Gene Summary

Gene:BLNK; B cell linker
Aliases: bca, AGM4, BASH, LY57, SLP65, BLNK-S, SLP-65
Summary:This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:B-cell linker protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (11)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 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.

  • Protein-Tyrosine Kinases
  • Signal Transduction
  • Apoptosis
  • Neoplasm Proteins
  • Immunohistochemistry
  • Spleen
  • Cell Proliferation
  • Flow Cytometry
  • Cohort Studies
  • Phosphoproteins
  • Gene Expression Profiling
  • Mutation
  • Leukemic Gene Expression Regulation
  • Tissue Array Analysis
  • DNA-Binding Proteins
  • Transcription Factors
  • Signal Transducing Adaptor Proteins
  • Transcription
  • Translocation
  • Lymphocyte Activation
  • Young Adult
  • Intracellular Signaling Peptides and Proteins
  • Agammaglobulinaemia Tyrosine Kinase
  • Acute Myeloid Leukaemia
  • Biomarkers, Tumor
  • Retinoic Acid
  • Receptors, Antigen, B-Cell
  • Adolescents
  • Cancer Gene Expression Regulation
  • PAX5 Transcription Factor
  • fms-Like Tyrosine Kinase 3
  • Diffuse Large B-Cell Lymphoma
  • B-Lymphocytes
  • p53 Protein
  • Recurrence
  • Chromosome 10
  • Oligonucleotide Array Sequence Analysis
  • MicroRNAs
  • Acute Lymphocytic Leukaemia
  • Syk Kinase
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: BLNK (cancer-related)

Tian H, Wang X, Lu J, et al.
MicroRNA-621 inhibits cell proliferation and metastasis in bladder cancer by suppressing Wnt/β-catenin signaling.
Chem Biol Interact. 2019; 308:244-251 [PubMed] Related Publications
Increasing evidence has shown that dysregulation of microRNA-621 (miR-621) is demonstrated to be associated with several cancers. However, the role of miR-621 in bladder cancer (BCa) remains unclear. Herein, we aimed to study the expression pattern, biological function, and molecular mechanism of miR-621 in BCa. First, we demonstrated that miR-621 was frequently downregulated in BCa tissues and cell lines compared with the adjacent normal BCa tissues and non-cancerous immortalized urothelial cell line. In addition, the expression of miR-621 was negatively correlated with overall survival of BCa patients. Functional experiments suggessted that miR-621 inhibited the proliferation and metastasis of BCa cells. Notably, dual-luciferase assay showed that miR-621 directly targeted the 3' UTR of TRIM29, which was frequently upregulated in BCa tissues and displayed inverse correlation with miR-621 expression. Furthermore, we demonstrated that miR-621 inhibited the proliferation and metastasis of BCa cells via Wnt/β-catenin signaling pathway by targeting TRIM29. Our study suggested that the miR-621/TRIM29 axis inhibits the proliferation and metastasis of BCa cells via Wnt/β-catenin signaling pathway and may have potential applications for development of BCa diagnosis or treatment.

Mao W, Huang X, Wang L, et al.
Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression.
J Exp Clin Cancer Res. 2019; 38(1):169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FGFR3 plays an important role in the development of bladder cancer (BCa). Hsa_circ_0068871 is a circRNA generated from several exons of FGFR3. However, the potential functional role of hsa_circ_0068871 in BCa remains largely unknown. Here we aim to evaluate the role of hsa_circ_0068871 in BCa.
METHODS: We selected miR-181a-5p as the potential target miRNA of hsa_circ_0068871. The expression levels of hsa_circ_0068871 and miR-181a-5p were examined in BCa tissues and paired adjacent normal tissues by quantitative real-time PCR. To characterize the function of hsa_circ_0068871, BCa cell lines were stably infected with lentivirus targeting hsa_circ_0068871, followed by examinations of cell proliferation, migration and apoptosis. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0068871 in BCa. Biotinylated RNA probe pull-down assay, fluorescence in situ hybridization and luciferase reporter assay were conducted to confirm the relationship between hsa_circ_0068871, miR-181a-5p and FGFR3.
RESULTS: Hsa_circ_0068871 is over-expressed in BCa tissues and cell lines, whereas miR-181a-5p expression is repressed. Depletion of has_circ_0068871 or upregulation of miR-181a-5p inhibited the proliferation and migration of BCa cells in vitro and in vivo. Mechanistically, hsa_circ_0068871 upregulated FGFR3 expression and activated STAT3 by targeting miR-181a-5p to promote BCa progression.
CONCLUSIONS: Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote BCa progression, and it may serve as a potential biomarker.

Jeong H, Park J, Shim JK, et al.
Combined treatment with 2'-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness.
J Neurooncol. 2019; 143(1):69-77 [PubMed] Related Publications
INTRODUCTION: Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2'-hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs).
METHODS: Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model.
RESULTS: Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model.
CONCLUSION: Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

Song Y, Yang Y, Liu L, Liu X
Association between five polymorphisms in vascular endothelial growth factor gene and urinary bladder cancer risk: A systematic review and meta-analysis involving 6671 subjects.
Gene. 2019; 698:186-197 [PubMed] Related Publications
BACKGROUND: Vascular endothelial growth factor (VEGF) gene plays a key role in angiogenesis and tumor growth. The relationship between VEGF gene polymorphisms and bladder cancer (BCa) risk was studied extensively in recent years. However, the currently available results are controversial. To ascertain whether VEGF polymorphisms are associated with the susceptibility to BCa, we conducted this systematic review and meta-analysis.
MATERIALS AND METHODS: Relevant studies were collected systemically from PubMed, Medline, Embase, Web of Science databases and the Cochrane Library. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using random or fixed effects models by Stata statistical software. This systematic review protocol was registered at International prospective register of systematic reviews (PROSPERO) under number CRD42018099279.
RESULTS: A total of eight articles including twenty case-control studies with 3206 BCa cases and 3645 controls were enrolled for this meta-analysis. By pooling all eligible studies, we found that rs3025039, rs833052 and rs25648 polymorphisms were significantly associated with BCa risk. However, in subgroup analyses by stage, we identified a decreased association between the rs699947 A-allele and Muscle-invasive Bladder Cancer (MIBC) under allele contrast, homozygous and recessive genetic models (A vs C: OR = 0.76; AA vs CC: OR = 0.49, 95%CI = 0.27-0.90, I
CONCLUSION: Our meta-analysis suggested that rs3025039 (C > T), rs833052 (C > A) and rs25648 (C > T) polymorphisms of VEGF gene increased susceptibility to BCa risk. And our study also demonstrated homozygous TT genotype in rs3025039, homozygous AA genotype in rs833052 and homozygous TT genotype in rs25648 were significantly relevant to elevated BCa risk. In the meanwhile, it is worth noting that rs699947 (C > A) A-allele should be thought as a protective factor for MIBC.

