Gene Summary

Gene:RFC1; replication factor C subunit 1
Summary:This gene encodes the large subunit of replication factor C, a five subunit DNA polymerase accessory protein, which is a DNA-dependent ATPase required for eukaryotic DNA replication and repair. The large subunit acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It may also have a role in telomere stability. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:replication factor C subunit 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Breast Cancer
  • Polymerase Chain Reaction
  • Infant
  • Tetrahydrofolate Dehydrogenase
  • Cancer Gene Expression Regulation
  • Metabolic Networks and Pathways
  • Polymorphism
  • Childhood Cancer
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Alleles
  • Genetic Predisposition
  • Nucleic Acid Hybridization
  • Risk Factors
  • Drug Resistance
  • Sigmoidoscopy
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Pyrophosphatases
  • Young Adult
  • Methotrexate
  • Replication Protein C
  • Carbon
  • Adolescents
  • Case-Control Studies
  • Pharmacogenetics
  • DNA Methylation
  • Thymidylate Synthase
  • Acute Lymphocytic Leukaemia
  • Wilms Tumour
  • Cervical Cancer
  • Genotype
  • Folic Acid
  • Membrane Transport Proteins
  • Substrate Specificity
  • Colorectal Cancer
  • Single Nucleotide Polymorphism
  • Genetic Association Studies
  • Reduced Folate Carrier Protein
  • Carrier Proteins
  • Chromosome 4
  • Smoking
  • Antimetabolites, Antineoplastic
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RFC1 (cancer-related)

Odin E, Sondén A, Carlsson G, et al.
Folate pathway genes linked to mitochondrial biogenesis and respiration are associated with outcome of patients with stage III colorectal cancer.
Tumour Biol. 2019; 41(6):1010428319846231 [PubMed] Related Publications
5-fluorouracil in combination with the folate leucovorin is the cornerstone in treatment of colorectal cancer. Transport of leucovorin into cells, and subsequent metabolic action, require expression of several genes. The aim was to analyze if tumoral expression of genes putatively involved in leucovorin transport, polyglutamation, or metabolism was associated with outcome of patients with stage III colorectal cancer treated with adjuvant chemotherapy. A total of 363 stage III colorectal cancer patients who received adjuvant bolus 5-fluorouracil + leucovorin alone, or in combination with oxaliplatin according to Nordic bolus regimes were included. Expression of 11 folate pathway genes was determined in tumors using quantitative real-time polymerase chain reaction and related to disease-free survival. The median follow-up time was 5 years. During follow-up, 114 (31%) patients suffered from recurrent disease. A high tumoral expression of the genes

Park YL, Kim SH, Park SY, et al.
Forkhead‑box A1 regulates tumor cell growth and predicts prognosis in colorectal cancer.
Int J Oncol. 2019; 54(6):2169-2178 [PubMed] Related Publications
Forkhead box A1 (FOXA1) functions as a tumor suppressor gene or an oncogene in various types of cancer; however, the distinct function of FOXA1 in colorectal cancer is unclear. The present study aimed to evaluate whether FOXA1 affects the oncogenic behavior of colorectal cancer cells, and to investigate its prognostic value in colorectal cancer. The impact of FOXA1 on tumor cell behavior was investigated using small interfering RNA and the pcDNA6‑myc vector in human colorectal cancer cell lines. To investigate the role of FOXA1 in the progression of human colorectal cancer, an immunohistochemical technique was used to localize FOXA1 protein in paraffin‑embedded tissue blocks obtained from 403 patients with colorectal cancer. Tumor cell apoptosis and proliferation were evaluated using a terminal deoxynucleotidyl transferase‑mediated dUTP nick‑end labeling assay and Ki‑67 immunohistochemical staining, respectively. FOXA1 knockdown inhibited tumor cell invasion in colorectal cancer cells, and induced apoptosis and cell cycle arrest. FOXA1 knockdown activated cleaved caspase‑poly (ADP‑ribose) polymerase, upregulated the expression of p53 upregulated modulator of apoptosis, and downregulated BH3 interacting domain death agonist and myeloid cell leukemia‑1, leading to the induction of apoptosis. FOXA1 knockdown increased the phosphorylation level of signal transducer and activator of tran-scription‑3. By contrast, these results were reversed following the overexpression of FOXA1. The overexpression of FOXA1 was associated with differentiation, lymphovascular invasion, advanced tumor stage, depth of invasion, lymph node metastasis and poor survival rate. The mean Ki‑67 labeling index value of FOXA1‑positive tumors was significantly higher than that of FOXA1‑negative tumors. However, no significant association was observed between the expression of FOXA1 and the mean apoptotic index value. These results indicate that FOXA1 is associated with tumor progression via the modulation of tumor cell survival in human colorectal cancer.

Świerczewska M, Sterzyńska K, Wojtowicz K, et al.
PTPRK Expression Is Downregulated in Drug Resistant Ovarian Cancer Cell Lines, and Especially in ALDH1A1 Positive CSCs-Like Populations.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications

Rao C, Miao X, Zhao G, et al.
MiR-219a-5p enhances cisplatin sensitivity of human non-small cell lung cancer by targeting FGF9.
Biomed Pharmacother. 2019; 114:108662 [PubMed] Related Publications
Cisplatin (DDP) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). MicroRNA-219a-5p (miR-219a-5p) has been reported to be a tumor suppressor in several cancers, but whether it regulates chemosensitivity in NSCLC remains unclear. Here, using quantitative real time PCR analysis, we observed that miR-219a-5p was down-regulated in responding tumor tissues compared with that in non-responding tumor tissues from NSCLC patients received DDP-based chemotherapy. Consistently, miR-219a-5p expression was lower in cisplatin (DDP)-resistant NSCLC cell lines (A549-R and SPC-A1-R) than that in corresponding parental cells (A549 and SPC-A1). Gain of-function assay showed ectopic expression of miR-219a-5p reversed DDP chemoresistance of NSCLC cells in vitro and in vivo. Using bioinformatics prediction and dual-luciferase reporter assays, we identified the FGF9 gene as a novel direct target of miR-219a-5p. Moreover, restoration of FGF9 expression reversed the miR-219a-5p-mediated chemosensitivity. In conclusion, this study demonstrated miR-219a-5p plays a crucial role in the development of acquired drug resistance to DDP in NSCLC cells by targeting FGF9 and might be a therapeutic target for DDP resistance in clinical practice.

