Gene Summary

Gene:TFRC; transferrin receptor
Aliases: T9, TR, TFR, p90, CD71, TFR1, TRFR, IMD46
Summary:This gene encodes a cell surface receptor necessary for cellular iron uptake by the process of receptor-mediated endocytosis. This receptor is required for erythropoiesis and neurologic development. Multiple alternatively spliced variants have been identified. [provided by RefSeq, Sep 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transferrin receptor protein 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: TFRC (cancer-related)

Xu L, Wu Q, Zhou X, et al.
TRIM13 inhibited cell proliferation and induced cell apoptosis by regulating NF-κB pathway in non-small-cell lung carcinoma cells.
Gene. 2019; 715:144015 [PubMed] Related Publications
Tripartite Motif Containing 13 (TRIM13), a member of TRIM proteins, is deleted in multiple tumor types, especially in B-cell chronic lymphocytic leukemia and multiple myeloma. The present study explored the expression and potential role of TRIM13 in non-small-cell lung carcinoma (NSCLC). We found that TRIM13 mRNA and protein expression was reduced in NSCLC tissues and cell lines in comparison to paired non-cancerous tissues and a human normal bronchial epithelial cell line, respectively. Overexpression of TRIM13 in NCI-H1975 and SPC-A-1 cells hampered cell proliferation. Additionally, TRIM13 overexpression increased the levels of cleaved caspase-3. TRIM13-induced NSCLC cell apoptosis was attenuated by a caspase-3 inhibitor Ac-DEVD-CHO, suggesting that TRIM13 induced cell apoptosis partially through a caspase-3-dependent pathway. Moreover, it has been reported that TRIM13 can regulate nuclear factor kappaB (NF-κB) activity. Our data showed that TRIM13 overexpression inactivated NF-κB as indicated by the increased cytosolic NF-κB and decreased nuclear NF-κB. Exposure to an NF-κB inhibitor PDTC significantly blocked the impact of TRIM13 knockdown on cell proliferation and apoptosis, indicating the functions of TRIM13 in NSCLC cells were mediated by the NF-κB pathway. Finally, we demonstrated that TRIM13 overexpression suppressed tumor growth and induced cell apoptosis in vivo by using a xenograft mouse model. Collectively, our results indicate that TRIM13 behaves as a tumor suppressor in NSCLC through regulating NF-κB pathway. Our findings may offer a promising therapeutic target for NSCLC.

Tokgun PE, Tokgun O, Kurt S, et al.
MYC-driven regulation of long non-coding RNA profiles in breast cancer cells.
Gene. 2019; 714:143955 [PubMed] Related Publications
AIM: MYC deregulation contributes to breast cancer development and progression. Deregulated expression levels of long non-coding RNAs (lncRNA) have been demonstrated to be critical players in development and/or maintenance of breast cancer. In this study we aimed to evaluate lncRNA expressions depending on MYC overexpression and knockdown in breast cancer cells.
MATERIALS AND METHODS: Cells were infected with lentiviral vectors by either knockdown or overexpression of c-MYC. LncRNA cDNA was transcribed from total RNA samples and lncRNAs were evaluated by qRT-PCR.
RESULTS: Our results indicated that some of the lncRNAs having tumor suppressor (GAS5, MEG3, lincRNA-p21) and oncogenic roles (HOTAIR) are regulated by c-MYC.
CONCLUSION: We observed that c-MYC regulates lncRNAs that have important roles on proliferation, cell cycle and etc. Further studies will give us a light to identify molecular mechanisms related to MYC-lncRNA regulatory pathways in breast cancer.

Bishayee K, Habib K, Sadra A, Huh SO
Targeting the Difficult-to-Drug CD71 and MYCN with Gambogic Acid and Vorinostat in a Class of Neuroblastomas.
Cell Physiol Biochem. 2019; 53(1):258-280 [PubMed] Related Publications
BACKGROUND/AIMS: Although neuroblastoma is a heterogeneous cancer, a substantial portion overexpresses CD71 (transferrin receptor 1) and MYCN. This study provides a mechanistically driven rationale for a combination therapy targeting neuroblastomas that doubly overexpress or have amplified CD71 and MYCN. For this subset, CD71 was targeted by its natural ligand, gambogic acid (GA), and MYCN was targeted with an HDAC inhibitor, vorinostat. A combination of GA and vorinostat was then tested for efficacy in cancer and non-cancer cells.
METHODS: Microarray analysis of cohorts of neuroblastoma patients indicated a subset of neuroblastomas overexpressing both CD71 and MYCN. The viability with proliferation changes were measured by MTT and colony formation assays in neuroblastoma cells. Transfection with CD71 or MYCN along with quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect expression changes. For pathway analysis, gene ontology (GO) and Protein-protein interaction analyses were performed to evaluate the potential mechanisms of GA and vorinostat in treated cells.
RESULTS: For both GA and vorinostat, their pathways were explored for specificity and dependence on their targets for efficacy. For GA-treated cells, the viability/proliferation loss due to GA was dependent on the expression of CD71 and involved activation of caspase-3 and degradation of EGFR. It relied on the JNK-IRE1-mTORC1 pathway. The drug vorinostat also reduced cell viability/proliferation in the treated cells and this was dependent on the presence of MYCN as MYCN siRNA transfection led to a blunting of vorinostat efficacy and conversely, MYCN overexpression improved the vorinostat potency in those cells. Vorinostat inhibition of MYCN led to an increase of the pro-apoptotic miR183 levels and this, in turn, reduced the viability/proliferation of these cells. The combination treatment with GA and vorinostat synergistically reduced cell survival in the MYCN and CD71 overexpressing tumor cells. The same treatment had no effect or minimal effect on HEK293 and HEF cells used as models of non-cancer cells.
CONCLUSION: A combination therapy with GA and vorinostat may be suitable for MYCN and CD71 overexpressing neuroblastomas.

