-Xin Liu ◽  
Xian-Chuang Wu ◽  
Shan-Shan Han ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Anticancer Agents ◽  
Clinical Importance ◽  
Prognostic Indicator ◽  
Tnm Staging ◽  
Dna Lesions ◽  
Cell Cycle Distribution ◽  
Dna Double Strand Breaks ◽  
Normal Tissues

Background/Aims: Inhibition of the repair of 5-fluorouracil (5-FU)-induced DNA lesions may improve the responses of tumors to anticancer agents. XRCC2 is a key factor in DNA repair. However, the role of XRCC2 in the chemoresistance of colorectal cancer (CRC) treated with 5-FU remains unclear. The aim of this study is to investigate whether XRCC2 expression affects the chemosensitivity of colorectal cancer. Methods: XRCC2 expression in CRC tissues was assessed, and the outcomes were analyzed to determine the clinical importance of XRCC2 expression. Following treatment with 5-FU, the effect of XRCC2 on proliferation was evaluated via a CCK-8 assay, the effects on cell cycle distribution and apoptosis were analyzed using flow cytometry, and γH2AX foci formation assays were performed to examine the influence of 5-FU on DNA Double-strand breaks(DSBs) repair in CRC cells. Results: XRCC2 expression in CRC tissues was significantly higher than that in normal tissues, and this increased XRCC2 expression was associated with advanced T staging, M staging, TNM staging, Duke’s staging, and greater liver and lymph node metastases. XRCC2 expression might be an independent prognostic indicator for CRC patients. Patients with negative XRCC2 expression exhibit greater sensitivity to treatment with 5-FU-based chemotherapy than those with positive XRCC2 expression. Moreover, our observations revealed that the knockdown of XRCC2 in CRC cells increased the sensitivities to 5-FU in terms of cell proliferation, apoptosis and cell cycle arrest. DNA DSBs repair was slower in the XRCC2-deficient cells than in the XRCC2-wild type cells. Conclusion: Our study demonstrated that XRCC2 might play an important role in CRC and function as a novel prognostic indicator and that the down-regulation of XRCC2 may be useful for sensitizing CRC cells during 5-FU chemotherapy.

scholarly journals Molecular subtyping improves prognostication of Stage 2 colorectal cancer

2019 ◽  
Author(s):  
Rachel Violet Purcell ◽  
Sebastian Schmeier ◽  
Yee Chen Lau ◽  
John F Pearson ◽  
Francis A Frizelle
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Tissue Bank ◽  
Prognostic Indicator ◽  
Good Prognosis ◽  
Tnm Staging ◽  
Tumour Suppressor Genes ◽  
Molecular Subtyping ◽  
Prognostic Effect ◽  
Treatment Naïve

Abstract Background: Post-surgical staging is the mainstay of prognostic stratification for colorectal cancer (CRC). Here, we compare TNM staging to consensus molecular subtyping (CMS) and assess the value of subtyping in addition to stratification by TNM. Methods: Three hundred and eight treatment-naïve colorectal tumours were accessed from our institutional tissue bank. CMS typing was carried out using tumour gene-expression data. Post-surgical TNM-staging and CMS were analysed with respect to clinicopathologic variables and patient outcome. Results : CMS alone was not associated with survival, while TNM stage significantly explained mortality. Addition of CMS to TNM-stratified tumours showed a prognostic effect in stage 2 tumours; CMS3 tumours had a significantly lower overall survival (P = 0.006). Stage 2 patients with a good prognosis showed immune activation and up-regulation of tumour suppressor genes. Conclusions : Although stratification using CMS does not outperform TNM staging as a prognostic indicator, gene-expression based subtyping shows promise for improved prognostication in stage 2 CRC.

scholarly journals Long non-coding RNA RP11-468E2.5 curtails colorectal cancer cell proliferation and stimulates apoptosis via the JAK/STAT signaling pathway by targeting STAT5 and STAT6

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Li Jiang ◽  
Xu-Hai Zhao ◽  
Yin-Ling Mao ◽  
Jun-Feng Wang ◽  
Hui-Jun Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Target Genes ◽  
Biological Activities ◽  
Janus Kinase ◽  
Normal Tissues ◽  
Stat Signaling