Mao Y, Zhang L, Li Y
circEIF4G2 modulates the malignant features of cervical cancer via the miR‑218/HOXA1 pathway.
Mol Med Rep. 2019; 19(5):3714-3722 [PubMed] Free Access to Full Article Related Publications
Circular RNAs (circRNAs) serve important roles in tumorigenesis and may be used as novel molecular biomarkers for clinical diagnosis. However, the role and molecular mechanisms of circRNAs in cervical cancer (CC) remain unknown. In the present study, circRNA isoform of eukaryotic translation initiation factor 4γ2 (circEIF4G2) was revealed to be significantly upregulated in CC tissues and cell lines. Furthermore, increased expression of circEIF4G2 was associated with poor prognosis in patients with CC. circEIF4G2 knockdown suppressed the malignant features of CC cells, including cell proliferation, colony formation, migration and invasion. Additionally, circEIF4G2 was identified to serve as a sponge for microRNA‑218 (miR‑218), which targeted homeobox A1 (HOXA1). Furthermore, circEIF4G2 may increase the expression levels of HOXA1 by sponging miR‑218. Rescue experiments suggested that transfection with a miR‑218 inhibitor attenuated the inhibitory effects of circEIF4G2 knockdown on cell proliferation, migration and invasion. Furthermore, silencing HOXA1 reversed the effects of the miR‑218 inhibitor on CC cells. Collectively, the present findings suggested that circEIF4G2 promoted cell proliferation and migration via the miR‑218/HOXA1 pathway.

Zóia MAP, Azevedo FVP, Vecchi L, et al.
Inhibition of Triple-Negative Breast Cancer Cell Aggressiveness by Cathepsin D Blockage: Role of Annexin A1.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancers (TNBCs) are more aggressive than other breast cancer (BC) subtypes and lack effective therapeutic options. Unraveling marker events of TNBCs may provide new directions for development of strategies for targeted TNBC therapy. Herein, we reported that Annexin A1 (AnxA1) and Cathepsin D (CatD) are highly expressed in MDA-MB-231 (TNBC lineage), compared to MCF-10A and MCF-7. Since the proposed concept was that CatD has protumorigenic activity associated with its ability to cleave AnxA1 (generating a 35.5 KDa fragment), we investigated this mechanism more deeply using the inhibitor of CatD, Pepstatin A (PepA). Fourier Transform Infrared (FTIR) spectroscopy demonstrated that PepA inhibits CatD activity by occupying its active site; the OH bond from PepA interacts with a CO bond from carboxylic acids of CatD catalytic aspartate dyad, favoring the deprotonation of Asp

Simonian M, Mosallaei M, Khosravi S, Salehi R
rs12904 polymorphism in the 3'-untranslated region of ephrin A1 ligand and the risk of sporadic colorectal cancer in the Iranian population.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):15-19 [PubMed] Related Publications
Background: Colorectal cancer (CRC) is rated as the second cause of cancer death. Genetic determinants are considered as driving forces in the development of sporadic CRC. Single-nucleotide polymorphisms (SNPs), due to their abundance in the human genome with collectively huge effect on cellular signaling pathways, are attributed as the main genetic factor in disease susceptibility including cancers. MicroRNAs are contributing to posttranslational gene regulation. They exert their regulatory function by binding to their specific recognition sequences located at 3'-untranslated region (UTR) of mRNAs. In the present study, we have elucidated the role of rs12904, a naturally occurring SNP, in the recognition site of miR200c in the 3'UTR of ephrin A1 ligand gene, in the development of sporadic CRC in the Iranian population.
Materials and Methods: A case-control study using 152 CRC patients and 160 noncancerous counterparts was conducted to determine the rs12904 genotypes using polymerase chain reaction-restriction fragment length polymorphism method.
Results: The results revealed no significant association between the rs12904 and sporadic CRC (odds ratio = 0.97, 95% confidence interval = 0.70-1.34). The frequency of genotypes and also alleles of the mentioned polymorphism were not significantly different between case and control groups (P = 0.765 and P = 0.847, respectively).
Conclusion: The results suggest that this polymorphism probably has not a crucial role in the Iranian CRC risk and is not an important potential risk factor in molecular diagnostics of mentioned disease among the Iranian population.

Choi SJ, Ryu E, Lee S, et al.
Adenosine Induces EBV Lytic Reactivation through ADORA1 in EBV-Associated Gastric Carcinoma.
Int J Mol Sci. 2019; 20(6) [PubMed] Free Access to Full Article Related Publications