Silva OB, Correia NAA, de Barros FT, et al.
3' untranslated region A>C (rs3212227) polymorphism of Interleukin 12B gene as a potential risk factor for Hodgkin's lymphoma in Brazilian children and adolescents.
Tumour Biol. 2019; 41(7):1010428319860400 [PubMed] Related Publications
Interleukin 12 plays an important role in immunoregulation between the T helper 1/T helper 2 lymphocytes and in the antiviral and antitumor immune response. The aim of this study was to investigate the possible association between the interleukin 12B polymorphism rs3212227 and the risk to develop Hodgkin's lymphoma in childhood and adolescents. A total of 100 patients with Hodgkin's lymphoma and a group of 181 healthy controls were selected at random from a forensic laboratory of the University of Pernambuco. The AA genotype was detected in the controls (53.04%) and the AC genotype was found in the patients (54%). The AC genotype showed an association with the development of Hodgkin's lymphoma (odds ratio = 2.091, 95% confidence interval = 1.240-3.523, p = 0.007). When AC + CC genotypes were analyzed together, an increase in risk of 1.9 times more chances for HL development could be observed (odds ratio = 1.923, 95% confidence interval = 1.166-3.170, p = 0.014). However, there was no association between the AC and CC genotypes of the interleukin 12B polymorphism with the clinical risk group (p = 0.992, p = 0.648, respectively). Our results suggest that the presence of the C allele may be contributing to the development of Hodgkin's lymphoma in children and adolescents.

Park CS, Eom DW, Ahn Y, et al.
Can heme oxygenase-1 be a prognostic factor in patients with hepatocellular carcinoma?
Medicine (Baltimore). 2019; 98(26):e16084 [PubMed] Free Access to Full Article Related Publications
Heme oxygenase-1 (HO-1) is an important catalytic enzyme in heme degradation, which increases during stressful conditions. It plays a major role in antioxidative and antiapoptotic processes and is associated with tumor growth and metastasis.This study aimed to evaluate the degree of HO-1 expressions in hepatocellular carcinoma (HCC) surgical specimens and the correlation between HO-1 expression and patient prognosis. Formalin-fixed, paraffin-embedded HCC tissue samples (n = 96) were included in the analysis, and the expression of HO-1 was evaluated by immunohistochemical staining. We reviewed clinical features of patients and evaluated the prognostic role of HO-1 in patient survival and recurrence.Positive HO-1 expression was identified in 43 cases (44.8%) and was frequently found in patients with advanced histology (Edmondson-Steiner [E-S] grade 2, 3, 4), α-fetoprotein (AFP) level of more than 200 IU/mL, and the presence of microvascular and capsular invasion (P < .05). In the univariate analysis, the overall survival (OS) and disease-free survival (DFS) of patients with HO-1-positive HCC were not statistically different from those with HO-1-negative HCC. Moreover, HO-1 expression was not associated with patient survival and recurrence based on the multivariate analysis. In the subgroup analysis of patients without preoperative transarterial chemoembolization (TACE) (n = 61), HO-1 was not also associated with tumor recurrence (P = .681).The clinical implication of HO-1 activity is controversial in various malignancies. However, HO-1 expression did not seem to influence the prognosis of HCC patients.

Zhang Y, Chen H, Zhu H, Sun X
CBX8 promotes tumorigenesis and confers radioresistance in esophageal squamous cell carcinoma cells through targeting APAF1.
Gene. 2019; 711:143949 [PubMed] Related Publications
As a transcriptional repressor, Chromobox 8 (CBX8) overexpression is found to be associated with tumorigenesis in several cancers. However, its role in radiotherapy resistance remains poorly characterized. Our study is the first to explore the correlation between CBX8 and radioresistance. We report here that CBX8 is upregulated in Esophageal Squamous Cell Carcinoma (ESCC) tissues and cells and serves as an indicator of poor prognosis for ESCC patients. CBX8 knockdown inhibits cell proliferation, colony formation capability, DNA repair and promotes cell apoptosis. Moreover, the transcriptome sequencing analysis demonstrates that CBX8 downregulates the expression of Apoptotic protease activating factor 1 (APAF1), which is the core protein that mediates mitochondrial apoptotic pathways. APAF1 depletion could abrogate apoptosis induced by CBX8 knockdown in irradiated ESCC cells. Our results provide novel insight into CBX8 as a therapeutic target to improve the radiosensitivity of ESCC.