Abstract Background Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of colorectal cancer (CRC). This study aims to examine the effects of lncRNA RP11-468E2.5 and its target genes (STAT5 and STAT6) on the biological activities of CRC cells via the Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway. Methods We initially screened the GEO database for differentially expressed lncRNAs related to CRC and then made a prediction of the implicated target genes. Then we collected CRC tissues and adjacent normal tissues from 169 CRC patients. Human CRC HCT116 and SW480 cells were treated with small interference RNA (siRNA) against RP11-468E2.5, AG490 (an inhibitor of the JAK/STAT signaling pathway), or both in combination. Next, we measured the effects of RP11-468E2.5 treatment on cellular activities such as cell viability, cycle distribution and cell apoptosis, and studied interactions among RP11-468E2.5, STAT5/STAT6, and the JAK/STAT signaling pathway. Finally, an in vivo tumor formation assay was performed to observe the effect of RP11-468E2.5 on tumor growth. Results The CRC-related gene microarray data showed low expression of RP11-468E2.5 in CRC surgical specimens. However, RP11-468E2.5 was confirmed to target STAT5 and STAT6, which participate in the JAK/STAT signaling pathway. CRC tissues showed lower expression of RP11-468E2.5, higher expression of STAT5, STAT6 and of the cell cycle marker Cyclin D1 (CCND1), compared to the findings in adjacent normal tissues. The treatment of siRNA against RP11-468E2.5 increased expression of JAK2, STAT3, STAT5, STAT6, CCND1 and Bcl-2 along with the extent of STAT3, STAT5 and STAT6 phosphorylation, while lowering expression of P21 and P27. Treatment with AG490 exhibited approximately opposite effects, whereas siRNA against RP11-468E2.5 treatment stimulated CRC cell proliferation and reduced cell apoptosis, while promoting cell cycle entry; AG490 treatment reversed these results. Conclusions Altogether, we conclude that up-regulation of RP11-468E2.5 inhibits the JAK/STAT signaling pathway by targeting STAT5 and STAT6, thereby suppressing cell proliferation and promoting cell apoptosis in CRC.

scholarly journals O11 Activated leukocyte cell adhesion molecule (ALCAM/CD166) is an important clinical and prognostic indicator in pancreatic cancer

2021 ◽  
Vol 108 (Supplement_5) ◽  
Author(s):  
Y M Yang ◽  
A J Sanders ◽  
X Dong ◽  
Y Cui ◽  
C Hao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Prognostic Indicator ◽  
Tnm Staging ◽  
Normal Tissues ◽  
Heterotypic Interactions ◽  
A Cell ◽  
Cancer Tissues

Abstract Introduction Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a cell adhesion molecule and one of the potential metastasis ‘soil’ receptors that via homotypic and heterotypic interactions, mediates cell adhesion. The present study investigated the clinical, pathological and prognostic value of ALCAM in patients with pancreatic cancer. Method Pancreatic cancer tissues (n = 223), collected immediately after surgery, were analysed for levels of the ALCAM transcripts. The expression was analysed against clinical, pathological and clinical outcome of the patients. We validated our findings with an available TCGA database (n = 117), including correlations with the ALCAM interactive partners. Result Pancreatic cancer tissues had significantly higher levels of ALCAM transcript than normal tissues (P < 0.00001). There were no significant differences with staging, differentiation and tumour locations. Tumours from patients who died of pancreatic cancer had significantly high levels of ALCAM compared with those who lived (P = 0.018), finding also supported by ROC analysis (P = 0.016). Multivariant analysis showed ALCAM as an independent prognosis factor for overall survival (hazardous ratio 5.485), with both nodal status and TNM staging contributing to the model (HR 2.578 and 3.02 respectively). A surprising finding was the relationship between ALCAM expression and microvessel embolism of tumour cells (P = 0.021, with vs without tumour embolism). ALCAM significantly correlated with its interactive protein partners including CD6 and ITGB1, but not L1CAM. Conclusion ALCAM/CD166 expression is aberrant in pancreatic cancer and the raised expression is an independent prognostic factor for the survival of the patients and the microvessel embolism by cancer cells. Take-home Message ALCAM is a prognostic indicator for survival and tumour embolism in pancreatic cancer

eIF6 Promotes Colorectal Cancer Proliferation and Invasion by Regulating AKT-Related Signaling Pathways

