scholarly journals Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

2021 ◽  
Author(s):  
Atma Ivancevic ◽  
David M Simpson ◽  
Edward B Chuong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Regulatory Networks ◽  
Specific Activity ◽  
Binding Activity ◽  
Endogenous Retroviruses ◽  
Oncogenic Signaling ◽  
Transcriptional Regulatory Networks ◽  
Growth And Survival ◽  
Functional Studies

Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the processes that configure these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are an abundant source of enhancers that show cancer-specific activity. In colorectal cancer and other epithelial tumors, AP1 signaling drives aberrant activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements are involved in regulating multiple genes associated with tumorigenesis, including ATG12. Within the human population, individual LTR10 elements show frequent structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers mediate transcriptional dysregulation in response to oncogenic signaling, and shape the evolution of cancer-specific regulatory networks.

scholarly journals Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3941
Author(s):  
Eun-Ji Ko ◽  
Mee-Sun Ock ◽  
Yung-Hyun Choi ◽  
Juan L. Iovanna ◽  
Seyoung Mun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Gene Knockout ◽  
Endogenous Retroviruses ◽  
Human Endogenous Retrovirus ◽  
Ros Generation ◽  
Nude Mouse Model ◽  
Env Protein

Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K env gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K env KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K env KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K env KO cells. Whereas, they were enhanced in HERV-K env over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K env KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K env KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K env KO cells. These results suggest that the HERV-K env gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway.

scholarly journals Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis

Medicina ◽  
2019 ◽  
Vol 55 (1) ◽  
pp. 20 ◽  
Author(s):  
Md. Rezanur Rahman ◽  
Tania Islam ◽  
Esra Gov ◽  
Beste Turanli ◽  
Gizem Gulfidan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regulatory Networks ◽  
Prognostic Biomarker ◽  
Drug Repositioning ◽  
Gene Expression Omnibus ◽  
Transcriptional Regulatory Networks ◽  
Survival Analyses ◽  
Drug Candidates ◽  
Protein Protein Interaction ◽  
Kaplan Meier

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report aimed to identify molecular biomarker signatures in CRC. We analyzed two microarray datasets (GSE35279 and GSE21815) from the Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein–protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity Map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. A total of 727 upregulated and 99 downregulated DEGs were detected. The PI3K/Akt signaling, Wnt signaling, extracellular matrix (ECM) interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and two microRNAs (miRNAs) (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan–Meier curves indicated remarkable performance of reporter molecules in the estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting the development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

scholarly journals ID:2037 Molecular mechanisms underlying resistance to MEK1/2 inhibitor in BRAF-mutated colorectal cancer

2017 ◽  
Vol 4 (S) ◽  
pp. 68
Author(s):  
Hong-Quan Duong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Scaffold Protein ◽  
Colorectal Carcinomas ◽  
Intrinsic Resistance ◽  
Oncogenic Signaling ◽  
Colorectal Cancer Cells

Colorectal carcinomas are characterized by multiple genetic alterations, including constitutive Wnt activity and gain-of-function mutations in K-RAS and B-RAF. BRAF encodes a Ser/Thr kinase acting in the Ras/MEK/ERK pathway and the V600E mutation found in 11% of colorectal cancers renders this kinase constitutively active. B-RAF mutated colorectal carcinomas represents a very aggressive entity with a poor prognosis. Understanding the molecular mechanisms activated downstream of mutated B-RAF is urgently needed to design new therapeutic avenues to treat B-ARF mutated colorectal carcinomas and to circumvent resistance to therapies targeting the Ras/Raf/MEK1/ERK1/2 pathway. In a search for candidates that critically contribute to both intrinsic and acquired resistance to MEK1 inhibition in B-RAF mutated colorectal cancer cells, we identified one scaffold protein whose expression is driven by both NF-kB and AP-1 families of transcription factors. This scaffold protein promotes the expression of HER2 and HER3 in colorectal cancer cells subjected to MEK1 or B-RAF inhibition (Selumetinib and Vemurafenib, respectively) and, as such, is critically involved in the intrinsic resistance to these targeted therapies. The same scaffold protein is also strongly induced in B-RAF but not K-RAS mutated colorectal cancer cells showing acquired resistance to MEK1 inhibition. Interfering with the expression of this scaffold protein circumvents both intrinsic and acquired resistance to Selumetinib in B-RAF mutated colorectal cancer cells. Our study defines a new molecular actor critically involved in oncogenic signaling pathways triggered by mutated B-RAF. Our study also defineS new combinatory therapies to better treat B-RAF-mutated colorectal carcinomas.