Chen YN, Ren CC, Yang L, et al.
MicroRNA let‑7d‑5p rescues ovarian cancer cell apoptosis and restores chemosensitivity by regulating the p53 signaling pathway via HMGA1.
Int J Oncol. 2019; 54(5):1771-1784 [PubMed] Related Publications
Ovarian cancer (OC) is the gynecological malignancy type with the highest mortality rate in females. The regulatory effect of microRNAs (miRs) on their target genes serves a key role in tumor development. Therefore, in the present study, whether miR let‑7d‑5p targeting high mobility group A1 (HMGA1) regulated biological characteristics and chemosensitivity of OC cells by mediating the p53 signaling pathway was investigated. The let‑7d‑5p level was detected in OC tissues and adjacent normal tissues, followed by detection in OC cell lines SKOV3, A2780, OVCAR‑3 and CaOV3, and human normal ovarian epithelial cell line (IOSE‑80), in order to select the OC cell line for the following experiments. Subsequently, OC cells were treated with the let‑7d‑5p mimic, siHMGA1 and Tenovin‑1. The targeting association between let‑7d‑5p and HMGA1 was then examined, and the OC cell viability, migration, cycle and apoptosis were evaluated. Subsequently, the chemosensitivity of OC cells to cisplatin was verified. Finally, expression levels of let‑7d‑5p, HMGA1, p21, B‑cell lymphoma‑2 (Bcl‑2)‑associated X (Bax), p27, p53 wild‑type (p53wt), p53 mutated (p53mut), proliferating cell nuclear antigen (PCNA), cyclin‑dependent kinase 2 (CDK2), matrix metallopeptidase (MMP)2, MMP9 and Bcl‑2 were determined. As demonstrated in the results, let‑7d‑5p expression was low in OC tissues and had an increased reduction in the OVCAR‑3 cell line. HMGA1 was confirmed as a target of let‑7d‑5p, and its expression was also silenced by let‑7d‑5p. let‑7d‑5p repressed OC cell viability, migration, cell cycle progression and apoptosis, while it promoted the chemosensitivity of OC cells to cisplatin by targeting HMGA1. The expression of let‑7d‑5p, p21, Bax, p27 and p53wt was increased, while that of HMGA1, p53mut, PCNA, CDK2, MMP2, MMP9 and Bcl‑2 was reduced following cell transfection. The results in the present study provided evidence that let‑7d‑5p may suppress proliferation, and facilitate apoptosis and cisplatin chemosensitivity of OC cells by silencing HMGA1 via the p53 signaling pathway.

Carabet LA, Leblanc E, Lallous N, et al.
Computer-Aided Discovery of Small Molecules Targeting the RNA Splicing Activity of hnRNP A1 in Castration-Resistant Prostate Cancer.
Molecules. 2019; 24(4) [PubMed] Free Access to Full Article Related Publications
The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a versatile RNA-binding protein playing a critical role in alternative pre-mRNA splicing regulation in cancer. Emerging data have implicated hnRNP A1 as a central player in a splicing regulatory circuit involving its direct transcriptional control by c-Myc oncoprotein and the production of the constitutively active ligand-independent alternative splice variant of androgen receptor, AR-V7, which promotes castration-resistant prostate cancer (CRPC). As there is an urgent need for effective CRPC drugs, targeting hnRNP A1 could, therefore, serve a dual purpose of preventing AR-V7 generation as well as reducing c-Myc transcriptional output. Herein, we report compound VPC-80051 as the first small molecule inhibitor of hnRNP A1 splicing activity discovered to date by using a computer-aided drug discovery approach. The inhibitor was developed to target the RNA-binding domain (RBD) of hnRNP A1. Further experimental evaluation demonstrated that VPC-80051 interacts directly with hnRNP A1 RBD and reduces AR-V7 messenger levels in 22Rv1 CRPC cell line. This study lays the groundwork for future structure-based development of more potent and selective small molecule inhibitors of hnRNP A1⁻RNA interactions aimed at altering the production of cancer-specific alternative splice isoforms.

Wang Y, Yang L, Chen T, et al.
A novel lncRNA MCM3AP-AS1 promotes the growth of hepatocellular carcinoma by targeting miR-194-5p/FOXA1 axis.
Mol Cancer. 2019; 18(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with poor clinical outcomes. Increasing amount of long non-coding RNAs (lncRNAs) have been revealed to be implicated in the carcinogenesis and progression of HCC. However, the expressions, clinical significances, and roles of most lncRNAs in HCC are still unknown.
METHODS: The expression of lncRNA MCM3AP antisense RNA 1 (MCM3AP-AS1) in HCC tissues and cell lines was detected by qRT-PCR and fluorescence in situ hybridization. Immunoblotting, CCK-8, EdU, colony formation and flow cytometry were performed to investigate the role of MCM3AP-AS1 in HCC cell proliferation, cell cycle and apoptosis in vitro. A subcutaneous tumor mouse model was constructed to analyze in vivo growth of HCC cells after MCM3AP-AS1 knockdown. The interactions among MCM3AP-AS1, miR-194-5p and FOXA1 were measured by RNA pull-down, RNA immunoprecipitation and luciferase reporter assay.
RESULTS: We revealed a novel oncogenic lncRNA MCM3AP-AS1, which is overexpressed in HCC and positively correlated with large tumor size, high tumor grade, advanced tumor stage and poor prognosis of HCC patients. MCM3AP-AS1 knockdown suppressed HCC cell proliferation, colony formation and cell cycle progression, and induced apoptosis in vitro, and depletion of MCM3AP-AS1 inhibited tumor growth of HCC in vivo. Mechanistically, MCM3AP-AS1 directly bound to miR-194-5p and acted as competing endogenous RNA (ceRNA), and subsequently facilitated miR-194-5p's target gene forkhead box A1 (FOXA1) expression in HCC cells. Interestingly, FOXA1 restoration rescued MCM3AP-AS1 knockdown induced proliferation inhibition, G1 arrest and apoptosis of HCC cells.
CONCLUSIONS: Our results recognized MCM3AP-AS1 as a novel oncogenic lncRNA, which indicated poor clinical outcomes in patients with HCC. MCM3AP-AS1 exerted an oncogenic role in HCC via targeting miR-194-5p and subsequently promoted FOXA1 expression. Our findings suggested that MCM3AP-AS1 could be a potential prognostic biomarker and therapeutic target for HCC.

Shishkin SS, Kovalev LI, Pashintseva NV, et al.
Heterogeneous Nuclear Ribonucleoproteins Involved in the Functioning of Telomeres in Malignant Cells.
Int J Mol Sci. 2019; 20(3) [PubMed] Free Access to Full Article Related Publications
Heterogeneous nuclear ribonucleoproteins (hnRNPs) are structurally and functionally distinct proteins containing specific domains and motifs that enable the proteins to bind certain nucleotide sequences, particularly those found in human telomeres. In human malignant cells (HMCs), hnRNP-A1-the most studied hnRNP-is an abundant multifunctional protein that interacts with telomeric DNA and affects telomerase function. In addition, it is believed that other hnRNPs in HMCs may also be involved in the maintenance of telomere length. Accordingly, these proteins are considered possible participants in the processes associated with HMC immortalization. In our review, we discuss the results of studies on different hnRNPs that may be crucial to solving molecular oncological problems and relevant to further investigations of these proteins in HMCs.