Tan Y, Zhang T, Zhou L, et al.
MiR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.
Med Sci Monit. 2019; 25:1323-1335 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Chemoresistance is a main limitation in chemotherapy for therapeutic cancer. MicroRNA (miRNA) has been indicated in the progression and tumorigenesis of many types of cancer, but the effect of miR-34b-3p in bladder cancer (BCa) cells is still unknown. MATERIAL AND METHODS This research compared the multidrug-sensitive (5637) BCa cell line and the multidrug-resistant (EJ) BCa cell line. We found that CCND2 (G1/S-specific cyclin-D2) and P2RY1 (purinergic receptor P2Y1) were the targets of miR-34b-3p, as further validated by qRT-PCR (quantitative real-time polymerase chain reaction) and western blot analysis. RESULTS Forced reversal of the levels of miR-34b-3p or CCND2/P2RY1 changed the chemoresistance profiles in both 5637 cells and EJ cells. Further experiments suggested that the CCND2 gene and the P2RY1 gene act in concert to negatively correlate with miR-34b-3p effect on BCa multidrug-chemoresistance. CONCLUSIONS These results not only reveal new players regulating BCa chemoresistance, but also provide clues for effective chemotherapy for BCa patients.

Kusuhara Y, Daizumoto K, Kawai K, et al.
Low Expression of Toll-like Receptor 4 Is Associated With Poor Prognosis in Bladder Cancer.
Anticancer Res. 2019; 39(2):703-711 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to elucidate the relationship between the progression of bladder cancer (BCa) and TLR4 expression.
MATERIALS AND METHODS: The relationship between TLR4 expression and prognosis of BCa patients was analyzed using a publicly available database and immunohistochemical staining of clinical samples. The effect of TLR4 knockdown was also examined on the invasive capabilities of BCa cells. Finally, to investigate the biological function of TLR4, the gene expression profile of TLR4-depleted BCa cells was analyzed by microarray analysis.
RESULTS: Expression of TLR4 was inversely associated with prognosis of patients with invasive BCa, and depletion of TLR4 significantly enhanced the invasive capability of BCa cells. Gene expression profiling revealed that depletion of TLR4 led to high expression of epithelial differentiation genes. Furthermore, expression of TLR4 was found to be extremely low in areas of squamous differentiation.
CONCLUSION: Low TLR4 expression was correlated with tumor progression.

Wang X, Peng J, Yang Z, et al.
Elevated expression of Gab1 promotes breast cancer metastasis by dissociating the PAR complex.
J Exp Clin Cancer Res. 2019; 38(1):27 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer (BCa) remains as the second leading cause of cancer-related death in women worldwide. The majority of the deaths are due to its progression to metastatic BCa. Although Grb2-associated binding protein 1 (Gab1) has been implicated in tumor proliferation and metastasis in multiple tumors including colorectal cancer, hepatocellular carcinoma and ovarian cancer, whether and how it regulates BCa metastasis are still poorly understood.
METHODS: Western blot assay and immunohistochemical (IHC) staining were performed to assess expression of Gab1 in primary and metastatic BCa clinical samples. Biological function assay studies in vitro and in vivo were employed to investigate the functions of Gab1 during BCa metastasis. Co-immunoprecipitation (co-IP) assessment, western blot assay and immunofluorescence (IF) staining were carried out to investigate the underlying mechanism for the function of Gab1 on BCa metastasis.
RESULTS: In this study, we found that expression level of Gab1 was increased significantly in BCa tissue samples compared to that in benign mammary hyperplastic tissues. Furthermore, elevated expression of Gab1 was positively associated with metastasis in HER2 and TNBC subtypes of BCa. In BCa cell line MDA-MB-231 and SK-BR3 cells, stable overexpression of Gab1 promoted, while knockdown of Gab1 inhibited cell migration in vitro and metastasis in vivo. Mechanistically, overexpression of Gab1 enhanced its interaction with Par3, a key component of the polarity-associated partitioning defective (PAR) complex, leading to a dissociation of the PAR complex. Consequently, dissociated PAR complex induced epithelial-to-mesenchymal transition (EMT) for breast tumor metastasis. By restoration assessment, we found that only re-expression of a fully functional Gab1, but not a mutant Gab1 that harbors either Par3 binding-deficiency or Par1b binding-deficiency, could reverse the repressive phenotype of cell migration in vitro and metastasis in vivo due to Gab1 knockdown.
CONCLUSIONS: Our findings indicate that elevated expression of Gab1 promotes BCa metastasis by dissociating the PAR complex that leads to EMT, implicating a role of Gab1 as a potential biomarker of metastatic BCa. Moreover, inhibition of Gab1 expression might be a promising therapeutic strategy for BCa metastasis.