scholarly journals Knock-Down of LRP/LR Influences Signalling Pathways in Late Stage Colorectal Carcinoma Cells

2020 ◽  
Author(s):  
Leila Vania ◽  
Gavin Morris ◽  
Eloise Ferreira ◽  
Stefan Weiss
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Late Stage ◽  
Telomerase Activity ◽  
Laminin Receptor ◽  
Signalling Pathways ◽  
Continuous Growth ◽  
Growth And Survival ◽  
Knock Down ◽  
Colorectal Cancer Cells

Abstract BackgroundThe 37kDa/67kDa laminin receptor (LRP/LR) is involved in several tumourigenic-promoting processes including cellular viability maintenance and apoptotic evasion. Thus, the aim of this study was to assess the molecular mechanism of LRP/LR on apoptotic pathways in late stage (DLD-1) colorectal cancer cells upon siRNA-mediated down-regulation of LRP/LR. MethodssiRNAs were used to down-regulate the expression of LRP/LR in DLD-1 cells which was assessed using western blotting and qPCR. To evaluate the mechanistic role of LRP/LR, proteomic analysis of pathways involved in proliferation and apoptosis were investigated. The data from the study was analysed using a one-way ANOVA, followed by a two-tailed student’s t-test with a confidence interval of 95%. ResultsHere we show that knock-down of LRP/LR led to significant changes in the proteome of DLD-1 cells, exposing new roles of the protein. Moreover, analysis showed that LRP/LR may alter components of the MAPK, p53-apoptotic and autophagic signalling pathways to aid colorectal cancer cells in continuous growth and survival. Knock-down of LRP/LR also resulted in significant decreases in telomerase activity and telomerase-related proteins in the DLD-1 cells. ConclusionsThese findings show that LRP/LR is critically implicated in apoptosis and cell viability maintenance and suggest that siRNA-mediated knock-down of LRP/LR may be a possible therapeutic strategy for the treatment of colorectal cancer.

scholarly journals Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Eunsu Yoo ◽  
Jaehak Lee ◽  
Pattawika Lertpatipanpong ◽  
Junsun Ryu ◽  
Chong-Tai Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Bioactive Compound ◽  
Binding Activity ◽  
In Vitro Assays ◽  
Transcriptional Level ◽  
Wide Range ◽  
Colorectal Cancer Cells

Abstract Background A. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. Methods Our study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays. Results Both A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity. Conclusion In summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.

scholarly journals Chemoresistant colorectal cancer cells and cancer stem cells mediate growth and survival of bystander cells

2011 ◽  
Vol 105 (11) ◽  
pp. 1759-1767 ◽  
Author(s):  
D Bose ◽  
L J Zimmerman ◽  
M Pierobon ◽  
E Petricoin ◽  
F Tozzi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Growth And Survival ◽  
Colorectal Cancer Cells ◽  
Bystander Cells

scholarly journals Knock-down of LRP/LR influences signalling pathways in late-stage colorectal carcinoma cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Leila Vania ◽  
Gavin Morris ◽  
Eloise Ferreira ◽  
Stefan F. T. Weiss
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Late Stage ◽  
Telomerase Activity ◽  
Laminin Receptor ◽  
Signalling Pathways ◽  
Continuous Growth ◽  
Growth And Survival ◽  
Knock Down ◽  
Colorectal Cancer Cells