Bertolini I, Terrasi A, Martelli C, et al.
A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.
EBioMedicine. 2019; 41:225-235 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.
METHODS: Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.
FINDINGS: GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.
INTERPRETATION: We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND: This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).

Ke RS, Zhang K, Lv LZ, et al.
Prognostic value and oncogene function of heterogeneous nuclear ribonucleoprotein A1 overexpression in HBV-related hepatocellular carcinoma.
Int J Biol Macromol. 2019; 129:140-151 [PubMed] Related Publications
Previous study has shown heterogeneous nuclear ribonucleoprotein A1(HNRNPA1) is highly expressed in various human cancers. In order to study the clinical value and potential function of HNRNPA1 in HBV-related hepatocellular carcinoma (HCC), three datasets from the GEPIA, GEO and TCGA were analyzed. HNRNPA1 expression was found to be significantly higher in HBV-positive HCC samples, which was supported with IHC validation. Both GO and KEGG analyses demonstrated that HNRNPA1 co-expressed genes were involved in translation, ribonucleoprotein complex biogenesis and assembly, ribosome biogenesis, RNA processing, RNA splicing, etc. Survival analysis showed a significant reduction in overall survival of patients with high HNRNPA1 expression from both the GSE14520 cohort and 151 patients with HBV-related HCC cohort. Furthermore, Gene set enrichment analysis (GSEA) revealed that HNRNPA1 may regulate HCC progression by influencing the cell cycle and WNT signaling pathway, etc. HNRNPA1 overexpression has diagnostic value in distinguishing between HCC and non-HCC liver tissue (AUC = 0.730). Finally, HNRNPA1 was a directly target gene of miR-22 manifested by the reduced luciferase activity and decreased HNRNPA1 expression in the cells with overexpression of miR-22. HNRNPA1 might function as an oncogene through the EGFR signaling pathway in HBV-related HCC, which has not been reported in previous studies.

Mohanta S, Sekhar Khora S, Suresh A
Cancer Stem Cell based molecular predictors of tumor recurrence in Oral squamous cell carcinoma.
Arch Oral Biol. 2019; 99:92-106 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify the cancer stem cell specific biomarkers that can be effective candidate prognosticators of oral squamous cell carcinoma.
DESIGN: Microarray-based meta-analysis derived transcriptional profile of head and neck cancers was compared with the Cancer Stem Cell database to arrive at a subset of markers. This subset was further co-related with clinico-pathological parameters, recurrence and survival of oral cancer patients (n = 313) in The Cancer Genome Atlas database and in oral cancer (n = 28) patients.
RESULTS: Meta-analysis in combination with database comparison identified a panel of 221 genes specific to head and neck cancers. Correlation of expression levels of these markers in the oral cancer cohort of The Cancer Genome Atlas (n = 313) with treatment outcome identified 54 genes (p < 0.05 or fold change >2) associated with disease recurrence, 8 genes (NQO1, UBE2C, EDNRB, FKBP4, STAT3, HOXA1, RIT1, AURKA) being significant with high fold change. Assessment of the efficacy of the subset (n = 54) as survival predictors identified an additional 4 genes (CDK1, GINS2, PHF5 A, ERBB2) that co-related with poor disease-free survival (p < 0.05). CDK1 showed a significant association with the clinical stage, margin status and with advanced pathological parameters. Initial patient validation indicated that CDK1 and NQO1 significantly co-related with the poor disease-free and overall survival (p < 0.05).
CONCLUSION: This panel of oral cancer specific, cancer stem cell associated markers identified in this study, a subset of which was validated, will be of clinical benefit subject to large scale validation studies.

Aird D, Teng T, Huang CL, et al.
Sensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators.
Nat Commun. 2019; 10(1):137 [PubMed] Free Access to Full Article Related Publications
Dysregulation of RNA splicing by spliceosome mutations or in cancer genes is increasingly recognized as a hallmark of cancer. Small molecule splicing modulators have been introduced into clinical trials to treat solid tumors or leukemia bearing recurrent spliceosome mutations. Nevertheless, further investigation of the molecular mechanisms that may enlighten therapeutic strategies for splicing modulators is highly desired. Here, using unbiased functional approaches, we report that the sensitivity to splicing modulation of the anti-apoptotic BCL2 family genes is a key mechanism underlying preferential cytotoxicity induced by the SF3b-targeting splicing modulator E7107. While BCL2A1, BCL2L2 and MCL1 are prone to splicing perturbation, BCL2L1 exhibits resistance to E7107-induced splicing modulation. Consequently, E7107 selectively induces apoptosis in BCL2A1-dependent melanoma cells and MCL1-dependent NSCLC cells. Furthermore, combination of BCLxL (BCL2L1-encoded) inhibitors and E7107 remarkably enhances cytotoxicity in cancer cells. These findings inform mechanism-based approaches to the future clinical development of splicing modulators in cancer treatment.