Stasik S, Salomo K, Heberling U, et al.
Evaluation of TERT promoter mutations in urinary cell-free DNA and sediment DNA for detection of bladder cancer.
Clin Biochem. 2019; 64:60-63 [PubMed] Related Publications
BACKGROUND: Cell-free DNA (cfDNA) is proposed to be a valuable source of biomarkers in liquid biopsies for various diseases as it is supposed to partially originate from tumor cells. However, data about the diagnostic implications of cfDNA in urine for the detection of bladder cancer (BCa) is sparse.
METHODS: We evaluated the usability of urinary cfDNA for diagnostic purposes compared to urine sediment DNA (sDNA) in 53 BCa patients and 36 control subjects by analyzing two abundant point-mutations (C228T/C250T) in the TERT promoter using Next-Generation Sequencing.
RESULTS: Mutations were detected in 77% of the urinary sDNA compared to 63% of the cfDNA samples. Moreover, the TERT mutation allele frequencies (MAF) were highly correlated in cfDNA and sDNA. In comparison, the accuracy of the TERT assay was higher in sDNA (84%) compared to cfDNA or voided urine cytology (both 77%). Interestingly, MAFs from leukocyte-rich urines were higher in cfDNA than in sDNA, indicating a diagnostic advantage of cfDNA in such urines.
CONCLUSIONS: Urine-based mutation detection has the ability to augment and surpass voided urine cytology as the current gold-standard for the non-invasive detection and surveillance of BCa. The analysis of cell-free DNA provides no general diagnostic advantage compared to urine sediment DNA.

Zhang WT, Zhang ZW, Guo YD, et al.
Discovering biomarkers in bladder cancer by metabolomics.
Biomark Med. 2018; 12(12):1347-1359 [PubMed] Related Publications
It has become increasingly clear that the development of cancer, a multifactorial disease, cannot be explained by a single molecule or gene mutation. As a new discipline, metabolomics focuses on the body's metabolite changes, and attempts to find differences to explain the development of cancer; it has proven to be effective and credible. Metabolic studies of bladder cancer (BCa) lag behind those of other tumors. This review systematically outlines the specific process of metabolomics and the use of metabolomics in BCa studies in recent years. We have reviewed the in vitro cell line, bladder tumor tissue and biofluid (urine, plasma and serum) studies used in metabolomics analyses of BCa. The advantages and drawbacks of the use of different samples were compared. Based on the available studies, we have further described the aberrant metabolic pathways of BCa and have suggested some metabolites that may be potential biomarkers for BCa detection.

Zhang J, Mao S, Wang L, et al.
MicroRNA‑154 functions as a tumor suppressor in bladder cancer by directly targeting ATG7.
Oncol Rep. 2019; 41(2):819-828 [PubMed] Free Access to Full Article Related Publications
Aberrant expression of miR‑154 is usually found in cancer studies; however, the role of miR‑154 has seldom been reported in bladder cancer (BCa). In this study, we observed that miR‑154 expression was significantly downregulated in BCa tissues and cell lines, and was associated with several clinicopathological characteristics, including advanced T stage, lymphatic invasion, and distant metastasis. Low expression level of miR‑154 was associated with poor survival outcomes in BCa patients. Overexpression of miR‑154 led to significant decrease in the proliferation, migration, and invasion of BCa cells, while knockdown of miR‑154 yielded the opposite effect. ATG7 was identified as a direct target of miR‑154. ATG7 expression was negatively correlated with miR‑154 expression in BCa tissues. Silencing of ATG7 achieved a similar effect to miR‑154 overexpression; overexpression of ATG7 reversed the inhibitory effect of miR‑154 on BCa cell proliferation, migration and invasion. A xenograft study revealed that miR‑154 inhibited BCa cell growth in vivo, and suppressed ATG7 expression. Altogether, this study demonstrated that miR‑154 may function as a tumor suppressor in BCa and indicated that miR‑154 may be a potential therapeutic target for BCa patients.

Tian W, Hao S, Gao B, et al.
Lobaplatin inhibits breast cancer progression, cell proliferation while it induces cell apoptosis by downregulating MTDH expression.
Drug Des Devel Ther. 2018; 12:3563-3571 [PubMed] Free Access to Full Article Related Publications
Objective: Lobaplatin shows antitumor activity against a wide range of tumors, including metastatic breast cancer (BCa). The overexpression of metadherin (MTDH) is associated with poor prognosis of BCa patients. This study was designed to investigate the effect of lobaplatin on MCF-7 cell proliferation and its association with MTDH expression.
Patients and methods: Clinical treatment for BCa using lobaplatin, in combination with other general chemotherapy drugs, was administered to 32 BCa patients. The safety, effectiveness, and prognosis in lobaplatin-treated BCa patients were compared with those in controls (n=32). In vitro experiments were performed in MCF-7 cells to investigate the effect of lobaplatin on cell proliferation, apoptosis, and MTDH expression.
Results: We found the intraoperative local chemotherapy using lobaplatin was safe and effective for BCa treatment, in comparison with the patients administered general chemotherapy drugs. Treatment of MCF-7 cell cultures with lobaplatin significantly reduced cell proliferation and increased cell apoptotic percentage. The expression of MTDH and Bcl-2 was inhibited by lobaplatin and that of Bax was increased by lobaplatin. Moreover, we observed the inhibition of MTDH by shRNA reduced cell proliferation and enhanced cell apoptosis.
Conclusion: Lobaplatin was a safe and effective adjuvant chemotherapy for BCa. The effect of lobaplatin on inhibiting MCF-7 cell proliferation and inducing cell apoptosis might be, as least in part, mediated by suppressing the expression of oncogene MTDH.

Ou Z, Wang Y, Chen J, et al.
Estrogen receptor β promotes bladder cancer growth and invasion via alteration of miR-92a/DAB2IP signals.
Exp Mol Med. 2018; 50(11):152 [PubMed] Free Access to Full Article Related Publications
Although early studies suggested that bladder cancer (BCa) is more prevalent in men than in women, muscle-invasive rates are higher in women than in men, suggesting that sex hormones might play important roles in different stages of BCa progression. In this work, we found that estrogen receptor beta (ERβ) could increase BCa cell proliferation and invasion via alteration of miR-92a-mediated DAB2IP (DOC-2⁄DAB2 interacting protein) signals and that blocking miR-92a expression with an inhibitor could partially reverse ERβ-enhanced BCa cell growth and invasion. Further mechanism dissection found that ERβ could increase miR-92a expression at the transcriptional level via binding to the estrogen-response-element (ERE) on the 5' promoter region of its host gene C13orf25. The ERβ up-regulated miR-92a could decrease DAB2IP tumor suppressor expression via binding to the miR-92a binding site located on the DAB2IP 3' UTR. Preclinical studies using an in vivo mouse model also confirmed that targeting this newly identified ERβ/miR-92a/DAB2IP signal pathway with small molecules could suppress BCa progression. Together, these results might aid in the development of new therapies via targeting of this ERβ-mediated signal pathway to better suppress BCa progression.