Nguyen HH, Kim T, Nguyen T, et al.
A Selective Inhibitor of Ubiquitin-Specific Protease 4 Suppresses Colorectal Cancer Progression by Regulating β-Catenin Signaling.
Cell Physiol Biochem. 2019; 53(1):157-171 [PubMed] Related Publications
BACKGROUND/AIMS: Dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of key proteins, has been implicated in many human diseases, including cancers. Thus, DUBs can be considered as potential therapeutic targets for many diseases. Among them, USP4 has been proposed as a promising target for colon cancer drugs since USP4 controls the stability of β-catenin, a key factor in the Wnt signaling involved in the tumorigenesis of colorectal cancer. However, developing potential DUB inhibitors has been hindered because many DUBs harbor similar active site structures and show broad substrate specificities.
METHODS: By performing in vitro deubiquitinating activity assays using a chemical library, we identified several potential DUB inhibitors. Among them, only neutral red (NR) showed selective inhibitory activity on USP4 in a cell-based assay system. In colon cancer cells, NR affected the protein stability of β-catenin, as shown by immunoblotting, and it affected the target gene expression of β-catenin, as shown by quantitative real-time PCR. NR's potential as an anticancer drug was further estimated by colony formation and cell migration assays and by using a mouse xenograft model.
RESULTS: We identified NR as an uncompetitive inhibitor of USP4 and validated its effects in colorectal cancer. NR-treated cells showed decreased β-catenin stability and reduced expression of β-catenin target genes. Additionally, treating colon cancer cells with NR significantly reduced colony formation and cell migration, and injecting NR into a mouse xenograft model reduced the tumor volume.
CONCLUSION: The current results suggest that NR could be developed as an anticancer drug targeting USP4, and they support the possibility of developing specific DUB inhibitors as therapeutic agents.

Alvur O, Tokgun O, Baygu Y, et al.
The triazole linked galactose substituted dicyano compound can induce autophagy in NSCLC cell lines.
Gene. 2019; 712:143935 [PubMed] Related Publications
As seen in other types of cancer, development of drug resistance in NSCLC treatment causes adverse effects on disease fighting process. Recent studies have shown that one of the drug resistance development mechanisms is that cancer cells may acquire the ability to escape from cell death. Therefore, development of anticancer drugs which have the strategy to redirect cancer cells to any cell death pathways may provide positive results for cancer treatments. Autophagy may be a target mechanism of alternative cancer treatment strategy in cases of blocked apoptosis. There is also a complex molecular link between autophagy and apoptosis, has not been fully understood yet. The dicyano compound which we used in our study caused cell death in NSCLC cell lines. When we analyzed the cells which were treated with dicyano compound by transmission electron microscope, we observed autophagosome structures. Upon this result, we investigated expression levels of autophagic proteins in the dicyano compound-treated cells by immunoblotting and observed that expression levels of autophagic proteins were increased significantly. The TUNEL assay and qRT-PCR for pro-apoptotic and anti-apoptotic gene expression, which we performed to assess apoptosis in the dicyano compound-treated cells, showed that the cell death does not occur through apoptotic pathway. We showed that the dicyano compound, which was developed in our laboratories, may play a role in molecular link between apoptosis and autophagy and may shed light on development of new anticancer treatment strategies.

Barajas-Olmos FM, Ortiz-Sánchez E, Imaz-Rosshandler I, et al.
Analysis of the dynamic aberrant landscape of DNA methylation and gene expression during arsenic-induced cell transformation.
Gene. 2019; 711:143941 [PubMed] Related Publications
Inorganic arsenic is a well-known carcinogen associated with several types of cancer, but the mechanisms involved in arsenic-induced carcinogenesis are not fully understood. Recent evidence points to epigenetic dysregulation as an important mechanism in this process; however, the effects of epigenetic alterations in gene expression have not been explored in depth. Using microarray data and applying a multivariate clustering analysis in a Gaussian mixture model, we describe the alterations in DNA methylation around the promoter region and the impact on gene expression in HaCaT cells during the transformation process caused by chronic exposure to arsenic. Using this clustering approach, the genes were grouped according to their methylation and expression status in the epigenetic landscape, and the changes that occurred during the cellular transformation were identified adequately. Thus, we present a valuable method for identifying epigenomic dysregulation.