Men L, Nie D, Nie H
microRNA‑577 inhibits cell proliferation and invasion in non‑small cell lung cancer by directly targeting homeobox A1.
Mol Med Rep. 2019; 19(3):1875-1882 [PubMed] Related Publications
An increasing number of studies have indicated that the dysregulation of microRNAs (miRNAs/miR) is closely associated with non‑small cell lung cancer (NSCLC) development and progression by acting as tumor suppressors or oncogenes. Therefore, an in‑depth understanding of the biological roles of miRNAs in NSCLC may provide novel therapeutic methods for the treatment of patients with this disease. In the present study, reverse transcription‑quantitative polymerase chain reaction was used to detect miR‑577 expression in NSCLC tissues and cell lines. Cell Counting Kit‑8 and Transwell invasion assays were performed to determine the effects of miR‑577 on NSCLC cell proliferation and invasion. Luciferase reporter assays were used to demonstrate the relationship between miR‑577 and homeobox A1 (HOXA1) in NSCLC cells. The results revealed that miR‑577 was markedly downregulated in NSCLC tissues and cell lines. Additionally, restoration of miR‑577 expression significantly decreased the proliferation and invasion of NSCLC cells. Furthermore, miR‑577 negatively regulated HOXA1 expression in NSCLC cells by directly binding to its 3'‑untranslated region. HOXA1 was significantly upregulated in NSCLC tissues, and its upregulation was inversely correlated with miR‑577. Notably, restored HOXA1 expression abrogated the reduced proliferation and invasion of NSCLC cells caused by miR‑577 overexpression. Taken together, these results indicated that miR‑577 may have served tumor suppressive roles in NSCLC by directly targeting HOXA1. Therefore, this miRNA may be developed as a potential therapeutic target for the therapy of patients with NSCLC.

Abbasian MH, Abbasi B, Ansarinejad N, et al.
Association of interleukin-1 gene polymorphism with risk of gastric and colorectal cancers in an Iranian population.
Iran J Immunol. 2018; 15(4):321-328 [PubMed] Related Publications
BACKGROUND: Chronic inflammation is associated with neoplasms and several types of cancer. Therefore, polymorphisms in the inflammation-related genes could modify the cancer susceptibility.
OBJECTIVE: To investigate the associations between IL-1RN VNTR and rs419598 polymorphisms in IL-1 receptor antagonist (IL-1ra) and colorectal cancer (CRC) and gastric cancer (GC) in an Iranian population.
METHODS: In this study, 126 cancer cases (91 CRC and 35 GC) and 97 healthy controls were included. Genotyping of IL-1RN VNTR and rs419598 was performed by PCR amplification and PCR-RFLP, respectively. Logistic regression was applied to identify the independent risk factors for colorectal and gastric cancers by computing the odds ratio (OR) and 95% confidence intervals (95% CI). All statistical analyses were performed using the SPSS statistical software.
RESULTS: There were significant differences between cancer groups and control group concerning the frequency of A1/A2 genotypes in IL-1RN VNTR polymorphism. The carrier status of IL-1RN* 2 allele was associated with increased risk of CRC (p = 0.0003; OR = 0.02; 95% CI: 0.491-0.85) and GC (p = 0.0006; OR = 0.106; 95% CI: 0.321-0.035). Also, the homozygous ILRN *2/*2 genotype was associated with increased risk of gastric cancer (p = 0.04; OR = 0.133; 95% CI: 0.020-0.908). There was no association between different alleles of rs419598 and CRC and GC.
CONCLUSION: This study demonstrates an association between the carrier status of IL-1RN* 2 and CRC and GC in an Iranian population.

Jendoubi-Ferchichi M, Satouri L, Ghoul F, et al.
Phylogeny and Classification of Human Papillomavirus (HPV)16 and HPV18 Variants Based on E6 and L1 genes in Tunisian Women with Cervical Lesions
Asian Pac J Cancer Prev. 2018; 19(12):3361-3366 [PubMed] Free Access to Full Article Related Publications
Background: High-risk human papillomavirus (HPV) types are the main etiological factors for cervical cancer. HPV16 and HPV18 are generally the most common forms associated with development of high-grade cervical lesions. This study was undertaken to identify intratypic variants of HPV16 and HPV18 among women with cervical lesions in Tunisia. Materials and Methods: DNA was extracted from cervical samples collected from 49 women. using a PureLinkTM Genomic DNA mini Kit (Invitrogen). E6 and L1 open reading frames (ORF) were amplified by PCR and viral DNA amplicons were subjected to automated sequencing using Big Dye Terminators technology (Applied Biosystems). The obtained sequences were analyzed using an appropriate software program to allow phylogenetic trees to be generated. Results: HPV16 and HPV18 were detected in 15 and 5 cases, respectively. HPV16 E6 sequences clustered with the European German lineage (A2) whereas one isolate diverged differently in the L1 region and clustered with the African sub-lineage (B1). HPV 18 E6 sequences clustered with the European sub-lineage (A1) but L1 sequences clustered as a new clade which diverged from A1-A5. Conclusions: Our results suggest that the distribution of HPV16 and HPV18 sequences in women with cervical lesions in Tunisia is mainly related to European epidemiological conditions and point to the presence of recombinant HPV forms.

Zhang T, Guo J, Gu J, et al.
Identifying the key genes and microRNAs in colorectal cancer liver metastasis by bioinformatics analysis and in vitro experiments.
Oncol Rep. 2019; 41(1):279-291 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is one of the principal causes of cancer‑associated mortality worldwide. The high incidence of liver metastasis is the leading risk factor of mortality in patients with CRC, and the mechanisms of CRC liver metastasis are poorly understood. In the present study, 7 datasets, including 3 gene expression profile datasets and 4 microRNA (miRNA) expression profile datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify potential key genes and miRNAs, which may be candidate biomarkers for CRC liver metastasis. Differentially expressed (DE) genes (DEGs) and DE miRNAs of primary CRC tumor tissues and liver metastatic CRC tumor tissues were selected using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery online database. Furthermore, Cytoscape with cytoHubba and the Molecular Complex Detection (MCODE) plug‑in were used to visualize a protein‑protein interaction (PPI) network for these DEGs, and to screen hub genes and gene modules in the PPI network. In addition, the online databases, TargetScan, miRanda, PITA, miRWalk and miRDB, were used to identify the target genes of the DE miRNAs. In the present study, 141 DEGs (97 upregulated and 44 downregulated) and 3 DE miRNAs (2 upregulated and 1 downregulated) were screened from the 3 gene expression microarray datasets and 4 miRNA expression microarray datasets, respectively. In total, 10 hub genes with a high degree of connectivity were selected from the PPI network, including albumin (ALB), coagulation factor II (F2), thrombin, apolipoprotein H (APOH), serpin family C member 1 (SERPINC1), apolipoprotein A1 (APOA1), α‑1‑microglobulin/bikunin precursor (AMBP), apolipoprotein C3 (APOC3), plasminogen (PLG), α‑2 HS glycoprotein (AHSG) and apolipoprotein B (APOB). The most important module was detected in the PPI network using the MCODE plug‑in. A total of 20 DEGs were identified to be potential target genes of these DE miRNAs, and novel miRNA‑DEGs regulatory axes were constructed. In vitro experiments were performed to demonstrate that miR‑885 promoted CRC cell migration by, at least partially, decreasing the expression of von Willebrand factor (vWF) and insulin‑like growth factor binding protein 5 (IGFBP5). In conclusion, by using integrated bioinformatics analysis and in vitro experiments, key candidate genes were identified and novel miRNA‑mRNA regulatory axes in CRC liver metastasis were constructed, which may improve understanding of the molecular mechanisms underlying CRC liver metastasis.

