GJB2

Gene Summary

Gene:GJB2; gap junction protein beta 2
Aliases: HID, KID, PPK, CX26, DFNA3, DFNB1, NSRD1, DFNA3A, DFNB1A
Location:13q12.11
Summary:This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:gap junction beta-2 protein
Source:NCBIAccessed: 11 March, 2017

Ontology:

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 (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: GJB2 (cancer-related)

Liu A, Wu M, Guo X, et al.
Clinical, pathological, and genetic evaluations of Chinese patient with otodental syndrome and multiple complex odontoma: Case report.
Medicine (Baltimore). 2017; 96(5):e6014 [PubMed] Free Access to Full Article Related Publications
Otodental syndrome is a rare autosomal-dominant disease characterized by globodontia, associated with sensorineural, high-frequency hearing loss. Here, we describe the clinical, pathological, and genetic evaluations of a 9-year-old girl with otodental syndrome and multiple complex odontoma.The patient presented with a draining sinus tract in her left cheek, globodontia, and hearing loss. The odontomas which caused the cutaneous sinus tracts were extracted because of the odontogenic infection. The extracted odontoma and primary tooth was studied by micro-CT and further observed histopathologically. The micro-CT findings revealed that the primary tooth had three crowns with two separated pulp chambers, and their root canals were partially fused. The histological findings showed abnormal morphologies of odontoblasts and dentin, hyperplasia of enamel, and malformation of odontogenic epithelium. Furthermore, DNA sequencing and analyze of deafness associated gene GJB2, GJB3, and PDS had not revealed any SNP or mutation; but exon 3 of the causative gene FGF3 could not be amplified, which may be associated with the microdeletion at chromosome 11q13.3. Three month after surgery, the patient was found to be asymptomatic and even the evidence of the extra-oral sinus had disappeared.The dental abnormality of otodental syndrome included congenital missing teeth, globodontia, and multiple complex odontoma. Globodontia exhibited characteristic features of fusion teeth. In addition, gene FGF3 haploinsufficiency was likely to be the cause of otodental syndrome. The report provides some new information in the field of otodental syndrome, which would make dentists more familiar with this disease.

Lan TT, Keller-Ramey J, Fitzpatrick C, et al.
Unclassified renal cell carcinoma with tubulopapillary architecture, clear cell phenotype, and chromosome 8 monosomy: a new kid on the block.
Virchows Arch. 2016; 469(1):81-91 [PubMed] Related Publications
Accurate subtyping of renal cell carcinomas (RCCs) has become clinically important for therapy and prognostication. RCC subtypes are defined by distinct morphologic and immunohistochemical profiles, and in some instances recurrent cytogenetic and molecular properties. However, some tumors exhibit overlapping morphologic and immunophenotypic features, frequent enough to pose diagnostic dilemmas. This report concerns six histologically unusual RCCs that showed tubulopapillary architecture, clear cell phenotype, and non-diagnostic immunohistochemical profiles. Further investigation of these tumors utilized a single nucleotide polymorphism (SNP) microarray platform (OncoScan®, Affymetrix) that employed molecular inversion probe (MIP) technology to investigate genome-wide chromosomal copy number changes and loss of heterozygosity in formalin-fixed paraffin-embedded sections. The six tumors were assayed in parallel with and in comparison to RCC with typical morphologic or immunohistochemical features for a specific subtype (clear cell, clear cell papillary, and microphthalmia transcription factor (MiT) family translocation RCC). Three of the unusual RCCs showed a molecular signature of clear cell RCC and one of papillary RCC. The remaining two showed monosomy of chromosome 8. Those two cases were tested via next-generation sequencing, and no pathogenic variants were detected, including those in the genes VHL, PBRM1, SETD2, KDM5C, or BAP1. The addition of molecular investigations such as reported here as applied to histologically and immunohistochemically unusual RCC may help to define additional subtypes and contribute to the development of targeted therapy for renal cancer.