Zhu Y, Wang J, Wang F, et al.
Differential MicroRNA Expression Profiles as Potential Biomarkers for Pancreatic Ductal Adenocarcinoma.
Biochemistry (Mosc). 2019; 84(5):575-582 [PubMed] Related Publications
Pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge due to its poor prognosis. Therefore, the early diagnosis of PDAC is extremely important for achieving a cure. MicroRNAs (miRNAs) could serve as a potential biomarker for the early detection and prognosis of PDAC. In this work we analyzed plasma samples from healthy persons and PDAC patients to assess differential miRNA expression profiles by next generation sequencing technology and bioinformatics analysis. In this way, 165 mature miRNAs were found to be significantly deregulated in the patient group, of which 75 and 90 mature miRNAs were up- and down-regulated compared with healthy individuals, respectively. Furthermore, 1029 novel miRNAs were identified. In conclusion, plasma miRNA expression profiles are different between healthy individuals and patients with PDAC. These data provide a possibility for use of miRNA as diagnostic and prognostic biomarkers of PDAC.

D'Alise AM, Leoni G, Cotugno G, et al.
Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade.
Nat Commun. 2019; 10(1):2688 [PubMed] Free Access to Full Article Related Publications
Neoantigens (nAgs) are promising tumor antigens for cancer vaccination with the potential of inducing robust and selective T cell responses. Genetic vaccines based on Adenoviruses derived from non-human Great Apes (GAd) elicit strong and effective T cell-mediated immunity in humans. Here, we investigate for the first time the potency and efficacy of a novel GAd encoding multiple neoantigens. Prophylactic or early therapeutic vaccination with GAd efficiently control tumor growth in mice. In contrast, combination of the vaccine with checkpoint inhibitors is required to eradicate large tumors. Gene expression profile of tumors in regression shows abundance of activated tumor infiltrating T cells with a more diversified TCR repertoire in animals treated with GAd and anti-PD1 compared to anti-PD1. Data suggest that effectiveness of vaccination in the presence of high tumor burden correlates with the breadth of nAgs-specific T cells and requires concomitant reversal of tumor suppression by checkpoint blockade.

Mensali N, Myhre MR, Dillard P, et al.
Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy.
Cancer Immunol Immunother. 2019; 68(8):1235-1243 [PubMed] Free Access to Full Article Related Publications
Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.

Mohamedi Y, Fontanil T, Cobo T, et al.
Antitumor Potential of Fibulin-5 in Breast Cancer Cells Depends on Its RGD Cell Adhesion Motif.
Cell Physiol Biochem. 2019; 53(1):87-100 [PubMed] Related Publications
BACKGROUND/AIMS: Different components of the tumor microenvironment can be either tumor-promoting or tumor-suppressive agents depending on factors which are not fully understood. Fibulins are components of the extracellular matrix from different tissues and constitute a clear example of this dual function. In fact, fibulins may either support tumor growth or abolish progression of malignant cells depending on the crosstalk between tumor cells and their surrounding stroma through mechanisms that remain to be elucidated. Among all fibulins, fibulin-5 contains a particular structural hallmark which consists in the presence of a RGD motif within its architecture. Previous reports have highlighted the importance of the interaction of this motif with integrins, and not only in normal functions but also in a tumor context.
METHODS: Site-Directed Mutagenesis technique was employed to introduce the change RGD to RGE (RGD-to-RGE) within Fbln5 cDNA sequence. Cell proliferation was measured using the MTT assay or by counting Ki-67 positive cell nuclei. Cell adhesion was analysed using culture plates coated with different extracellular matrix components. Cell invasion was evaluated using 24-well Matrigel-coated invasion chambers, and mammosphere formation was monitored using ultralow attachment culture plates. BALB/c mice were employed to induce subcutaneous tumors.
RESULTS: The RGD-to-RGE change alters the capacity of breast cancer cells to adhere to different extracellular matrix proteins as well as to α
CONCLUSION: These data highlight the importance of the RGD motif of fibulin-5 to induce antitumor effects and provide new insights into the involvement of fibulins in tumor processes.

Özcan Şimşek NÖ, Özgür A, Gürgen F
Statistical representation models for mutation information within genomic data.
BMC Bioinformatics. 2019; 20(1):324 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As DNA sequencing technologies are improving and getting cheaper, genomic data can be utilized for diagnosis of many diseases such as cancer. Human raw genome data is huge in size for computational systems. Therefore, there is a need for a compact and accurate representation of the valuable information in DNA. The occurrence of complex genetic disorders often results from multiple gene mutations. The effect of each mutation is not equal for the development of a disease. Inspired from the field of information retrieval, we propose using the term frequency (tf) and BM25 term weighting measures with the inverse document frequency (idf) and relevance frequency (rf) measures to weight genes based on their mutations. The underlying assumption is that the more mutations a gene has in patients with a certain disease and the less mutations it has in other patients, the more discriminative that gene is.
RESULTS: We evaluated the proposed representations on the task of cancer type classification. We applied various machine learning techniques using the tf-idf and tf-rf schemes and their BM25 versions. Our results show that the BM25-tf-rf representation leads to improved classification accuracy and f-score values compared to the other representations. The highest accuracy (76.44%) and f-score (76.95%) are achieved with the BM25-tf-rf based data representation.
CONCLUSIONS: As a result of our experiments, the BM25-tf-rf scheme and the proposed neural network model is shown to be the best performing classification system for our case study of cancer type classification. This system is further utilized for causal gene analysis. Examples from the most effective genes that are used for decision making are found to be in the literature as target or causal genes.