Xu DH, Li Q, Hu H, et al.
Transmembrane protein GRINA modulates aerobic glycolysis and promotes tumor progression in gastric cancer.
J Exp Clin Cancer Res. 2018; 37(1):308 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent observations indicate a decreased cancer risk in patients with Alzheimer's disease (AD). AD is a severe neurodegenerative disorder characterized by progressive cognitive decline. The 8q24 region has been shown to be involved in AD aetiology. We aimed to identify and explore the potential oncogenes or antioncogenes on chromosome 8q24.
METHODS: We compared expression of genes on Chromosome 8q24 in 32 pairs of samples from The Cancer Genome Atlas (TCGA) database. We conducted bioinformatics analysis of the commonly used gastric cancer databases and performed clinical verification of gastric cancer samples, combined with assessment of biological function both in vitro and in vivo to determine the relationship between upregulated expression of GRINA and gastric cancer progression. We also explored the molecular mechanism of GRINA upregulation and its function in gastric cancer development and progression.
RESULTS: The expression of GRINA in cancer tissues was significantly higher than that in normal tissues. GRINA indicated poor prognosis in gastric cancer. GRINA promoted the proliferation, migration and invasion capacity of gastric cancer cells. GRINA was transcriptionally mediated by c-Myc and promotes cell cycle transition. GRINA knockdown decreased PI3K/Akt/mTOR signaling and glycolytic metabolism in gastric cancer cells. The apoptosis rate was significantly increased in gastric cancer cell lines after knockdown of GRINA. The expression of pro-apoptotic protein Bax was significantly upregulated, whereas the anti-apoptotic protein Bcl-2 was significantly downregulated in GRINA silenced cells.
CONCLUSIONS: Human gastric cancers have increased levels of GRINA, which promotes growth of gastric cancer and inhibits tumor cells apoptosis.

Pessolano E, Belvedere R, Bizzarro V, et al.
Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression.

Yamanoi M, Yamanoi K, Fujii C, et al.
Annexin A1 expression is correlated with malignant potential of renal cell carcinoma.
Int J Urol. 2019; 26(2):284-290 [PubMed] Related Publications
OBJECTIVES: To evaluate the expression of annexin A1 protein in patients with renal cell carcinoma.
METHODS: Annexin A1 expression was examined in renal cell carcinoma specimens from 27 patients, and their disease-free survival was analyzed using the log-rank test. Annexin A1 knockdown in the human renal cell carcinoma cell line Caki-1 was carried out, and its proliferation, invasion, motility and adhesion were compared with those of control cells.
RESULTS: In 13 out of 27 patients, annexin A1 was highly expressed in the membrane of renal cell carcinoma tumor cells, whereas in the rest of the patients, annexin A1 expression was weak or negligible in the membrane of those cells. Patients with high annexin A1 expression had significantly poorer disease-free survival than those with weak or negligible annexin A1 expression (P = 0.031). In the renal cell carcinoma cell line, annexin A1 knockdown cells showed significantly decreased proliferation, invasion, motility and adhesion relative to control cells, and expressed lower relative levels of membrane-type 1 matrix metalloproteinase and hypoxia-inducible factor 1-alpha transcripts, showing a potential pathway regulated by annexin A1.
CONCLUSION: Annexin A1 is associated with renal cell carcinoma malignant potential and could serve as a marker of poor prognosis.

Mi Y, Liu F, Liang X, et al.
Tumor suppressor let-7a inhibits breast cancer cell proliferation, migration and invasion by targeting MAGE-A1.
Neoplasma. 2019; 66(1):54-62 [PubMed] Related Publications
Let-7 was one of the earliest discovered miRNAs and while it reportedly acts as a tumor suppressor in various solid tumors, its function in breast cancer has not been fully studied. Therefore, we examined let-7a and MAGE-A1 expression in breast tissues by qRT-PCR and found that let-7a expression significantly correlates with larger tumor size, higher histological grade (p<0.05) and is significantly lower in patients with Her-2-positive cancers and Ki-67 >14% (p=0.028 and p=0.023). MAGE-A1 expression incidence is 50.8% (33/65) and it inversely correlates with let-7a expression (p=0.008). let-7a inhibition of breast cancer cell proliferation, migration and invasion was also observed in in vitro cell culture experiments, and dual-luciferase reporter assays showed that melanoma-associated antigen A1 (MAGE-A1) was its target gene; the target comprised bases 451-457 of the 3'UTR region of the MAGE-A1 mRNA. RT-qPCR and Western blot analyses showed that let-7a inhibited MAGE-A1 expression at both the nucleic acid and protein levels. In our final co-transfection experiment, we targeted MAGE-A1 in a breast cancer cell line and observed that let-7a inhibited cell proliferation, migration and invasion. These combined results confirm that let-7a functions as a tumor suppressor by targeting MAGE-A1 in breast cancer and it therefore provides a novel target in breast cancer clinical treatment.