Wang F, Zu Y, Zhu S, et al.
Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression.
Biochem Biophys Res Commun. 2018; 507(1-4):231-235 [PubMed] Related Publications
Bladder cancer (BCa) belongs to a popular urological malignancy and leads to large numbers of deaths worldwide. Recently, emerging evidences indicate that long noncoding RNAs (lncRNAs) are closely related with BC occurrence and progression. However, the function of lncRNA MAGI2-AS3 remains poorly understood in BC. In this present study, we screened out a novel lncRNA MAGI2-AS3 whose expression was downregulated in BCa tissues. We showed that MAGI2-AS3 downregulation in BCa patients indicated a poor prognosis. Functionally, we showed that MAGI2-AS3 overexpression inhibits proliferation, migration and invasion of BCa cells. Moreover, ectopic expression of MAGI2-AS3 suppresses BCa growth in vivo. Bioinformatics analysis revealed that MAGI2-AS3 could serve as a competing endogenous RNA (ceRNA) for miR-15b-5p. In the meantime, miR-15b-5p directly targeted CCDC19, a tumor suppressor in BCa. Rescue assays demonstrated that knockdown of CCDC19 restored the proliferation, migration and invasion of BCa cells suppressed by MAGI2-AS3 overexpression. In conclusion, this study identified a novel mechanism that MAGI2-AS3/miR-15b-5p/CCDC19 signaling pathway regulates BCa progression.

Sekiguchi N, Nomoto J, Nagata A, et al.
Gene Expression Profile Signature of Aggressive Waldenström Macroglobulinemia with Chromosome 6q Deletion.
Biomed Res Int. 2018; 2018:6728128 [PubMed] Free Access to Full Article Related Publications
Background: Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoma. Clinically, chromosome 6q deletion (6q del) including loss of the B lymphocyte-induced maturation protein 1 gene (BLIMP-1) is reported to be associated with poor prognosis. However, it remains unclear how the underlying biological mechanism contributes to the aggressiveness of WM with 6q del.
Methods: Here, we conducted oligonucleotide microarray analysis to clarify the differences in gene expression between WM with and without 6q del. Gene ontology (GO) analysis was performed to identify the main pathways underlying differences in gene expression. Eight bone marrow formalin-fixed paraffin-embedded samples of WM were processed for interphase fluorescence in situ hybridization analysis, and three were shown to have 6q del.
Results: GO analysis revealed significant terms including "lymphocyte activation" (corrected p value=6.68E-11), which included 31 probes. Moreover,
Conclusion: The present study suggested that the BCR signaling pathway and

Verma A, Lam YM, Leung YC, et al.
Combined use of arginase and dichloroacetate exhibits anti-proliferative effects in triple negative breast cancer cells.
J Pharm Pharmacol. 2019; 71(3):306-315 [PubMed] Related Publications
OBJECTIVES: Drug combination in cancer therapy aims to achieve synergistic therapeutic effect, reduced drug dosage, reduced drug toxicity and minimizes or delays the induction of drug resistance. In the present study, we investigated the anticancer effects of the combination of two metabolic modulators, dichloroacetate (DCA) and bacillus caldovelox arginase (BCA) (or pegyated human arginase (HA)).
METHODS: The combination treatments were evaluated in MCF-7 and MDA-MB 231 cells as well as in MDA-MB 231 breast cancer xenograft model.
KEY FINDINGS: Dichloroacetate and BCA combination exhibited anti-proliferative effects on MCF-7 cells, which were found to be synergistic. Analysis of the gene expression upon drug treatments revealed that the synergistic anti-proliferative effect on MCF-7 cells was possibly in part due to the activation of the p53 pathway. A similar synergistic anti-proliferative effect was observed in the combined use of DCA and HA on MCF-7 and MDA-MB231 cells, which was due to induction of cell cycle arrest at G2/M phase. Moreover, the combination enhanced anti-tumour activity in a MDA-MB 231 xenograft mouse model.
CONCLUSIONS: Our results suggested that dichloroacetate and arginase combination exhibited enhanced anti-cancer effects in preclinical breast cancer models which may offer an additional treatment option for breast cancer.

Wang S, Zhang G, Zheng W, et al.
MiR-454-3p and miR-374b-5p suppress migration and invasion of bladder cancer cells through targetting ZEB2.
Biosci Rep. 2018; 38(6) [PubMed] Free Access to Full Article Related Publications
Bladder cancer (BCa) threatens human health due to the high occurrence and mortality. Nowadays, more and more researchers focussed on the molecular mechanisms and biological functions of miRNAs in human cancers. The present study aims to study the biological role of miR-454-3p and miR-374b-5p in BCa. The expression levels of miR-454-3p and miR-374b-5p were detected in BCa tissues and cell lines by qRT-PCR analysis. Kaplan-Meier analysis revealed that the expression levels of miR-454-3p and miR-374b-5p were positively correlated with the overall survival (OS) rate of BCa patients. Gain-of-function assays were conducted to demonstrate the inhibitory effects of miR-454-3p and miR-374b-5p on the invasion, migration, and epithelial-mesenchymal transition (EMT) of BCa cells. Mechanically, ZEB2 was found to be a target of both miR-454-3p and miR-374b-5p. Rescue assays revealed that ZEB2 reversed the inhibitory effects of miR-454-3p and miR-374b-5p on the invasion and migration of BCa cell lines. In summary, miR-454-3p and miR-374b-5p negatively regulated invasion and migration of BCa cell lines via targetting ZEB2.