Örs Kumoğlu G, Döşkaya M, Gulce Iz S
The biomarker features of miR-145-3p determined via meta-analysis validated by qRT-PCR in metastatic cancer cell lines.
Gene. 2019; 710:341-353 [PubMed] Related Publications
MicroRNAs (miRNAs) play important roles in the cancer biology such as proliferation, differentiation, and apoptosis. The pivotal roles that miRNA expression plays, make them ideal candidates for detection of cancer progression as well as cancer metastasis. Especially for breast, lung and prostate cancer which are originated from soft tissues and prone to metastasis. Thus, the aim of this study is to evaluate the expression level of miR-145-3p which is a shared potential biomarker identified by meta-analysis of breast, prostate and lung cancer data sets. Six different data sets representative of three different cancer types were analyzed. These data sets are pooled together to have a master metamiRNA list while getting rid of the platform differentiations between them. As a result, 24 common differentially expressed miRNAs are determined in which miR-145-3p has the topmost rank. To mimic in vivo cancer microenvironment, hypoxia and serum deprivation were used to induce metastasis in breast (MCF-7, MDA-MB-231, MDA-MB-453), prostate (PC3, LNCaP, DU145), lung (A549, NCIH82,) cancer cell lines and noncancerous cell lines of the coresponding tissues (MCF10A, RWPE-1, MRC-5). miR-145-3p expression levels were determined by qRT-PCR. It has been shown that it is down regulated by the induction of metastasis in cancer cell lines while it is up regulated in normal cell lines to suppress the tumor formation. As a conclusion, as representing the same results in three different cancer cell types, miR-145-3p will be a promising biomarker to follow up its expression to detect cancer metastasis.

Xiong J, Zhao W
What we should know about natural killer/T-cell lymphomas.
Hematol Oncol. 2019; 37 Suppl 1:75-81 [PubMed] Related Publications
Natural-killer/T cell lymphoma (NKTCL) is the most common extranodal lymphoma with highly aggressive clinical outcome. System biology techniques provide novel insights into the pathogenesis, risk stratification, and clinical management in NKTCL. Comparative genomic hybridization analysis reveal most frequent deletion of chromosome 6q21. Whole-exome sequencing studies identify recurrent somatic gene mutations, involving RNA helicases, tumor suppressors, JAK-STAT pathway molecules, and epigenetic modifiers. Genome-wide association study reports strongest association of HLA-DPB1 rs9277378 with lymphomagenesis. Alterations of oncogenic signaling pathways as well as epigenetic dysregulation of microRNA and long non-coding RNAs are also observed in NKTCL. Epstein-Barr virus (EBV) is the major etiology of NKTCL and the pathogenic mechanism remains unclear. Different risk stratification models are proposed based on clinical parameters (IPI, PINK, and PINK-E, etc.) or biomarkers (Ki67, C-reactive protein level, and EBV DNA, etc.). Therapeutic strategies vary according to disease stage, including radiotherapy, asparaginase-based chemotherapy, hematopoietic stem-cell transplantation, targeted therapy (immune checkpoints inhibitors, and histone deacetylation inhibitors, etc.). Future investigations will be emphasized on EBV-related pathogenesis of NKTCL, prognostic and therapeutic biomarkers, as well as multi-center clinical trials, so as to optimize personalized treatment of NKTCL in the era of precision medicine.

Gong W, Hoffmann JM, Stock S, et al.
Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells.
Cancer Immunol Immunother. 2019; 68(7):1195-1209 [PubMed] Related Publications
The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (T

Zang W, Bian H, Huang X, et al.
Traditional Chinese Medicine (TCM)
Anticancer Res. 2019; 39(6):2739-2747 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs).
MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a.
RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-β. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control.
CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.

Liu C, Jiang YH, Zhao ZL, et al.
Knockdown of Histone Methyltransferase WHSC1 Induces Apoptosis and Inhibits Cell Proliferation and Tumorigenesis in Salivary Adenoid Cystic Carcinoma.
Anticancer Res. 2019; 39(6):2729-2737 [PubMed] Related Publications
BACKGROUND/AIM: Salivary adenoid cystic carcinoma (SACC) is the most common malignancy of the salivary gland with a poor prognosis and survival. The present study aimed to investigate the role of histone methyltransferase WHSC1 in SACC.
MATERIALS AND METHODS: Human SACC specimens were evaluated for WHSC1 expression by RT-PCR and immunohistochemistry. The effects of WHSC1 knockdown on SACC cells proliferation, cell cycle, clone and tumorsphere formation, and apoptosis as well as on the expression of related genes were examined. A xenograft mouse model of SACC was used to evaluate the in vivo effects of WHSC1 knockdown on SACC tumorigenesis.
RESULTS: WHSC1 expression was up-regulated in human SACC tissues (p<0.01). WHSC1 knockdown in SACC cells significantly inhibited cell proliferation, clone and tumorsphere formation (p<0.05). Cell distribution at the S and G
CONCLUSION: Knockdown of WHSC1 inhibited cell proliferation, induced apoptosis and affected tumorigenesis in SACC.

