• ABC transporter
• Chemotherapy
• Drug resistance
• MDR
• MicroRNA
• Multidrug resistance

• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/metabolism
• Drug Resistance, Neoplasm/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Resistance, Multiple

• ABC transporters
• Anticancer drugs
• Cancer
• Multidrug resistance

• Humans
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/genetics
• Neoplasms/pathology
• Drug Resistance, Neoplasm/genetics
• ATP-Binding Cassette Transporters/metabolism
• ATP-Binding Cassette Transporters/genetics
• Drug Resistance, Multiple/genetics
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Animals
• Neoplasm Proteins/metabolism
• Neoplasm Proteins/genetics

• Biomarkers
• Cardiomyopathies
• E2F family
• Therapeutic targets
• Transcription factors

• Humans
• Cardiomyopathies/metabolism
• Cardiomyopathies/pathology
• Cardiomyopathies/genetics
• E2F Transcription Factors/metabolism
• E2F Transcription Factors/genetics
• Animals
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/pathology
• Apoptosis

• BUB1
• DTL
• E2F1
• Melanoma
• Pathogenesis

• Melanoma/pathology
• Melanoma/metabolism
• Melanoma/genetics
• Humans
• E2F1 Transcription Factor/metabolism
• E2F1 Transcription Factor/genetics
• Cell Movement/genetics
• Cell Proliferation
• Cell Line, Tumor
• Animals
• Gene Expression Regulation, Neoplastic
• Protein Serine-Threonine Kinases/metabolism
• Protein Serine-Threonine Kinases/genetics
• Mice
• Skin Neoplasms/pathology
• Skin Neoplasms/genetics
• Skin Neoplasms/metabolism
• Extracellular Signal-Regulated MAP Kinases/metabolism
• Signal Transduction

• QN202130 Academy-level Science and Technology Plan of The First Affiliated Hospital of Shihezi University
• No. 81972565 the General Program of the National Natural Science Foundation of China

• E2F
• HPV
• ageing
• oral cancer
• therapeutic targets
• transcription factors

• ARF
• E2F
• p53
• pRB

• Biomarker
• Chemosensitization
• Chemotherapy
• Prostate cancer
• Radiation
• microRNA

• Male
• Humans
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/pathology
• MicroRNAs/genetics
• Apoptosis/genetics

• R01 CA206069 NCI NIH HHS
• R01 CA210192 NCI NIH HHS
• SC1 GM139727 NIGMS NIH HHS

• E2F transcription factor 1 (E2F1)
• cell cycle
• cell migration
• cell proliferation
• lysine acetyltransferase 2A (KAT2A)
• pan-cancer
• ubiquitin conjugating enzyme E2 C (UBE2C)

• Ubiquitin-Conjugating Enzymes/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• E2F Transcription Factors
• Lysine Acetyltransferases
• Neoplasms/genetics

• anticancer drug resistance
• anticancer therapy
• apoptosis
• autophagy
• cytomegalovirus
• oncomodulation

The increasing incidence and mortality of colorectal cancer (CRC) urgently requires updated biomarkers. The ABC transporter family is a widespread family of membrane-bound proteins involved in the transportation of substrates associated with ATP hydrolysis, including metabolites, amino acids, peptides and proteins, sterols and lipids, organic and inorganic ions, sugars, metals, and drugs. They play an important role in the maintenance of homeostasis in the body.

This study aims to search for new markers in the ABC transporter gene family for diagnostic and prognostic purposes through data mining of The Cancer Genome Atlas (TCGA) and GEO (Gene Expression Omnibus) datasets.

A total of 980 samples, including 684 CRC patients and 296 controls from five different datasets, were included for analysis. The construction of the PPI (protein-protein interaction) network and pathway analysis were performed in STRING database and DAVID (database for annotation, visualization, and integrated discovery), respectively. In addition, GSEA (gene set enrichment analysis) and WGCNA (weighted gene co-expression network analysis) were also used for functional analysis.