Cheng H, Zhu H, Cao M, et al.
HtrA1 suppresses the growth of pancreatic cancer cells by modulating Notch-1 expression.
Braz J Med Biol Res. 2018; 52(1):e7718 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer is well known to be the most deadly malignancy with the worst survival rate of all cancers. High temperature requirement factor A1 (HtrA1) plays an important role in cancer cell proliferation, migration, apoptosis, and differentiation. This study aimed to explore the function of HtrA1 in pancreatic cancer cell growth and its underlying mechanism. We found that the expression of HtrA1 was lower in pancreatic cancer tissue compared to the adjacent normal tissue. Consistently, HtrA1 levels were also decreased in two human pancreatic cancer cell lines, PANC-1 and BXPC-3. Moreover, enforced expression of HtrA1 inhibited cell viability and colony formation of PANC-1 and BXPC-3 cells. Overexpression of HtrA1 promoted apoptosis and suppressed migratory ability of tumor cells. On the contrary, siRNA-mediated knockdown of HtrA1 promoted the growth potential of pancreatic cancer cells. In addition, we found that up-regulation of HtrA1 reduced the expression of Notch-1 in pancreatic cancer cells. On the contrary, knockdown of HtrA1 increased the expression levels of Notch-1. Furthermore, overexpression of Notch-1 abolished the anti-proliferative effect of HtrA1 on pancreatic cancer cells. Taken together, our findings demonstrated that HtrA1 could inhibit pancreatic cancer cell growth via regulating Notch-1 expression, which implied that HtrA1 might be developed as a novel molecular target for pancreatic cancer therapy.

Clark KR, Tong WL, Callahan BM, et al.
TRB-J1 usage, in combination with the HLA-A*01:01 allele, represents an apparent survival advantage for uterine corpus endometrial carcinoma: Comparisons with microscopic assessments of lymphocyte infiltrates.
Int J Immunogenet. 2019; 46(1):31-37 [PubMed] Related Publications
The opportunity for the highly efficient recovery of immune receptor recombination data from cancer specimens, including the ready assessment of immune receptor V and J usage, raises the issue of establishing precise values of assessing the immune receptor status as opposed to obtaining basic information regarding lymphocyte infiltration, in the cancer setting. In this report, we obtained the lymphocyte infiltration percentages from the cancer digital slide archive representing uterine corpus endometrial carcinoma (UCEC) and correlated these data with recovery of the immune receptor recombination reads from corresponding UCEC exome files. Results indicated a basic correlation of the recovery of productive T-cell receptor beta (TRB) recombination reads with lymphocyte infiltration percentages. However, the recovery of specific immune receptor recombination reads did not indicate the same survival outcomes as microscope detection of lymphocyte infiltrate percentages. To further exploit the value of recovery of the TRB recombination reads from the UCEC exome files, we determined the survival outcomes for combinations of TRB gene segment usage and HLA class I alleles, with the most important result being that the combination of HLA-A*01:01 and TRB-J1 segment usage reflected a strikingly high survival rate. Overall, this report emphasized the increased value of the knowledge of the immune receptor recombinations, in comparison with basic lymphocyte infiltration percentages, in assessing cancer survival rates.

Yu JH, Shi WW, Zhou MY, et al.
Genetic variability and oncogenic risk association of human papillomavirus type 58 E6 and E7 genes in Taizhou area, China.
Gene. 2019; 686:171-176 [PubMed] Related Publications
It is well recognized that the association of human papillomavirus (HPV) and cervical carcinogenesis is based on the presence of HPV DNA sequence. The E6 and E7 oncoproteins encoded by high-risk HPV types play a key role in carcinogenesis. HPV58 type accounts for a larger share of cervical disease in China, whereas data on HPV58 genetic variability in China is limited. We aimed to evaluate the diversity of HPV58 genetic variants by sequencing the entire E6 and E7 genes. Phylogenetic trees were constructed by Maximum likelihood method by MEGA 5.05 software. In this study, the overall HPV infection rate was 22.6% (2891/12780) in Southeast China and the prevalence of HPV58 infection rate was 2.6% (335/12780). 26 nucleotides substitutions were observed in E6 and E7 genes with 10 novel substitutions and 17 non-synonymous substitutions. We obtained 25 distinct variation patterns which the accession GenBank numbers as MH348918-MH348942. All of HPV58 variants belong to lineage A, while no lineage B, C and D were detected in Taizhou area, Southeast China. The sublineage A1, A2, and A3 variants were found in 136 (68.3%), 39 (19.6%), and 24 (12.1%) of HPV58 isolates, respectively. The sublineage A3 variants with T20I/G63S substitutions at E7 oncoprotein carried a significantly higher risk for high-grade cervical intraepithelial neoplasia (CIN2 or worse, CIN2+) when compared with other HPV58 variants (odds ratio = 4.41, P < 0.05). Nevertheless, there was no association between HPV58 (sub) lineages and cervical lesions. These data provide the critical characteristics of HPV58 variants to assist further investigation of carcinogenic association and the development of next generation vaccines and diagnostic assays in China.