Fortis SP, Vaxevanis CK, Mahaira LG, et al.
Serum miRNA-based distinct clusters define three groups of breast cancer patients with different clinicopathological and immune characteristics.
Cancer Immunol Immunother. 2019; 68(1):57-70 [PubMed] Related Publications
Breast cancer (BCa) is a heterogeneous disease with different histological, prognostic and clinical aspects. Therefore, the need for identification of novel biomarkers for diagnosis, prognosis and monitoring of disease, as well as treatment outcome prediction remains at the forefront of research. The search for circulating elements, obtainable by simple peripheral blood withdrawal, which may serve as possible biomarkers, constitutes still a challenge. In the present study, we have evaluated the expression of 6 circulating miRNAs, (miR-16, miR-21, miR-23α, miR-146α, miR-155 and miR-181α), in operable BCa patients, with non-metastatic, invasive ductal carcinoma, not receiving neoadjuvant chemotherapy. These miRNAs, known to be involved in both tumor cell progression and immune pathways regulation, were analyzed in relation to circulating cytokines, tumor immune-cell infiltration and established prognostic clinicopathological characteristics. We have identified three different clusters, with overall low (C1), moderate (C2) or high (C3) expression levels of these six circulating miRNAs, which define three distinct groups of non-metastatic BCa patients characterized by different clinicopathological and immune-related characteristics, with possibly different clinical outcomes. Our data provide the proof-of-principle to support the notion that, up- or down-regulation of the same circulating miRNA may reflect different prognosis in BCa. Nonetheless, the prognostic and/or predictive potential of these three "signatures" needs to be further evaluated in larger cohorts of BCa patients with an, at least, 5-year clinical follow-up.

Liu X, Sun Y, Tian W, et al.
Sema4A Responds to Hypoxia and Is Involved in Breast Cancer Progression.
Biol Pharm Bull. 2018; 41(12):1791-1796 [PubMed] Related Publications
Semaphorin4A (Sema4A) is a family member of semaphorins expressed in immune cells and is also related with disease progression of tumor disease. In this study, we investigate the expression and pathological role of Sema4A in breast cancer (BCa). Our data showed that the expression of Sema4A increased in the tissues and serum of BCa patients when compared with normal controls. The expression of Sema4A in BCa cells could be induced by hypoxic treatment, whereas silencing hypoxia-inducible factor (HIF)-1α could attenuate the above induced. Furthermore, chromatin immunoprecipitation (ChIP) analysis demonstrated that HIF-1α could regulate the expression of Sema4A through directly binding to the promoter of Sema4A gene, whose enrichment could be further enhanced by hypoxic stimulation. In addition, silencing Sema4A could inhibit the proliferation, vascular endothelial growth factor (VEGF) production and the phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and signal transduction and activator of transcription (STAT)3, but induce apoptosis of BCa cells in the presence of hypoxia. In contrast, recombinant human Sema4A treatment showed the opposite effects. Taken together, these results suggest that Sema4A could promote progression of BCa in the presence of hypoxia and it may hold potential for treatment target for BCa.

Budak Diler S, Aybuğa F
Association of Autophagy Gene ATG16L1 Polymorphism with Human Prostate Cancer and Bladder Cancer in Turkish Population
Asian Pac J Cancer Prev. 2018; 19(9):2625-2630 [PubMed] Free Access to Full Article Related Publications
Background: Urological cancers (prostate cancer and bladder cancers) are the most common cancers in Western population and its rate is increasing in the Eastern World. Autophagy has appeared as a fundamental repair mechanism for degrading damaged organelles and proteins. It was clear that autophagy gene polymorphisms are correlated with development of inflammatory bowel disease and it can also be related with prostate cancer (PCa) or bladder cancer (BCa). In this study, we aimed to determine if ATG16L1 (Thr300Ala) polymorphism is associated with an increased risk of developing PCa and BCa and to establish correlations between ATG16L1 genotypes and morphological parameters. Methods: This study included 269 healthy controls and 131 patients (62 PCa and 69 BCa) with PCa and BCa. The ATG16L1 (rs2241880) gene regions were amplified using polymerase chain reaction (PCR), detected by restriction fragment length polymorphism (RFLP). Results: At the end of our research, we found out that the genotype AG was prevalent on patients and controls (34% vs 42%), followed by genotypes AA (35% vs 27%) and GG (31% vs 31%) in PCa. The prevalence of genotypes of AA (wild-type), AG (heterozygous mutant) and GG (homozygous mutant) profiles for the ATG16L1 Thr300Ala polymorphism were 35%, 40% and 25% respectively in BCa patients, and 32%, 40% and 28% respectively in healthy control groups. The G allele frequency was 0.53 for in BCa patients and the control groups. Conclusion: No association was found between ATG16L1 (Thr300Ala) polymorphism and patients with PCa and BCa in Turkish population we studied.

Ye J, Zhang Y, Cai Z, et al.
Increased expression of immediate early response gene 3 protein promotes aggressive progression and predicts poor prognosis in human bladder cancer.
BMC Urol. 2018; 18(1):82 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Immediate early response gene 3 (IER3) is a stress-inducible gene, which exerts diverse effects in regulating cell apoptosis and cell cycle. Growing evidence shows that IER3 functions either as an oncogene or a tumor suppressor in various human cancers with a cancer type-dependent manner. However, the involvement of IER3 in human bladder cancer (BCa) has not been elucidated. In the current study, we aimed to investigate the expression pattern and the clinical significance of IER3 in BCa.
METHODS: We performed immunohistochemistry analysis to examine the subcellular localization and the expression levels of IER3 protein in 88 BCa specimens obtained from Department of Pathology in Massachusetts General Hospital. The associations of IER3 protein expression with various clinicopathological features and patients' overall survival were statistically evaluated.
RESULTS: IER3 protein was mainly expressed in the cytoplasm in bladder cancer cell. Of 88 BCa tissue specimens, 39 (44.3%) showed high expression of IER3 protein and 49 (55.7%) showed low expression. High IER3 protein expression was significantly associated with high pathologic nodal stage (p = 0.018). Kaplan-Meier analysis revealed that the overall survival of BCa patients with overexpression of IER3 protein was shorter than that with low expression (p < 0.01). Multivariate analysis by Cox regression further identified IER3 as an independent prognostic factor of BCa patients (p = 0.010).
CONCLUSIONS: Our findings suggest for the first time that the increased expression of IER3 protein may promote the aggressive progression of BCa. Importantly, IER3 may be a potential prognostic marker for BCa patients.