After several rounds of screening and validation, only the ABCB5 gene was retained among the 49 genes.

The results demonstrated that ABCA5 expression is reduced in CRC and patients with high ABCA5 expression have better OS, which can provide guidance for better management and treatment of CRC in the future.

• Bcl2
• apoptosis
• chemosensitivity
• colon cancer
• deoxyelephantopin

• Humans
• Antineoplastic Agents, Phytogenic/pharmacology
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/genetics
• Fluorouracil/pharmacology
• Gene Expression Regulation, Neoplastic
• Lactones/pharmacology
• MicroRNAs/drug effects
• MicroRNAs/genetics
• Proto-Oncogene Proteins c-bcl-2/drug effects
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Reactive Oxygen Species/metabolism
• Sesquiterpenes/pharmacology

• 2017YFC1308601 Hongjuan Cui
• 81872071 Hongjuan Cui
• cstc2019jcyj-zdxmX0033 Hongjuan Cui
• XYDS201912 Hongjuan Cui
• CXTDX201601010 Hongjuan Cui

To explore the mechanism of E2F transcription Factor 1 (E2F-1)-mediated ataxia-telangiectasia-mutated protein (ATM) in cisplatin (DDP)-resistant nasopharyngeal carcinoma (NPC).

E2F-1 and ATM expression was assessed in DDP-resistant NPC cell lines (CNE2/DDP and HNE1/DDP) and parental cells. Then, DDP-resistant NPC cells were transfected with control shRNA (short hairpin RNA) or E2F-1 shRNAs with or without ATM lentiviral activation particles. The half maximal inhibitory concentration (IC50) was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the cell cycle and cell proliferation were measured by flow cytometry and EdU staining, respectively. In addition, the expression of genes and proteins was quantified by quantitative reverse-transcription polymerase chain reaction (qRT–PCR) and western blotting, respectively.

Both E2F-1 and ATM expression in DDP-resistant NPC cells was much higher than that in parental cells. E2F-1 shRNA reduced ATM expression in DDP-resistant NPC cells, but ATM overexpression had no significant effect on E2F-1. ATM overexpression enhanced DDP resistance in DDP-resistant NPC cells with increased IC50 values, which was reversed by E2F-1 inhibition. Meanwhile, ATM overexpression resulted in upregulation of ABCA2 and ABCA5 in DDP-resistant NPC cells, induced elevations in the transition of the cells into S-phase, and increased cell proliferation with enhanced expression of cyclin E1, CDK2, and Ki67, which was reversed by E2F-1 shRNAs.

Downregulation of E2F-1, possibly by regulating ATM, could block the cell cycle in the G1 phase and reduce the proliferation of CNE2/DDP cells, thereby reversing the resistance of human NPC cells to DDP.

• Ataxia-telangiectasia-mutated protein
• Cisplatin
• E2F transcription Factor 1
• Nasopharyngeal carcinoma
• Resistance

The transcription factor p73 is a structural and functional homolog of TP53, the most famous and frequently mutated tumor-suppressor gene. The TP73 gene can synthesize an overwhelming number of isoforms via splicing events in 5′ and 3′ ends and alternative promoter usage. Although it originally came into the spotlight due to the potential of several of these isoforms to mimic p53 functions, it is now clear that TP73 has its own unique identity as a master regulator of multifaceted processes in embryonic development, tissue homeostasis, and cancer. This remarkable functional pleiotropy is supported by a high degree of mechanistic heterogeneity, which extends far-beyond the typical mode of action by transactivation and largely relies on the ability of p73 isoforms to form protein–protein interactions (PPIs) with a variety of nuclear and cytoplasmic proteins. Importantly, each p73 isoform carries a unique combination of functional domains and residues that facilitates the establishment of PPIs in a highly selective manner. Herein, we summarize the expanding functional repertoire of TP73 in physiological and oncogenic processes. We emphasize how TP73’s ability to control neurodevelopment and neurodifferentiation is co-opted in cancer cells toward neoneurogenesis, an emerging cancer hallmark, whereby tumors promote their own innervation. By further exploring the canonical and non-canonical mechanistic patterns of p73, we apprehend its functional diversity as the result of a sophisticated and coordinated interplay of: (a) the type of p73 isoforms (b) the presence of p73 interaction partners in the cell milieu, and (c) the architecture of target gene promoters. We suppose that dysregulation of one or more of these parameters in tumors may lead to cancer initiation and progression by reactivating p73 isoforms and/or p73-regulated differentiation programs thereof in a spatiotemporally inappropriate manner. A thorough understanding of the mechanisms supporting p73 functional diversity is of paramount importance for the efficient and precise p73 targeting not only in cancer, but also in other pathological conditions where TP73 dysregulation is causally involved.