Liu L, Wu SQ, Zhu X, et al.
Analysis of ceRNA network identifies prognostic circRNA biomarkers in bladder cancer.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Bladder cancer remains a very challenging disease to treat with the high rates of recurrence and progression associated with current therapies. Although the association between bladder cancer pathology and circRNAs remains undetermined, circRNAs signatures may be useful as prognostic and predictive factors and clinical tools for assessing disease state and outcome. This study investigates if these circRNAs can be used as biomarkers for bladder cancer diagnosis. Using bioinformatics method to analysis GEO databases (GSE37815, GSE39093, GSE97239, and GSE92675) for differentially expressed RNAs in bladder cancer and normal bladder tissues were screened from. The related volcanic maps and the interaction network maps of differentially expressed RNAs were drawn, and the mRNA-miRNA and miRNA-circRNA interaction were predicted to establish mRNA-miRNA-circRNA competitive endogenous RNA (ceRNA) network. The differential circRNAs related to prognosis of bladder cancer patients were screened based on the influence of miRNA interacting with the circRNA above on survival rate. The expression of miRNA (hsa-mir-214), circRNA (hsa_circ_0076704, hsa_circ_0081963, hsa_circ_0001361) in bladder cancer tissues, adjacent tissues, bladder cancer cells and normal bladder epithelial cells were validated by qRT-PCR. Kaplan Meier curve analysis confirmed the relationship between circRNA (hsa_circ_0076704) and overall survival and prognosis of bladder cancer patients. Through database screening and analysis, we found 19231 differentially expressed genes, 847 differentially expressed miRNAs, 7282 differentially expressed circRNAs. The establishment of ceRNA network consisted of 28 DERNAs (differentially- expressed RNAs), 12 Demi-RNAs and 12 DEcircRNAs. Further prognostic analysis showed that circRNA interacted miRNA hsa-miR-106b, hsa-miR-145 and hsa-miR-214 were associated with overall survival in patients with bladder cancer (P < 0.05). Among them, hsa_circ_0076704, hsa_circ_0081963 and hsa_circ_0001361 are potential circRNA related to OS in bladder cancer and expressed in bladder cancer. The expression of hsa-mir-214 was contrary. Further Kaplan Meier survival analysis showed that hsa_circ_0076704 had significant prognostic value (P < 0.05). In conclusion, hsa_circ_0076704 is independent prognostic factor for bladder cancer.

Xie C, Du LY, Guo F, et al.
Exosomes derived from microRNA-101-3p-overexpressing human bone marrow mesenchymal stem cells suppress oral cancer cell proliferation, invasion, and migration.
Mol Cell Biochem. 2019; 458(1-2):11-26 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) has been found to disrupt the progression of oral cancer. However, which miRNAs are most effective against oral cancer and how these miRNAs should be delivered are major unanswered problems. We aimed at investigating if human bone marrow mesenchymal stem cells (hBMSCs)-derived exosomes affect oral cancer development, and the potential regulatory mechanism associated with COL10A1 and miR-101-3p. COL10A1 was upregulated, while miR-101-3p was downregulated in oral cancer, and miR-101-3p targeted COL10A1 as verified by dual-luciferase reporter gene assay. Meanwhile, exosomes derived from hBMSCs were isolated and then co-cultured with oral cancer cells to identify the role of exosomes, and the results suggested that hBMSCs-derived exosomes overexpressing miR-101-3p inhibited oral cancer progression. Furthermore, tumorigenicity assay in nude mice further confirmed the inhibitory effects of hBMSCs-derived exosomes, loaded with miR-101-3p, on oral cancer, which provides a new theoretical basis in the treatment of oral cancer.

Zhao S, Li J, Zhang G, et al.
Exosomal miR-451a Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Targeting LPIN1.
Cell Physiol Biochem. 2019; 53(1):19-35 [PubMed] Related Publications
BACKGROUND/AIMS: Emerging evidence suggests that exosomal microRNAs (miRNAs) mediate hepatoma progression through the post-translational regulation of their targets. However, characteristically-expressed miRNAs and their functions in the tumor and tumor-associated angiogenesis remain poorly understood.
METHODS: miRNA sequencing (HiSeq 2500 SE50) was performed to identify miRNA species that are involved in the hepatocellular carcinoma (HCC) pathogenesis. We identified miR-451a downregulation according to its expression and TCGA analysis. miR-451a was found to be mainly involved in cell viability, apoptosis, cell cycle and migration both in HCC and endothelial cell lines. LPIN1 was predicted to be a target of this miRNA based on TargetScan, GSEA analysis, and the Uniprot database. We performed real time PCR and dual luciferase assays to confirm these results.
RESULTS: We identified that miR-451a is significantly downregulated in serum-derived exosomes from HCC patients, as compared to expression in those from normal individuals. We further confirmed that overexpression of miR-451a functions in HCC and endothelia cells in vitro and in vivo. Exosomal miR-451a, as a tumor suppressor, was found to induce apoptosis both in HCC cell lines and human umbilical vein endothelial cells (HUVECs). In addition, miR-451a suppressed HUVEC migration, tube formation, and vascular permeability. Importantly, we demonstrated that LPIN1 is a critical target of miR-451a, and promotes apoptosis in both HCC and endothelial cells.
CONCLUSION: Our study provides the novel finding that exosomal miR-451a targets LPIN1 to inhibit hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis. These results have clinical implications regarding the deregulation of miRNAs in HCC.