Liu Z, Sahli Z, Wang Y, et al.
Young age at diagnosis is associated with worse prognosis in the Luminal A breast cancer subtype: a retrospective institutional cohort study.
Breast Cancer Res Treat. 2018; 172(3):689-702 [PubMed] Related Publications
PURPOSE: Although age is a recognized independent prognostic risk factor, its relative importance among molecular subtypes of Breast cancer (BCA) is not well documented. The aim of this study was to evaluate the prognostic role of age at diagnosis among different immunohistochemical subtypes of BCA.
METHODS: We conducted a retrospective study of women with invasive BCA undergoing surgery at the Johns Hopkins Hospital, excluding patients presenting with stage IV breast cancer. Patients were stratified into three age groups: ≤ 40, 41-60, and > 60 years, and multivariable analysis was performed using Cox regression. We also identified differentially expressed genes (DEG) between age groups among BCA subtypes in the public TCGA dataset. Finally, we identified key driver genes within the DEGs using a weighted gene co-expression network analysis.
RESULTS: Luminal A breast cancer patients had significantly lower 5 year disease-free survival (DFS) and distant metastasis-free survival (DMFS) in the ≤ 40 year age group compared to the 41-60 year age group, while the other molecular subtypes showed no significant association of DFS or DMFS with age. Age was a stronger outcome predictor than tumor grade or proliferative index in Luminal A BCA patients, but not other subtypes. BCA TCGA gene expression data were divided into two groups (≤ 40 years, > 40 years). We identified 374 DEGs in the Luminal A BCA subset, which were enriched in seven pathways and two modules of co-expressed genes. No age group-specific DEGs were identified in non-Luminal A subtypes.
CONCLUSIONS: Age at diagnosis may be an important prognostic factor in Luminal A BCA.

Song Y, Hu J, Chen Q, et al.
Association between vascular endothelial growth factor rs699947 polymorphism and the risk of three major urologic neoplasms (bladder cancer, prostate cancer, and renal cell carcinoma): A meta-analysis involving 11,204 subjects.
Gene. 2018; 679:241-252 [PubMed] Related Publications
BACKGROUND: The relationship between vascular endothelial growth factor (VEGF) gene variant rs699947 polymorphism and urologic neoplasms risk was studied extensively in recent years. The VEGF gene plays a key role in angiogenesis of urologic neoplasms, but some conclusions are still inconclusive. The aim of this study was to determine whether this polymorphism is a risk factor for susceptibility to urologic neoplasms by conducting a meta-analysis.
METHODS: We performed a meta-analysis of 15 different publications from the PubMed, Embase and Medline databases, to better assess the association between VEGF rs699947 polymorphism and urologic neoplasms risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated using random or fixed effects models.
RESULTS: By pooling all eligible studies, we found that the VEGF rs699947 polymorphism was not associated with overall urologic neoplasms. However, subgroup analysis based on cancer types demonstrated that significantly increased association was found between VEGF rs699947 polymorphism and the risk of bladder cancer (BCa) under heterozygous genetic model (OR = 1.48, 95%CI = 1.17-1.89). And rs699947 polymorphism was also identified an increased risk of renal cell carcinoma (RCC) under dominant, recessive, homozygous, heterozygous and allelic contrast genetic models, while no association was observed in prostate cancer (PCa). In addition, in subgroup analysis by ethnicity, we found rs699947 polymorphism was associated with Asian population under dominant, homozygous, heterozygous and allelic contrast genetic models. No evidence of publication bias was found (Begg's test, P = 0.855; Egger's test, P = 0.590).
CONCLUSIONS: In summary, our study showed evidence that the VEGF rs699947 polymorphism was obviously associated with an increased risk of bladder cancer and renal cell carcinoma, particularly in Asian population, while no significant association was observed in overall urologic neoplasms. Future studies with larger sample sizes are warranted to further evaluate these associations in more details.

Wang F, Zu Y, Huang W, et al.
LncRNA CALML3-AS1 promotes tumorigenesis of bladder cancer via regulating ZBTB2 by suppression of microRNA-4316.
Biochem Biophys Res Commun. 2018; 504(1):171-176 [PubMed] Related Publications
An increasing number of studies have elucidated the essential roles of long noncoding RNAs (lncRNAs) in tumor development. LncRNAs are also closely associated with bladder cancer (BCa) progression. In the present study, we screened out a novel lncRNA CALML3-AS1 with increased expression value in BCa tissues. Particularly, we showed that CALML3-AS1 overexpression correlates with advanced staging and an unsatisfactory prognosis. Functional experiments illustrated that CALML3-AS1 knockdown suppressed BCa cell proliferation, arrested cell-cycle progression and impaired migration and invasion while promoting apoptosis. Mechanistic investigation revealed that CALML3-AS1 directly interacts with miR-4316 and inhibits its availability in BCa cells, leading to elevated expression of ZBTB2. Consequently, ZBTB2 promotes BCa tumorigenesis through repressing p21 and facilitating PDK4 transcription. In conclusion, our findings demonstrate a novel CALML3-AS1-mediated process involved in BCa progression and indicate it might be a promising therapeutic target.