• C-terminus
• cancer progression
• development and homeostasis
• differentiation
• gene promoter architecture
• neoneurogenesis
• p73
• protein–protein interactions(PPI)

• E2F1/2/3/6
• bioinformatics analysis
• cutaneous melanoma
• database mining
• prognostic value

miR-205 plays important roles in the physiology of epithelia by regulating a variety of pathways that govern differentiation and morphogenesis. Its aberrant expression is frequently found in human cancers, where it was reported to act either as tumor-suppressor or oncogene depending on the specific tumor context and target genes. miR-205 expression and function in different cell types or processes are the result of the complex balance among transcription, processing and stability of the microRNA. In this review, we summarize the principal mechanisms that regulate miR-205 expression at the transcriptional and post-transcriptional level, with particular focus on the transcriptional relationship with its host gene. Elucidating the mechanisms and factors regulating miR-205 expression in different biological contexts represents a fundamental step for a better understanding of the contribution of such pivotal microRNA to epithelial cell function in physiology and disease, and for the development of modulation strategies for future application in cancer therapy.

• Chemoprevention
• Chemotherapy
• Melanoma
• Non-melanoma skin cancer
• p53

MicroRNA 34c (miR-34c) has been reported to be associated with malignant types of cancer, however, it remains unknown whether miR-34c is involved in chemoresistance in gastric cancer (GC).

To investigate the effect of miR-34c and its upstream transcription factor E2F1 on paclitaxel combined with cisplatin resistance in GC cells.

Paired GC tissues and adjacent normal tissues were randomly sampled from 74 GC patients. miR-34c and E2F1 were detected by real-time quantitative PCR (qPCR) and Western blot. In addition, the drug resistance of GC cells to paclitaxel and cisplatin was induced by concentration gradient increasing methods, and changes in miR-34c and E2F1 during this process were measured. Furthermore, E2F1 and miR-34c overexpression or underexpression vectors were constructed and transfected into drug-resistant GC cells. MTT was employed to test the sensitivity of cells to paclitaxel combined with cisplatin, qPCR was adopted to detect the expression of miR-34c, Western blot was applied to detect the expression levels of E2F1, drug resistance-related proteins and apoptosis-related proteins, and flow cytometry was used for the determination of cell apoptosis and cell cycle status.

E2F1 was overexpressed while miR-34c was underexpressed in GC. After inducing GC cells to be resistant to paclitaxel and cisplatin, E2F1 expression increased while miR-34c expression decreased. Both silencing E2F1 and over-expressing miR-34c could increase the sensitivity of drug-resistant GC cells to paclitaxel combined with cisplatin, promote cell apoptosis and inhibit cell proliferation. Among which, silencing E2F1 could reduce the expression of drug resistance-related proteins and apoptosis-related proteins, while over-expression of miR-34c could upregulate the expression of apoptosis-related proteins without affecting the expression of MDR-1, MRP and other drug resistance-related proteins. Rescue experiments demonstrated that inhibiting miR-34c could significantly weaken the sensitization of drug resistant cells, and Si E2F1 to paclitaxel combined with cisplatin.