Wei W, Dong Z, Gao H, et al.
MicroRNA-9 enhanced radiosensitivity and its mechanism of DNA methylation in non-small cell lung cancer.
Gene. 2019; 710:178-185 [PubMed] Related Publications
In order to improve the therapeutic effect of non-small cell lung cancer (NSCLC), it is critical to combine radiation and gene therapy. Our study found that the activation of microRNA-9 (miR-9) conferred ionizing radiation (IR) sensitivity in cancer cells. Furthermore, increased microRNA-9 promoter methylation level was observed after IR. Our study combined the IR and microRNA-9 overexpression treatment which leads to a significant enhancement in the therapeutic efficiency in lung cancer both in vitro and in vivo. Therefore, it is plausible that microRNA-9 can be used as a novel therapeutic strategy of NSCLC. MTT assay was performed to detect the effect of microRNA-9 on the survival and growth of NSCLC cells. Flow cytometry results showed that microRNA-9 enhanced the apoptosis of NSCLC cells. Wound healing assay found that microRNA-9 can inhibit the migration of NSCLC cells and enhance the effect of radiation on the migration of NSCLC cells. In addition, bisulfate sequencing PCR was performed to analyze the methylation status of the microRNA-9 promoter. In order to determine the effect of microRNA-9 and its promoter methylation status on proliferation and radio-sensitivity in vivo, a subcutaneous tumor formation assay in nude mice was performed. Results have shown that microRNA-9 overexpression increased the radiosensitivity of A549 cells by inhibiting cell activity and migration, and by increasing apoptosis. In addition, the promoter methylation status of the microRNA-9 gene increased in response to ionizing radiation. Our study demonstrated that microRNA-9 enhanced radiosensitivity in NSCLC and this effect is highly regulated by its promoter methylation status. These results will help to clarify regulatory mechanisms of radiation resistance thus stimulate new methods for improving radiotherapy for NSCLC.

Buckley AR, Ideker T, Carter H, Schork NJ
Rare variant phasing using paired tumor:normal sequence data.
BMC Bioinformatics. 2019; 20(1):265 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In standard high throughput sequencing analysis, genetic variants are not assigned to a homologous chromosome of origin. This process, called haplotype phasing, can reveal information important for understanding the relationship between genetic variants and biological phenotypes. For example, in genes that carry multiple heterozygous missense variants, phasing resolves whether one or both gene copies are altered. Here, we present a novel approach to phasing variants that takes advantage of unique properties of paired tumor:normal sequencing data from cancer studies.
RESULTS: VAF phasing uses changes in variant allele frequency (VAF) between tumor and normal samples in regions of somatic chromosomal gain or loss to phase germline variants. We apply VAF phasing to 6180 samples from the Cancer Genome Atlas (TCGA) and demonstrate that our method is highly concordant with other standard phasing methods, and can phase an average of 33% more variants than other read-backed phasing methods. Using variant annotation tools designed to score gene haplotypes, we find a suggestive association between carrying multiple missense variants in a single copy of a cancer predisposition gene and earlier age of cancer diagnosis.
CONCLUSIONS: VAF phasing exploits unique properties of tumor genomes to increase the number of germline variants that can be phased over standard read-backed methods in paired tumor:normal samples. Our phase-informed association testing results call attention to the need to develop more tools for assessing the joint effect of multiple genetic variants.

Fu Y, Lin L, Xia L
MiR-107 function as a tumor suppressor gene in colorectal cancer by targeting transferrin receptor 1.
Cell Mol Biol Lett. 2019; 24:31 [PubMed] Free Access to Full Article Related Publications
Background: While microRNAs (miRNAs) are known to play a critical role in the progression of colorectal cancer, the role of miR-107 remains unknown. We evaluated its role and explored the underlying mechanism.
Materials & methods: MTT, wound-healing, transwell migration and transwell invasion assays were performed to evaluate the role of miR-107 in SW629 cell proliferation, migration and invasion. Real time-PCR and dual-luciferase reporter gene, TFR1 overexpression and western blotting assays were used to explore the underlying mechanism.
Results: MiR-107 is downregulated in colorectal cancer tissues and several human colorectal cancer cell lines. Low miR-107 expression often indicates a poor survival rate for colorectal cancer patients. MiR-107 suppresses the proliferation, migration and invasion of SW620 cells by negatively regulating transferrin receptor 1 (TFR1).
Conclusion: MiR-107 suppresses the metastasis of colorectal cancer and could be a potential therapy target in colorectal cancer patients.