Zhu N, Hou J, Wu Y, et al.
Integrated analysis of a competing endogenous RNA network reveals key lncRNAs as potential prognostic biomarkers for human bladder cancer.
Medicine (Baltimore). 2018; 97(35):e11887 [PubMed] Free Access to Full Article Related Publications
Human bladder cancer (BCa) is one of the most commonly diagnosed malignancies worldwide. It has high recurrence rates and low-grade malignancy, thus representing an important public health concern. An increasing number of studies suggest that long-noncoding RNAs (lncRNAs) play important roles in various biological processes and disease pathologies, including cancer.We analyzed the expression profiles of lncRNA, miRNA, and mRNA, along with the clinical information of BCa patients collected from the Cancer Genome Atlas database to identify lncRNA biomarkers for prognosis. We also constructed an lncRNA-miRNA-mRNA global triple network (competitive endogenous RNA network) by bioinformational approach.This BCa lncRNA-miRNA-mRNA network consisted of 23 miRNA nodes, 52 mRNA nodes, 59 lncRNA nodes, and 365 edges. Subsequent gene ontology (GO) and pathway analyses were performed using BinGO for Cytoscape and Database for Annotation, Visualization, and Integration Discovery, respectively, highlighting important GO terms and pathways that were enriched in the network. Subnetworks were created using 3 key lncRNAs (MAGI2-AS3, ADAMTS9-AS2, and LINC00330), revealing associations with BCa-linked mRNAs and miRNAs. Finally, an analysis of significantly differentiating RNAs found 6 DElncRNAs (AC112721.1, ADAMTS9-AS1, ADAMTS9-AS2, HCG22, MYO16-AS1, and SACS-AS1), 1 DEmiRNA (miRNA-195), and 6 DEmRNAs (CCNB1, FAM129A, MAP1B, TMEM100, AIFM3, and HOXB5) that correlated with BCa patient survival.Our results provide a novel perspective from which to study the lncRNA-related ceRNA network in BCa, contributing to the development of future diagnostic biomarkers and therapeutic targets.

Ding M, Zhan H, Liao X, et al.
Enhancer RNA - P2RY2e induced by estrogen promotes malignant behaviors of bladder cancer.
Int J Biol Sci. 2018; 14(10):1268-1276 [PubMed] Free Access to Full Article Related Publications
Enhancers are transcriptional regulatory elements that increase target gene expression. It has reported that enhancers could universally transcribe into enhancer RNAs (eRNAs) with stimulation. Increasing evidence showed eRNAs participated in various disease processes including malignant tumors. P2RY2 enhancer RNA (P2RY2e) is an estrogen-responsive eRNA and involved in the development of breast cancer. However, the relationship between P2RY2e and bladder cancer (BCa) is unclear. In the study, we discovered that P2RY2e was upregulated in BCa tissues and estrogen-treated cells. Estrogen promoted the malignant abilities of BCa cells. P2RY2e knockdown by CRISPR-Cas13a inhibit the cell multiplication, invasion and migration. Additionally, the cell apoptosis was facilitated. What's more, downregulation of P2RY2e could weaken the cancer-promoting effects of estrogen on BCa. Our study revealed that P2RY2e played a carcinogenic role in BCa and estrogen might promote the initiation of BCa by inducing P2RY2e. We provide a potential therapeutic target for BCa and a new perspective for the tumorigenesis of bladder cancer.

Li J, Qiu M, An Y, et al.
miR-7-5p acts as a tumor suppressor in bladder cancer by regulating the hedgehog pathway factor Gli3.
Biochem Biophys Res Commun. 2018; 503(3):2101-2107 [PubMed] Related Publications
Although important progresses have been made in the diagnosis and treatment of bladder cancer (BCa), the overall survival for patients with advanced BCa remains poor. It is necessary to uncover the molecular mechanism underlying the initiation and progression of bladder cancer. According to previous reports, mircoRNAs (miRNAs) can regulate tumorigenesis by targeting their downstream mRNAs. This study aims to explore and analyze a novel miRNA-mRNA axis which can regulate the progression of bladder cancer. Based on the microarray analysis, 182 mRNAs were found to be upregulated in BCa tissues. Gene oncology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that these upregulated mRNAs are related with hedgehog pathway. Gli3, an important factor of hedgehog pathway, belongs to these 182 upregulated mRNAs. Therefore, Gli3 was chosen to do further study. Kaplan-Meier analysis revealed that highly expressed Gli3 predicted unfavorable prognosis for patients with BCa. Results of functional experiments indicated the inhibitory effects of silenced Gli3 on cell proliferation, migration and EMT progress. Mechanically, Gli3 was the target mRNA of miR-7-5p in BCa cells. Finally, rescue assays were performed to validate the specific function of miR-7-5p/Gli3 axis in BCa progression. According to all data, we concluded that miR-7-5p acts as a tumor suppressor in BCa by downregulating Gli3.

Liu T, Han Z, Li H, et al.
LncRNA DLEU1 contributes to colorectal cancer progression via activation of KPNA3.
Mol Cancer. 2018; 17(1):118 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Accumulating evidences show that long noncoding RNAs (lncRNA) play essential roles in the development and progression of various malignancies. However, their functions remains poorly understood and many lncRNAs have not been defined in colorectal cancer (CRC). In this study, we investigated the role of DLEU1 in CRC.
METHODS: Quantitative real-time PCR was used to detect the expression of DLEU1 and survival analysis was adopted to explore the association between DLEU1 expression and the prognosis of CRC patients. CRC cells were stably transfected with lentivirus approach and cell proliferation, migration, invasion and cell apoptosis, as well as tumorigenesis in nude mice were performed to assess the effects of DLEU1 in BCa. Biotin-coupled probe pull down assay, RNA immunoprecipitation and Fluorescence in situ hybridization assays were conducted to confirm the relationship between DLEU1 and SMARCA1.
RESULTS: Here we revealed that DLEU1 was crucial for activation of KPNA3 by recruiting SMARCA1, an essential subunit of the NURF chromatin remodeling complex, in CRC. DLEU1 was indispensible for the deposition of SMARCA1 at the promoter of KPNA3 gene. Increased expression of DLEU1 and KPNA3 was observed in human CRC tissues. And higher expression of DLEU1 or KPNA3 in patients indicates lower survival rate and poorer prognosis. DLEU1 knockdown remarkably inhibited CRC cell proliferation, migration and invasion in vitro and in vivo while overexpressing KPNA3 in the meantime reversed it.
CONCLUSIONS: Our results identify DLEU1 as a key regulator by a novel DLEU1/SMARCA1/KPNA3 axis in CRC development and progression, which may provide a potential biomarker and therapeutic target for the management of CRC.