E2F1 inhibits miR-34c to promote the proliferation of GC cells and enhance the resistance to paclitaxel combined with cisplatin, and silencing E2F1 is conducive to improving the efficacy of paclitaxel combined with cisplatin in GC cells.

• E2F transcription factor 1
• MicroRNA 34c
• Gastric cancer
• Paclitaxel combined with cisplatin resistance

• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Apoptosis/genetics
• Case-Control Studies
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• Cisplatin/pharmacology
• Cisplatin/therapeutic use
• Drug Resistance, Neoplasm/genetics
• E2F1 Transcription Factor/genetics
• E2F1 Transcription Factor/metabolism
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• MicroRNAs/agonists
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Paclitaxel/pharmacology
• Paclitaxel/therapeutic use
• RNA, Small Interfering/metabolism
• Stomach/pathology
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology
• Up-Regulation

• TCGA
• TCPA
• head and neck squamous cell carcinoma
• prognosis
• proteomics

• Data Mining/methods
• Female
• Genomics/methods
• Humans
• Male
• Middle Aged
• Prognosis
• Proteins/metabolism
• Proteomics/methods
• Squamous Cell Carcinoma of Head and Neck/genetics

• Bortezomib
• Chemoresistance
• Label free analysis
• Multiple myeloma
• XPO1
• iTRAQ

• Antineoplastic Agents/pharmacology
• Bortezomib/pharmacology
• Bortezomib/therapeutic use
• Cell Count
• Cell Line, Tumor
• Computational Biology
• Drug Resistance, Neoplasm
• Flow Cytometry
• Gene Knockdown Techniques
• Humans
• Karyopherins/genetics
• Karyopherins/physiology
• Multiple Myeloma/drug therapy
• Proteomics/methods
• Receptors, Cytoplasmic and Nuclear/genetics
• Receptors, Cytoplasmic and Nuclear/physiology
• Exportin 1 Protein

• ABCA transporters
• Cancer biology
• Cholesterol homeostasis
• Drug resistance
• Metastasis

• Amino Acid Transport Systems/genetics
• Amino Acid Transport Systems/metabolism
• Cell Line, Tumor
• Cyclin-Dependent Kinase 4/antagonists & inhibitors
• Cyclin-Dependent Kinase 4/genetics
• Cyclin-Dependent Kinase 4/metabolism
• Cyclin-Dependent Kinase 6/antagonists & inhibitors
• Cyclin-Dependent Kinase 6/genetics
• Cyclin-Dependent Kinase 6/metabolism
• Drug Resistance, Neoplasm
• Humans
• Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
• Mechanistic Target of Rapamycin Complex 1/genetics
• Mechanistic Target of Rapamycin Complex 1/metabolism
• Melanoma, Experimental/drug therapy
• Melanoma, Experimental/genetics
• Melanoma, Experimental/metabolism
• Melanoma, Experimental/pathology
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Protein Kinase Inhibitors/pharmacology
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Symporters/genetics
• Symporters/metabolism
• Xenograft Model Antitumor Assays

• R01 CA217329 NCI NIH HHS
• U01 DA045300 NIDA NIH HHS
• P01 CA098101 NCI NIH HHS
• R01 CA176401 NCI NIH HHS
• R01 CA093237 NCI NIH HHS
• T32 DE017551 NIDCR NIH HHS
• National Cancer Institute
• Prostate Cancer Foundation
• Outrun the Sun

• Computational analysis
• miRNA maturation
• miRNA transcription
• miRNome
• ncRNAs
• p73 isoforms

• Animals
• Apoptosis/physiology
• Cell Proliferation
• Chromosomal Instability
• DNA Damage/physiology
• E2F Transcription Factors/genetics
• E2F Transcription Factors/metabolism
• Humans
• Molecular Targeted Therapy/methods
• Multigene Family
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Protein Processing, Post-Translational
• Protein Stability