2019 ◽  
Vol 15 (7) ◽  
pp. 1556-1567 ◽  
Author(s):  
Jinxin Lin ◽  
Xihu Yu ◽  
Liping Xie ◽  
Puning Wang ◽  
Tuoyang Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Large Scale ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Initiation Factor ◽  
Cancer Proliferation ◽  
Functional Studies ◽  
Normal Tissues ◽  
Cancer Signaling

Although abnormal expression of eukaryotic initiation factor 6 (eIF6) has been found in several human solid tumors, the functions and underlying mechanisms of eIF6 in the progression of colorectal cancer (CRC) still needs further elucidation. In the present study, large-scale gene analysis based on Oncomine and The Cancer Genome Atlas (TCGA) database revealed significantly higher baseline expression of eIF6 in colorectal cancer than in normal tissues. Furthermore, our Chinese cohort study revealed that high expression of eIF6 was correlated with aggressive characteristics and poor survival in CRC patients. Functional studies using magnetic nanoparticle extraction indicated that eIF6 was an oncogene in CRC cells. Regarding its mechanism, through Gene ontology (GO) and KEGG pathway analysis based on TCGA RNAseq database, we found that eIF6 can activate multiple AKT-related cancer signaling pathways, such as p-AKT\MMP1\cyclinD1\Bcl2-related signaling, to regulate cell proliferation, invasion, cell cycle and apoptosis in CRC. Collectively, these findings suggested that eIF6 can positively regulate AKT-related cancer signaling and enhance tumorigenicity in CRC, and may serve as a potential prognostic indicator and therapeutic target in CRC.

Hsa-miR-186-5p regulates TGFβ signaling pathway through expression suppression of SMAD6 and SMAD7 genes in colorectal cancer

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Zahra Bayat ◽  
Zahra Ghaemi ◽  
Mehrdad Behmanesh ◽  
Bahram M. Soltani
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Annexin V ◽  
Luciferase Assay ◽  
Tgfβ Signaling ◽  
Normal Tissues ◽  
A Cell ◽  
Bona Fide ◽  
And Migration ◽  
Hct116 Cells

Abstract TGFβ signaling is a known pathway to be involved in colorectal cancer (CRC) progression and miRNAs play crucial roles by regulating different components of this pathway. Hence, finding the link between miRNAs and the pathway could be beneficial for CRC therapy. Array data indicated that miR-186-5p is a differentially expressed miRNA in colorectal Tumor/Normal tissues and bioinformatics tools predicted SMAD6/7 (inhibitory SMADs) as bona fide targets of this miRNA. Here, we intended to investigate the regulatory effect of the miR-186-5p expression on TGFβ signaling in CRC. Firstly, the miR-186-5p overexpression in HCT116 cells resulted in a significant reduction of SMAD6/7 expression, measured through RT-qPCR. Then, the direct interactions of miR-186-5p with SMAD6/7 3′UTRs were supported through dual luciferase assay. Furthermore, miR-186-5p overexpression suppressed proliferation, cell viability, and migration while, it increased apoptosis in CRC cells, assessed by cell cycle, MTT, scratch and Annexin V/PI apoptosis assays. Consistently, miR-186-5p overexpression resulted in reduced CyclinD1 protein using western blot, and also resulted in increased P21 and decreased c-Myc expression. Overall, these results introduced miR-186-5p as a cell cycle suppressor through downregulation of SMAD6/7 expression. Thus, miR-186-5p might be served as a novel tumor suppressive biomarker and therapeutic target in CRC treatment.

UCA1, a long non-coding RNA up-regulated in colorectal cancer influences cell proliferation, apoptosis and cell cycle distribution

Pathology ◽  
2014 ◽  
Vol 46 (5) ◽  
pp. 396-401 ◽  
Author(s):  
Yu Han ◽  
Ying-nan Yang ◽  
Heng-heng Yuan ◽  
Ting-ting Zhang ◽  
Hong Sui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Distribution ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Molecular subtyping improves prognostication of Stage 2 colorectal cancer

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Rachel V. Purcell ◽  
Sebastian Schmeier ◽  
Yee Chen Lau ◽  
John F. Pearson ◽  
Francis A. Frizelle
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Tissue Bank ◽  
Prognostic Indicator ◽  
Good Prognosis ◽  
Tnm Staging ◽  
Tumour Suppressor Genes ◽  
Molecular Subtyping ◽  
Prognostic Effect ◽  
Treatment Naïve