Wu S, Zheng J, Li Y, et al.
Development and Validation of an MRI-Based Radiomics Signature for the Preoperative Prediction of Lymph Node Metastasis in Bladder Cancer.
EBioMedicine. 2018; 34:76-84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Preoperative lymph node (LN) status is important for the treatment of bladder cancer (BCa). However, a proportion of patients are at high risk for inaccurate clinical nodal staging by current methods. Here, we report an accurate magnetic resonance imaging (MRI)-based radiomics signature for the individual preoperative prediction of LN metastasis in BCa.
METHODS: In total, 103 eligible BCa patients were divided into a training set (n = 69) and a validation set (n = 34). And 718 radiomics features were extracted from the cancerous volumes of interest (VOIs) on T2-weighted MRI images. A radiomics signature was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm in the training set, whose performance was assessed and then validated in the validation set. Stratified analyses were also performed. Based on the multivariable logistic regression analysis, a radiomics nomogram was developed incorporating the radiomics signature and selected clinical predictors. Discrimination, calibration and clinical usefulness of the nomogram were assessed.
FINDINGS: Consisting of 9 selected features, the radiomics signature showed a favorable discriminatory ability in the training set with an AUC of 0.9005, which was confirmed in the validation set with an AUC of 0.8447. Encouragingly, the radiomics signature also showed good discrimination in the MRI-reported LN negative (cN0) subgroup (AUC, 0.8406). The nomogram, consisting of the radiomics signature and the MRI-reported LN status, showed good calibration and discrimination in the training and validation sets (AUC, 0.9118 and 0.8902, respectively). The decision curve analysis indicated that the nomogram was clinically useful.
INTERPRETATION: The MRI-based radiomics nomogram has the potential to be used as a non-invasive tool for individualized preoperative prediction of LN metastasis in BCa. External validation is further required prior to clinical implementation.

Oyama Y, Nishida H, Kusaba T, et al.
Difference in transducin-like enhancer of split 1 protein expression between basal cell adenomas and basal cell adenocarcinomas - an immunohistochemical study.
Diagn Pathol. 2018; 13(1):48 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are benign and malignant, basaloid salivary gland neoplasms, respectively. These tumors show a dual-cell proliferation of inner luminal/ductal cells and outer abluminal/myoepithelial or basal cells. The only difference between them is defined as a malignant morphology such as invasion. Recently, the nuclear expression of β-catenin and a catenin beta-1 (CTNNB1) mutation were found in BCA. Transducin-like enhancer of split 1 (TLE1) belongs to the Groucho/TLE family, and it functions in the "off" state in the Wnt/β-catenin signaling pathway. We hypothesized that if the dysregulation of the Wnt/β-catenin signaling pathway could be attributed to the tumorigenesis of BCA/BCAC, there might be differences in TLE1 expression between BCA and BCAC.
METHOD: The study included 35 BCA and 4 BCAC cases. We performed immunohistochemistry to detect TLE1 and β-catenin and investigated the catenin beta-1 (CTNNB1) mutational profile among BCA and BCAC cases.
RESULTS: In BCA, the expression of TLE1 was confined to luminal cells of glandular structures, in contrast to the expression of β-catenin in abluminal cells. The BCA cases harbored CTNNB1 gene mutations (12/35). In BCAC, luminal cell staining of TLE1 was identical to BCA in non-invasive areas (4/4) but indistinct in invasive areas (3/4). The BCAC cases were β-catenin positive for abluminal cells in both areas. The BCAC cases had CTNNB1 mutation (2/4) and the laser-captured microdissection allowed the separate collection of infiltrative and non-infiltrative areas to detect the same mutation.
CONCLUSIONS: Immunohistochemical analysis for TLE1 can identify BCA and BCAC by luminal cell staining difference, especially indistinct luminal cell expression for TLE1 in invasive areas of BCAC. Moreover, TLE1 can be luminal/ductal cell markers.

Xu YY, Yu HR, Sun JY, et al.
Upregulation of PITX2 Promotes Letrozole Resistance Via Transcriptional Activation of IFITM1 Signaling in Breast Cancer Cells.
Cancer Res Treat. 2019; 51(2):576-592 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Although the interferon α (IFNα) signaling and the paired-like homeodomain transcription factor 2 (PITX2) have both been implicated in the progression of breast cancer (BCa), it remains obscure whether these two pathways act in a coordinated manner. We therefore aimed to elucidate the expression and function of PITX2 during the pathogenesis of endocrine resistance in BCa.
Materials and Methods: PITX2 expression was assessed in BCa tissues using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry and in experimentally induced letrozole-resistant BCa cells using RT-qPCR and immunoblotting. Effects of PITX2 deregulation on BCa progression was determined by assessing MTT, apoptosis and xenograft model. Finally, using multiple assays, the transcriptional regulation of interferon-inducible transmembrane protein 1 (IFITM1) by PITX2 was studied at both molecular and functional levels.
RESULTS: PITX2 expression was induced in letrozole-resistant BCa tissues and cells, and PITX2 induction by IFNα signaling powerfully protected BCa cells against letrozole insult and potentiated letrozole-resistance. Mechanistically, PITX2 enhanced IFNα-induced AKT activation by transactivating the transcription of IFITM1, thus rendering BCa cells unresponsive to letrozoleelicited cell death. Additionally, ablation of IFITM1 expression using siRNA substantially abolished IFNα-elicited AKT phosphorylation, even in the presence of PITX2 overexpression, thus sensitizing BCa cells to letrozole treatment.
CONCLUSION: These results demonstrate that constitutive upregulation of PITX2/IFITM1 cascade is an intrinsic adaptive mechanism during the pathogenesis of letrozole-resistance, and modulation of PITX2/IFITM1 level using different genetic and pharmacological means would thus have a novel therapeutic potential against letrozole resistance in BCa.

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