• R01 CA121275 NCI NIH HHS

• long non-coding RNA
• melanoma
• microRNA
• oncogene

• Doxorubicin resistance
• E2F1
• Human cytomegalovirus
• MDL72.527
• Monocytic leukemia THP-1 cells
• p73 isoforms

• Biogenic Polyamines/metabolism
• Cytomegalovirus/metabolism
• Cytomegalovirus Infections/drug therapy
• Cytomegalovirus Infections/genetics
• Cytomegalovirus Infections/metabolism
• Cytomegalovirus Infections/pathology
• Doxorubicin/pharmacology
• Drug Resistance, Neoplasm/drug effects
• Enzyme Inhibitors/pharmacology
• Humans
• Leukemia, Monocytic, Acute/drug therapy
• Leukemia, Monocytic, Acute/genetics
• Leukemia, Monocytic, Acute/metabolism
• Leukemia, Monocytic, Acute/pathology
• THP-1 Cells
• Tumor Protein p73/metabolism

Metastasis management remains a long-standing challenge. High abundance of E2F1 triggers tumor progression by developing protein-protein interactions (PPI) with coregulators that enhance its potential to activate a network of prometastatic transcriptional targets.

Methods: To identify E2F1-coregulators, we integrated high-throughput Co-immunoprecipitation (IP)/mass spectometry, GST-pull-down assays, and structure modeling. Potential inhibitors of PPI discovered were found by bioinformatics-based pharmacophore modeling, and transcriptome profiling was conducted to screen for coregulated downstream targets. Expression and target gene regulation was validated using qRT-PCR, immunoblotting, chromatin IP, and luciferase assays. Finally, the impact of the E2F1-coregulator complex and its inhibiting drug on metastasis was investigated in vitro in different cancer entities and two mouse metastasis models.

Results: We unveiled that E2F1 forms coactivator complexes with metastasis-associated protein 1 (MTA1) which, in turn, is directly upregulated by E2F1. The E2F1:MTA1 complex potentiates hyaluronan synthase 2 (HAS2) expression, increases hyaluronan production and promotes cell motility. Disruption of this prometastatic E2F1:MTA1 interaction reduces hyaluronan synthesis and infiltration of tumor-associated macrophages in the tumor microenvironment, thereby suppressing metastasis. We further demonstrate that E2F1:MTA1 assembly is abrogated by small-molecule, FDA-approved drugs. Treatment of E2F1/MTA1-positive, highly aggressive, circulating melanoma cells and orthotopic pancreatic tumors with argatroban prevents metastasis and cancer relapses in vivo through perturbation of the E2F1:MTA1/HAS2 axis.

Conclusion: Our results propose argatroban as an innovative, E2F-coregulator-based, antimetastatic drug. Cancer patients with the infaust E2F1/MTA1/HAS2 signature will likely benefit from drug repositioning.

• E2F1-coregulator
• MTA1
• drug repositioning
• metastasis
• pharmacophore modeling

Since “Warburg effect” has been firstly uncovered in cancer cells in 1956, mounting evidence has supported the molecular mechanism underlying the energy metabolism in induced chemoresistance in cancers. MicroRNAs can mediate fine-tuning of genes in physiological process. MicroRNAs’ energy metabolic role in chemoresistance has been probed recently. In this review, we summarize 5 microRNAs in regulating glucose and lipid metabolism and other energy metabolism. They partially modulate chemoresistance to cancer treatments. Furthermore, we discuss the great therapeutic potential of metabolism-related microRNAs in novel combinatorial means to treat human cancers.