Abstract Background Post-surgical staging is the mainstay of prognostic stratification for colorectal cancer (CRC). Here, we compare TNM staging to consensus molecular subtyping (CMS) and assess the value of subtyping in addition to stratification by TNM. Methods Three hundred and eight treatment-naïve colorectal tumours were accessed from our institutional tissue bank. CMS typing was carried out using tumour gene-expression data. Post-surgical TNM-staging and CMS were analysed with respect to clinicopathologic variables and patient outcome. Results CMS alone was not associated with survival, while TNM stage significantly explained mortality. Addition of CMS to TNM-stratified tumours showed a prognostic effect in stage 2 tumours; CMS3 tumours had a significantly lower overall survival (P = 0.006). Stage 2 patients with a good prognosis showed immune activation and up-regulation of tumour suppressor genes. Conclusions Although stratification using CMS does not outperform TNM staging as a prognostic indicator, gene-expression based subtyping shows promise for improved prognostication in stage 2 CRC.

scholarly journals Worenine reverses the Warburg effect and inhibits colon cancer cell growth by negatively regulating HIF-1α

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Lijiang Ji ◽  
Weixing Shen ◽  
Feng Zhang ◽  
Jie Qian ◽  
Jie Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cancer Cell ◽  
Warburg Effect ◽  
Lactate Production ◽  
Colorectal Cancer Cell ◽  
Cell Cycle Distribution ◽  
Cancer Cell Growth ◽  
The Warburg Effect

Abstract Background Some natural compounds inhibit cancer cell growth in various cancer cell lines with fewer side effects than traditional chemotherapy. Here, we explore the pharmacological effects and mechanisms of worenine (isolated from Coptis chinensis) against colorectal cancer. Methods The effects of worenine on colorectal cancer cell proliferation, colony formation and cell cycle distribution were measured. Glycolysis was investigated by examining glucose uptake and consumption, lactate production, and the activities and expressions of glycolysis enzymes (PFK-L, HK2 and PKM2). HIF-1α was knocked down and stimulated in vitro to investigate the underlying mechanisms. Results Worenine somewhat altered the glucose metabolism and glycolysis (Warburg effect) of cancer cells. Its anti-cancer effects and capability to reverse the Warburg effect were similar to those of HIF-1α siRNA and weakened by deferoxamine (an HIF-1α agonist). Conclusion It is suggested that worenine targets HIF-1α to inhibit colorectal cancer cell growth, proliferation, cell cycle progression and the Warburg effect.

scholarly journals The relationship between miR-219-5p Gene Polymorphisms and the prognosis of colorectal cancer

2020 ◽  
Author(s):  
Yang Yan ◽  
Xiaohui Du ◽  
Shaoyou Xia ◽  
Songyan Li ◽  
Da Teng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regression Analysis ◽  
Prognostic Value ◽  
Cox Regression ◽  
Malignant Tumors ◽  
Survival Rates ◽  
Tnm Staging ◽  
Cox Regression Analysis ◽  
Normal Tissues ◽  
Kaplan Meier

Abstract Background Colorectal cancer (CRC) is one of the most common malignant tumors, its morbidity and mortality are increasing year by year, it is a serious threat to people's health. Some studies have reported that miR-219-5p acts as a tumor suppressor in some malignant tumors. So the purpose of this study was to investigate the prognostic value of miR-219-5p expression in CRC patients. Methods QRT-PCR was used to detect the expression levels of miR-219-5p in CRC tissues and corresponding normal tissues (P < 0.001). The prognostic value of miR-219-5p in CRC was analyzed by Kaplan-Meier and Cox regression analysis. Results The results indicated that the expression of miR-219-5p was significantly lower in CRC tissues, and its expression was closely correlated with tumor differentiation, TNM staging and lymph node metastasis (all P < 0.05). Moreover, Kaplan Meier survival analysis showed that the patients with low expression of miR-219-5p had worse overall survival rates (P < 0.05). Cox regression analysis further demonstrated that miR-219-5p expression was an independent prognostic factor for survival time in CRC patients (P = 0.018, HR = 2.026 and 95%CI: 1.127–3.643). Conclusions All the results suggest that miR-219-5p expression can be used as a potential prognostic biomarker for CRC patients.

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