Abstract Background The 37 kDa/67 kDa laminin receptor (LRP/LR) is involved in several tumourigenic-promoting processes including cellular viability maintenance and apoptotic evasion. Thus, the aim of this study was to assess the molecular mechanism of LRP/LR on apoptotic pathways in late stage (DLD-1) colorectal cancer cells upon siRNA-mediated down-regulation of LRP/LR. Methods siRNAs were used to down-regulate the expression of LRP/LR in DLD-1 cells which was assessed using western blotting and qPCR. To evaluate the mechanistic role of LRP/LR, proteomic analysis of pathways involved in proliferation and apoptosis were investigated. The data from the study was analysed using a one-way ANOVA, followed by a two-tailed student’s t-test with a confidence interval of 95%. Results Here we show that knock-down of LRP/LR led to significant changes in the proteome of DLD-1 cells, exposing new roles of the protein. Moreover, analysis showed that LRP/LR may alter components of the MAPK, p53-apoptotic and autophagic signalling pathways to aid colorectal cancer cells in continuous growth and survival. Knock-down of LRP/LR also resulted in significant decreases in telomerase activity and telomerase-related proteins in the DLD-1 cells. Conclusions These findings show that LRP/LR is critically implicated in apoptosis and cell viability maintenance and suggest that siRNA-mediated knock-down of LRP/LR may be a possible therapeutic strategy for the treatment of colorectal cancer.

scholarly journals Identification of Prognostic Biomarker Signatures and Candidate Drugs in Colorectal Cancer: Insights from Systems Biology Analysis

2018 ◽  
Author(s):  
Rezanur Rahman ◽  
Tania Islam ◽  
Esra Gov ◽  
Beste Turanli ◽  
Gizem Gulfidan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Regulatory Networks ◽  
Prognostic Biomarker ◽  
Drug Repositioning ◽  
Gene Expression Omnibus ◽  
Transcriptional Regulatory Networks ◽  
Survival Analyses ◽  
Drug Candidates ◽  
Protein Protein Interaction ◽  
Kaplan Meier

Background and objectives: Colorectal cancer (CRC) is the second most common cause of cancer-related death in the world, but early diagnosis ameliorates the survival of CRC. This report directed to identify molecular biomarker signatures in CRC. Materials and Methods: We analyzed two microarray datasets (GSE35279 and GSE21815) from Gene Expression Omnibus (GEO) to identify mutual differentially expressed genes (DEGs). We integrated DEGs with protein-protein interaction and transcriptional/post-transcriptional regulatory networks to identify reporter signaling and regulatory molecules; utilized functional overrepresentation and pathway enrichment analyses to elucidate their roles in biological processes and molecular pathways; performed survival analyses to evaluate their prognostic performance; and applied drug repositioning analyses through Connectivity map (CMap) and geneXpharma tools to hypothesize possible drug candidates targeting reporter molecules. Results: A total of 727 up-regulated and 99 down-regulated DEGs were detected. The PI3K-Akt signaling, Wnt signaling, ECM-interaction, and cell cycle were identified as significantly enriched pathways. Ten hub proteins (ADNP, CCND1, CD44, CDK4, CEBPB, CENPA, CENPH, CENPN, MYC, and RFC2), 10 transcription factors (ETS1, ESR1, GATA1, GATA2, GATA3, AR, YBX1, FOXP3, E2F4, and PRDM14) and 2 miRNAs (miR-193b-3p and miR-615-3p) were detected as reporter molecules. The survival analyses through Kaplan Meier curves indicated remarkable performance of reporter molecules in estimation of survival probability in CRC patients. In addition, several drug candidates including anti-neoplastic and immunomodulating agents were repositioned. Conclusions: This study presents biomarker signatures at protein and RNA levels with prognostic capability in CRC. We think that the molecular signatures and candidate drugs presented in this study might be useful in future studies indenting development of accurate diagnostic and/or prognostic biomarker screens and efficient therapeutic strategies in CRC.

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