• antineoplastic agents
• carcinoma
• drug resistance
• energy metabolism
• microRNAs

Cisplatin resistance is a major cause of treatment failure in advanced ovarian cancer. The limited evidence shows the paradoxical regulation of miR-205 on chemotherapy resistance in cancer. Herein, we found that miR-205-5p was enormously increased in cisplatin-resistant C13K ovarian cancer cells compared with its cisplatin-sensitive OV2008 parental cells using miRNA microarrays, which was further verified by quantitative PCR. Furthermore, we confirmed that inhibition of miR-205-5p upregulated PTEN and subsequently attenuated its downstream target p-AKT, which inversed C13K cells from cisplatin resistance to sensitivity. Our data suggest that miR-205-5p contributes to cisplatin resistance in C13K ovarian cancer cells may via targeting PTEN/AKT pathway.

• AKT
• PTEN
• cisplatin resistance
• miR-205-5p
• ovarian cancer

• Cancer stem cell targeting
• Clinical therapies
• Mathematical modeling
• Molecular signaling
• Network analysis

Colorectal cancer is a commonly diagnosed malignancy and also the major cause of death worldwide. Chemotherapy is the primary therapy for advanced colorectal cancer. Although oxaliplatin has potential effect in colorectal cancer therapy, the molecular mechanisms involved in its cytotoxic effects are not well elucidated. This study outlines the regulatory effects of oxaliplatin on miRNAs expression in colon cancer cells and correlates it with the changing microRNA expression with p53 and p73 expression status in cells. HCT116^p53+/+ and HCT116^p53-/- cells were exposed to oxaliplatin, and the cellular viability was determined by XTT. p73 was knocked down using siRNA and the tumor cells were then treated with oxaliplatin. The expression profile of 384 miRNAs was determined by TaqMan® human miRNA array and calculated by the ∆∆C_t method. Cellular viability was found to decrease after the treatment with oxaliplatin in a dose-dependent manner. The wild-type p53 cells were found to be more sensitive than the null-p53 derivatives. A selective set of miRNAs were either up-regulated or down-regulated in response to the oxaliplatin treatment with a presumable role of p53 and p73 proteins. The miRNAs expression is known to influence the pharmacodynamic mechanisms of oxaliplatin and these effects have been observed to be regulated by p53 and p73. Our results may therefore provide more evidence for identifying a suitable biomarker for the diagnosis of colon cancer.

• Oxaliplatin
• colon cancer cells.
• miRNAs
• p53
• p73

• Databases
• Immunotherapy
• Melanoma
• Network genomics
• Systems biology
• Therapy resistance

High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance.

Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance.

Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1.

Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance.

• Chemotherapy resistance
• E2F1
• Kinetic modelling.
• MicroRNA
• Molecular dynamics simulation

• CHK1
• Colorectal cancer (CRC)
• E2F1
• NFYB
• Oxaliplatin resistance

• E2F1
• Epithelial-mesenchymal transition
• Small cell lung cancer
• ZEB2

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• E2F1 Transcription Factor/metabolism
• Epithelial-Mesenchymal Transition
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Male
• Promoter Regions, Genetic
• Small Cell Lung Carcinoma/genetics
• Small Cell Lung Carcinoma/metabolism
• Up-Regulation
• Zinc Finger E-box Binding Homeobox 2/genetics
• Zinc Finger E-box Binding Homeobox 2/metabolism

• National Natural Science Foundation of China
• Natural Science Foundation of Shandong Province

• Cancer stem cell targeting
• Metastasis
• Nanoparticle
• Therapeutic strategies
• Viral delivery systems
• p53 family

• Animals
• Antineoplastic Agents/therapeutic use
• Humans
• Neoplasms/drug therapy
• Neoplasms/therapy
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology

• ABC transporters
• Breast cancer
• Melanoma
• Multi-drug resistance genes
• p53 family
• p73

• PRKDC
• drug resistance
• malignant melanoma
• miR-488-3p

• Cancer invasion
• Chemotherapy
• E2F1
• Experimental therapeutics
• Lymphangiogenesis
• Penile squamous cell carcinoma

• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Drug Resistance, Neoplasm/physiology
• E2F1 Transcription Factor/analysis
• E2F1 Transcription Factor/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Lymphangiogenesis/physiology
• Lymphatic Metastasis
• Male
• Neoplasm Staging
• Penile Neoplasms/drug therapy
• Penile Neoplasms/metabolism
• Penile Neoplasms/pathology
• Pilot Projects
• Prognosis
• Signal Transduction
• Vascular Endothelial Growth Factor C/metabolism
• Vascular Endothelial Growth Factor Receptor-3/metabolism

As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic integrity of the cell is disrupted—a hallmark of cancer. In addition, the DDR plays a dual role in cancer development and therapy. Cancer radiotherapy and chemotherapy are designed to eliminate cancer cells by inducing DNA damage, which in turn can promote tumorigenesis. Over the past two decades, an increasing number of microRNAs (miRNAs), small noncoding RNAs, have been identified as participating in the processes regulating tumorigenesis and responses to cancer treatment with radiation therapy or genotoxic chemotherapies, by modulating the DDR. The purpose of this review is to summarize the recent findings on how miRNAs regulate the DDR and discuss the therapeutic functions of miRNAs in cancer in the context of DDR regulation.

• DNA damage response
• DNA repair
• chemotherapy
• microRNAs
• radiotherapy

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• DNA Damage/genetics
• DNA Repair/drug effects
• DNA Repair/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasms/drug therapy
• Neoplasms/genetics

• Bioinformatics tools
• Biomarker prediction
• Integrative workflows
• Non-coding RNA
• Systems biology methods
• Therapeutic target identification
• microRNA

Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins. Signal transduction pathways, besides DDR itself, also control expression of genes whose products cause cell cycle arrest and/or apoptosis thus ultimately affecting the sensitivity of cells to genotoxic stress. In this study, using a number of experimental approaches we provide evidence that lysine-specific methyltransferase (KMT) Set7/9 affects DDR and DNA repair, at least in part, by regulating the expression of an E3 ubiquitin ligase, Mdm2. Furthermore, we show that Set7/9 physically interacts with Mdm2. Several cancer cell lines with inverse expression of Set7/9 and Mdm2 displayed diminished survival in response to genotoxic stress. These findings are signified by our bioinformatics studies suggesting that the unleashed expression of Mdm2 in cancer patients with diminished expression of Set7/9 is associated with poor survival outcome.

• DNA damage
• Mdm2
• Set7/9
• genotoxic stress
• operetta

• ABC transporters
• prognosis
• progression
• prostate cancer
• recurrence

• ATP-Binding Cassette Transporters/genetics
• ATP-Binding Cassette Transporters/metabolism
• Disease Progression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• Multidrug Resistance-Associated Protein 2
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/metabolism
• Neoplasm Recurrence, Local/pathology
• Prognosis
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology

Malignant melanoma is a highly aggressive cancer that retains functional p53 and p73, and drug unresponsiveness largely depends on defects in death pathways after epigenetic gene silencing in conjunction with an imbalanced p73/DNp73 ratio. We constructed oncolytic viruses armed with an inhibitor of deacetylation and/or p73 to specifically target metastatic cancer. Arming of the viruses is aimed at lifting epigenetic blockage and re-opening apoptotic programs in a staggered manner enabling both, efficient virus replication and balanced destruction of target cells through apoptosis. Our results showed that cooperative expression of shHDAC1 and p73 efficiently enhances apoptosis induction and autophagy of infected cells which reinforces progeny production. In vitro analyses revealed 100% cytotoxicity after infecting cells with OV.shHDAC1.p73 at a lower virus dose compared to control viruses. Intriguingly, OV.shHDAC1.p73 acts as a potent inhibitor of highly metastatic xenograft tumors in vivo. Tumor expansion was significantly reduced after intratumoral injection of 3 × 10⁸ PFU of either OV.shHDAC1 or OV.p73 and, most important, complete regression could be achieved in 100% of tumors treated with OV.shHDAC1.p73. Our results point out that the combination of high replication capacity and simultaneous restoration of cell death routes significantly enhance antitumor activity.