Wang S, Wu Y, Xu Y, Tang X
miR-10b promoted melanoma progression through Wnt/β-catenin pathway by repressing ITCH expression.
Gene. 2019; 710:39-47 [PubMed] Related Publications
Dysregulation of microRNAs (miRNAs) have been reported to contribute to malignant progression in melanoma. However, the roles and mechanisms of several miRNAs in melanoma remain poorly understood. In our study, we showed that miR-10b was significantly up-regulated in melanoma tissues and cell lines, and was associated with overall survival of melanoma patients. Inhibition of miR-10b dramatically suppressed melanoma cell proliferation, migration and invasion in vitro and inhibited tumor growth in vivo. Moreover, we defined ITCH as a direct and functional downstream target of miR-10b, and showed that there was an inverse correlation between the expression of ITCH and miR-10b on melanoma tissues. Down-regulation of ITCH partially attenuated the inhibitory effects of miR-10b inhibition on melanoma cell proliferation, migration and invasion. Furthermore,we found that miR-10b exerted its effects on melanoma by regulating the Wnt/β-catenin pathway. Taken together, our results demonstrated that miR-10b was an important epigenetic modifier, promoting melanoma progression through regulating ITCH/Wnt/β-catenin pathway. These results offer a new strategy for epigenetic cancer therapy.

Xie R, Okita Y, Ichikawa Y, et al.
Role of the kringle-like domain in glycoprotein NMB for its tumorigenic potential.
Cancer Sci. 2019; 110(7):2237-2246 [PubMed] Free Access to Full Article Related Publications
Glycoprotein NMB (GPNMB) is highly expressed in many types of malignant tumors and thought to be a poor prognostic factor in those cancers, including breast cancer. Glycoprotein NMB is a type IA transmembrane protein that has a long extracellular domain (ECD) and a short intracellular domain (ICD). In general, the ECD of a protein is involved in protein-protein or protein-carbohydrate interactions, whereas the ICD is important for intracellular signaling. We previously reported that GPNMB contributes to the initiation and malignant progression of breast cancer through the hemi-immunoreceptor tyrosine-based activation motif (hemITAM) in its ICD. Furthermore, we showed that the tyrosine residue in hemITAM is involved in induction of the stem-like properties of breast cancer cells. However, the contribution of the ECD to its tumorigenic function has yet to be fully elucidated. In this study, we focused on the region, the so-called kringle-like domain (KLD), that is conserved among species, and made a deletion mutant, GPNMB(ΔKLD). Enhanced expression of WT GPNMB induced sphere and tumor formation in breast epithelial cells; in contrast, GPNMB(ΔKLD) lacked these activities without affecting its molecular properties, such as subcellular localization, Src-induced tyrosine phosphorylation at least in overexpression experiments, and homo-oligomerization. Additionally, GPNMB(ΔKLD) lost its cell migration promoting activity, even though it reduced E-cadherin expression. Although the interaction partner binding to KLD has not yet been identified, we found that the KLD of GPNMB plays an important role in its tumorigenic potential.

Zhang Q, Lu Y, Xu X, et al.
MR molecular imaging of HCC employing a regulated ferritin gene carried by a modified polycation vector.
Int J Nanomedicine. 2019; 14:3189-3201 [PubMed] Free Access to Full Article Related Publications

Tang L, Wang Y, Wang H, et al.
Long noncoding-RNA component of mitochondrial RNA processing endoribonuclease is involved in the progression of cholangiocarcinoma by regulating microRNA-217.
Cancer Sci. 2019; 110(7):2166-2179 [PubMed] Free Access to Full Article Related Publications
Cholangiocarcinoma (CCA) is a malignant tumor originating from bile duct epithelium and its incidence is increasing year by year. In recent years, long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and progression of malignant tumors. In the present study, for the first time, abnormal expression of lnc-RNA component of mitochondrial RNA processing endoribonuclease (RMRP) and its possible role in CCA were found. We explored the effects of RMRP on various behaviors of CCA cells in vitro and in vivo. In addition, by second-generation sequencing, we explored the microRNA expression profiles that RMRP may affect in the HCCC-9810 cell line. We also validated and explored the role of microRNA-217 (miR-217) with high differential expression by in vitro experiments. Our findings indicated that RMRP can play a part in promoting cancer by regulating the expression of miR-217. RMRP is involved in the progression of CCA and can be a novel indicator of poor prognosis in patients with CCA.

Qi X, Li F, Wu Y, et al.
Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity.
Nat Commun. 2019; 10(1):2141 [PubMed] Free Access to Full Article Related Publications
Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB

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