Stewart MK, Bechberger JF, Welch I, et al.
Cx26 knockout predisposes the mammary gland to primary mammary tumors in a DMBA-induced mouse model of breast cancer.
Oncotarget. 2015; 6(35):37185-99 [PubMed] Free Access to Full Article Related Publications
Down-regulation of the gap junction protein connexin26 (Cx26) is an early event following breast cancer onset and has led to Cx26 being classically described as a tumor suppressor. Interestingly, mutations in theCx26 gene (GJB2) reduce or ablate Cx26 gap junction channel function and are the most common cause of genetic deafness. It is unknown if patients with loss-of-function GJB2 mutations have a greater susceptibility to breast tumorigenesis or aggressive breast cancer progression. To investigate these possibilities, 7, 12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated in BLG-Cre; Cx26fl/fl mice expressing Cre under the β-Lactoglobulin promoter (Cre+) compared to Cx26fl/fl controlmice (Cre-) following pituitary isograft driven Cx26 knockout. A significantly increased number of DMBA-treated Cre+ mice developed primary mammary tumors, as well as developed multiple tumors, compared to Cre- mice. Primary tumors of Cre+ mice were of multiple histological subtypes and had similar palpable tumour onset and growth rate compared to tumors from Cre- mice. Lungs were evaluated for evidence of metastases revealing a similar percentage of lung metastases in Cre+ and Cre- mice. Together, our results suggest that loss of Cx26 predisposes the mammary gland to chemically induced mammary tumour formation which may have important implications to patients with GJB2 mutations.

Yang J, Qin G, Luo M, et al.
Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT.
Cell Death Dis. 2015; 6:e1829 [PubMed] Free Access to Full Article Related Publications
Gefitinib efficiency in non-small-cell lung cancer (NSCLC) therapy is limited due to development of drug resistance. The molecular mechanisms of gefitinib resistance remain still unclear. In this study, we first found that connexin 26 (Cx26) is the predominant Cx isoform expressed in various NSCLC cell lines. Then, two gefitinib-resistant (GR) NSCLC cell lines, HCC827 GR and PC9 GR, from their parental cells were established. In these GR cells, the results showed that gefitinib resistance correlated with changes in cellular EMT phenotypes and upregulation of Cx26. Cx26 was detected to be accumulated in the cytoplasm and failed to establish functional gap-junctional intercellular communication (GJIC) either in GR cells or their parental cells. Ectopic expression of GJIC-deficient chimeric Cx26 was sufficient to induce EMT and gefitinib insensitivity in HCC827 and PC9 cells, while knockdown of Cx26 reversed EMT and gefitinib resistance in their GR cells both in vitro and in vivo. Furthermore, Cx26 overexpression could activate PI3K/Akt signaling in these cells. Cx26-mediated EMT and gefitinib resistance were significantly blocked by inhibition of PI3K/Akt pathway. Specifically, inhibition of the constitutive activation of PI3K/Akt pathway substantially suppressed Cx26 expression, and Cx26 was confirmed to functionally interplay with PI3K/Akt signaling to promote EMT and gefitinib resistance in NSCLC cells. In conclusion, the reciprocal positive regulation between Cx26 and PI3K/Akt signaling contributes to acquired gefitinib resistance in NSCLC cells by promoting EMT via a GJIC-independent manner.

Jiang H, Zhao L, Dong X, et al.
Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria.
Oncol Rep. 2015; 34(3):1487-93 [PubMed] Related Publications
Heterologous expression of the Drosophila melanogaster multi-substrate deoxyribonucleoside kinase (Dm-dNK) increases the sensitivity of cancer cells to several cytotoxic nucleoside analogs. Thus, it may be used as a suicide gene in combined gene/chemotherapy treatment of cancer. To further characterize this potential suicide gene, we constructed two retroviral vectors that enabled the expression of Dm-dNK in cancer cells. One vector harbored the wild‑type enzyme that localized to the nucleus. The other vector harbored a mitochondrial localized mutant enzyme that was constructed by deleting the nuclear localization signal and fusing it to a mitochondrial import signal of cytochrome c oxidase. A thymidine kinase-deficient osteosarcoma cell line was transduced with the recombinant viruses. The sensitivity and bystander cell killing in the presence of pyrimidine nucleoside analogs (E)-5-(2-bromovinyl)‑2'‑deoxyuridine and 1-β-D-arabinofuranosylthymine were investigated. Tanshinone IIA is a constituent of Danshen; a traditional Chinese medicine used in the treatment of cardiovascular diseases. This study also looked at the influence of Tanshinone IIA on the bystander effect and the underlying mechanisms. We showed that sensitivity of the osteosarcoma cell line to the nucleoside analogs and the efficiency of bystander cell killing were independent of the subcellular localization of Dm-dNK. The enhanced effect of tanshinone IIA on the bystander effect was related to the increased expression of Cx43 and Cx26.