Tian Y, Xu Y, Wang H, et al.
Comprehensive analysis of microarray expression profiles of circRNAs and lncRNAs with associated co-expression networks in human colorectal cancer.
Funct Integr Genomics. 2019; 19(2):311-327 [PubMed] Free Access to Full Article Related Publications
Increasing data demonstrate that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. However, the mechanisms in colorectal cancer (CRC) remain unclear. Here, hundreds of significantly expressed circRNAs, and thousands of lncRNAs as well as mRNAs were identified. By qRT-PCR, one abnormal circRNA, lncRNA, and three mRNAs were verified in 24 pairs of tissues and blood samples, respectively. Then, by GO analysis, we found that the gene expression profile of linear counterparts of upregulated circRNAs in human CRC tissues preferred positive regulation of GTPase activity, cellular protein metabolic process, and protein binding, while that of downregulated circRNAs of CRC preferred positive regulation of cellular metabolic process, acetyl-CoA metabolic process, and protein kinase C activity. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that p53 signaling pathway was an important pathway in upregulated protein-coding genes, whereas cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway was the top enriched KEGG pathway for downregulated transcripts. Furthermore, lncRNA-mRNA co-expression analysis demonstrated that downregulated lncRNA uc001tma.3 was negatively with CDC45 and positively with ELOVL4, BVES, FLNA, and HSPB8, while upregulated lncRNA NR_110882 was positively with FZD2. In addition, lncRNA-transcription factor (TF) co-expression analysis showed that the most relevant TFs were forkhead box protein A1 (FOXA1), transcription initiation factor TFIID submint 7 (TAF7), and adenovirus early region 1A(E1A)-associated protein p300 (EP300). Our findings offer a fresh view on circRNAs and lncRNAs and provide the foundation for further study on the potential roles of circRNAs and lncRNAs in colorectal cancer.

Zhuo W, Liu Y, Li S, et al.
Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS.
Gastroenterology. 2019; 156(3):676-691.e11 [PubMed] Related Publications
BACKGROUND & AIMS: We aimed to identify long noncoding RNAs (lncRNAs) that are up-regulated in gastric cancer tissues from patients and study their function in gastric tumor metastasis.
METHODS: We collected gastric tumor and nontumor tissues from patients in China and analyzed levels of lncRNAs by microarray analysis, proteins by immunohistochemistry, and RNAs by quantitative reverse-transcription polymerase chain reaction; we compared these with survival times of patients and tumor progression. RNA levels were knocked down or knocked out in BGC-823, SGC-7901, and MKN45 cell lines using small interfering or short hairpin RNAs or clustered regularly interspaced short palindromic repeats (ie, CRISPR)/CRISPR associated protein 9 (ie, Cas9) vectors. Genes were overexpressed from transfected plasmids in HGC-27 cells. Cells were analyzed by Northern blot and immunoblot, polysome profiling assay, and cell invasion assay. Cells were injected into the tail veins or spleens of nude mice or SCID mice; lung and liver tissues were collected, and metastases were counted. lncRNAs were cloned by using rapid amplification of complementary DNA ends. Their interactions with other genes were determined by RNA pulldown and mapping assays.
RESULTS: In microarray analyses, we identified 151 lncRNAs expressed at significantly higher levels in gastric tumor vs nontumor tissues. Levels of an lncRNA that we called gastric cancer metastasis associated long noncoding RNA (GMAN) were increased in gastric tumor tissues, compared with nontumor tissues; its up-regulation was associated with tumor metastasis and shorter survival times of patients. The GMAN gene overlaps with the ephrin A1 gene (EFNA1) and was highly expressed in BGC-823 and MKN45 cells. Knockdown of GMAN in these cells did not affect proliferation, colony formation, or adhesion but did reduce their invasive activity in Transwell assays. Ectopic expression of GMAN increased the invasive activity of HGC-27 cells. BGC-823 and MKN45 cells with knockdown of GMAN formed fewer metastases after injection into tail veins of nude mice. Knockdown or knockout of GMAN also reduced levels of ephrin A1 protein in cells. We found that GMAN promoted translation of ephrin A1 messenger RNA into protein by binding to the antisense GMAN RNA (GMAN-AS)-this antisense sequence is also complementary to that of ephrin A1 mRNA. Levels of ephrin A1 protein were also increased in gastric tumors from patients with metastases than in those without metastases. Knockout of ephrin A1 in BGC-823 cells reduced their invasive activity in Transwell assays and ability to form metastases after injection into SCID mice. Ectopic expression of ephrin A1 in BGC-823 cells with knockdown or knockout of GMAN restored their invasive activities and ability form metastases in nude or SCID mice. A CRISPR/Cas9-based strategy to disrupt the GMAN gene significantly reduced the numbers of metastases formed from SGC-7901 cells in mice.
CONCLUSIONS: We identified an lncRNA, which we call GMAN, that is increased in gastric tumors from patients and associated with survival and formation of metastases. It regulates translation of ephrin A1 mRNA by binding competitively to GMAN-AS. Knockdown or knockout of GMAN or ephrin A1 in gastric cancer cell lines reduces their invasive activity and ability to form metastases after injection into mice. These genes might be targeted to prevent or reduce gastric cancer metastasis.

Zhang C, Wang H, Liu X, et al.
Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP.
Oncogene. 2019; 38(11):1892-1904 [PubMed] Related Publications
Lung cancer is one of the most common malignant diseases globally, composed of non-small cell lung cancer (NSCLC, 85%) and small cell lung cancer (SCLC, 15%). MicroRNAs (miRNAs) are single-stranded noncoding RNAs having important roles in lung cancer development. miR-411-5p/3p were reported to be increased significantly in human NSCLC tissues and cell lines. Moreover, miR-411-5p/3p overexpression could accelerate cell proliferation and migration, and impede cell apoptosis in NSCLC cell lines. Mechanically, SPRY4 is confirmed a direct target of miR-411-5p/3p. Furthermore, our findings showed that miR-411-5p/3p promoted lung tumor growth in vivo, decreased SPRY4 expression dramatically, and induced EGFR, AKT signaling activation, as well as epithelial-mesenchymal transition (EMT) simultaneously in tumor tissues. In addition, we showed that miR-411-5p also targeted tumor suppressor TXNIP, involved in regulating positively cell cycle progress in SPC-A1 cells rather than in H1299. Whether cell specificity of low TXNIP mRNA level in H1299 is responsible for the different response to cell cycle between H1299 and SPC-A1 would need further explorations. Collectively, these results suggest that miR-411-5p/3p are required for NSCLC development by suppressing SPRY4 and TXNIP; thus, the miR-411-SPRY4-AKT axis might act as a promising target for lung cancer therapy clinically.

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