Homeida L, Wiley RT, Fatahzadeh M
Oral squamous cell carcinoma in a patient with keratitis-ichthyosis-deafness syndrome: a rare case.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2015; 119(4):e226-32 [PubMed] Related Publications
Keratitis-ichthyosis-deafness (KID) syndrome is a rare form of ectodermal dysplasia with significant visual and auditory impairment. Pathogenesis involves a mutation in the GJB2 gene, which encodes connexin-26, a protein in the epithelial gap junctions thought to be involved in the differentiation of ectodermally derived tissues. Affected patients are also at increased risk for the epithelial malignancies. To our knowledge, nearly 100 cases of KID syndrome, including 19 with squamous cell carcinoma (SCC) complications, have been reported worldwide. We report here a patient with KID syndrome who developed an ulcerative oral lesion causing him significant discomfort; he was subsequently diagnosed with oral SCC. We review the clinical presentation and symptomatology, including those affecting the oral cavity for this syndrome and highlight the importance of multidisciplinary collaboration and life-long screening aimed at prevention of the evolving complications.

Chen H, Liu KY, Xu LP, et al.
Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of philadelphia chromosome-positive acute lymphoblastic leukemia.
Biol Blood Marrow Transplant. 2015; 21(6):1110-6 [PubMed] Related Publications
The role of haploidentical related allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is not clear. We aimed to investigate the long-term survival of Ph(+) ALL patients who underwent haploidentical donor (HID)-HSCT and to analyze the factors influencing relapse and survival after allo-HSCT. The study population included Ph(+) ALL patients who underwent haploidentical related allo-HSCT. Additionally, Ph(+) ALL patients who underwent HLA-matched related donor (MRD) transplants during the same period were included to compare outcomes. BCR-ABL transcript levels were analyzed by using real-time quantitative reverse transcription PCR. Clinical data from 139 Ph(+) ALL patients who received allo-HSCT in our center were analyzed. Of these patients, 101 received HID transplants and 38 received MRD transplants. At a median follow-up of 36 months, 5-year disease-free survival (DFS) and overall survival (OS) rates in the HID transplant group were 65.8% and 74.0%, respectively. The 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) rates for the HID transplant group were 20.3% and 15.6%, respectively. In addition, there were no differences in OS, DFS, CIR, and NRM between the HID and MRD groups. Multivariate analysis showed that imatinib resistance was a significant factor influencing DFS and CIR in HID transplant patients. Haploidentical HSCT for the treatment of Ph(+) ALL achieves promising long-term survival, which is comparable with that of HLA-MRD HSCT. Imatinib resistance is a negative predictor of relapse and DFS after allo-HSCT.

Reikvam H, Ryningen A, Sæterdal LR, et al.
Connexin expression in human acute myeloid leukemia cells: identification of patient subsets based on protein and global gene expression profiles.
Int J Mol Med. 2015; 35(3):645-52 [PubMed] Free Access to Full Article Related Publications
Bone marrow stromal cells support both normal and malignant hematopoiesis. Τhis support is mediated through the local cytokine network and by direct cell‑cell interactions mediated via adhesion molecules and the formation of gap junctions by connexins. Previous studies on connexins in human acute myeloid leukemia (AML) have mainly focused on the investigation of leukemia cell lines. In the present study, we therefore investigated the expression of various connexins at the protein (i.e., cell surface expression) and mRNA level in primary human AML cells. The cell surface expression of the connexins, Cx26, Cx32, Cx37, Cx43 and Cx45, varied considerably between patients, and detectable levels were observed only for subsets of patients. On the whole, Cx43 and Cx45 showed the highest cell surface expression. Connexin expression was dependent on AML cell differentiation, but showed no association with cytogenetic abnormalities or mutations of the fms-related tyrosine kinase 3 (FLT3) or nucleophosmin (NPM)‑1 genes. By contrast, only Cx45 showed a significant variation between patients at the mRNA level. A high Cx45 expression was associated with the altered regulation of the mitogen‑activated protein kinase (MAPK) pathway and the release of pro-inflammatory cytokines [interleukin (IL)‑17, tumor necrosis factor (TNF), interferon‑γ], whereas a low Cx45 expression was associated with the altered regulation of protein functions (i.e., ligase activity, protein folding and catabolism). There was no significant correlation observed between the connexin mRNA and protein levels. Thus, differences in connexin expression can be used to subclassify AML patients. Differences in connexin cell surface expression profiles are not reflected at the mRNA level and have to be directly examined, whereas variations in Cx45 mRNA expression are associated with differences in cell signaling and the regulation of protein functions.

Teleki I, Szasz AM, Maros ME, et al.
Correlations of differentially expressed gap junction connexins Cx26, Cx30, Cx32, Cx43 and Cx46 with breast cancer progression and prognosis.
PLoS One. 2014; 9(11):e112541 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIMS: Connexins and their cell membrane channels contribute to the control of cell proliferation and compartmental functions in breast glands and their deregulation is linked to breast carcinogenesis. Our aim was to correlate connexin expression with tumor progression and prognosis in primary breast cancers.
MATERIALS AND METHODS: Meta-analysis of connexin isotype expression data of 1809 and 1899 breast cancers from the Affymetrix and Illumina array platforms, respectively, was performed. Expressed connexins were also monitored at the protein level in tissue microarrays of 127 patients equally representing all tumor grades, using immunofluorescence and multilayer, multichannel digital microscopy. Prognostic correlations were plotted in Kaplan-Meier curves and tested using the log-rank test and cox-regression analysis in univariate and multivariate models.
RESULTS: The expression of GJA1/Cx43, GJA3/Cx46 and GJB2/Cx26 and, for the first time, GJA6/Cx30 and GJB1/Cx32 was revealed both in normal human mammary glands and breast carcinomas. Within their subfamilies these connexins can form homo- and heterocellular epithelial channels. In cancer, the array datasets cross-validated each other's prognostic results. In line with the significant correlations found at mRNA level, elevated Cx43 protein levels were linked with significantly improved breast cancer outcome, offering Cx43 protein detection as an independent prognostic marker stronger than vascular invasion or necrosis. As a contrary, elevated Cx30 mRNA and protein levels were associated with a reduced disease outcome offering Cx30 protein detection as an independent prognostic marker outperforming mitotic index and necrosis. Elevated versus low Cx43 protein levels allowed the stratification of grade 2 tumors into good and poor relapse free survival subgroups, respectively. Also, elevated versus low Cx30 levels stratified grade 3 patients into poor and good overall survival subgroups, respectively.
CONCLUSION: Differential expression of Cx43 and Cx30 may serve as potential positive and negative prognostic markers, respectively, for a clinically relevant stratification of breast cancers.

Van den Bergh JM, Van Tendeloo VF, Smits EL
Interleukin-15: new kid on the block for antitumor combination therapy.
Cytokine Growth Factor Rev. 2015; 26(1):15-24 [PubMed] Related Publications
Interleukin (IL)-15 is one of the most promising molecules to be used in antitumor immune therapy, as it is able to stimulate the main killer cells of both the innate and adaptive immune system. Although this cytokine can be used as a stand-alone immunotherapeutic agent, IL-15 will probably be most efficient in combination with other strategies to overcome high tumor burden, immune suppression of the tumor microenvironment and/or the short half-life of IL-15. In this review, we will discuss the combination strategies with IL-15 that have been tested to date in different animal tumor models, which include chemotherapy, other immunostimulatory cytokines, targeted therapy, adoptive cell transfer and gene therapy. In addition, we give an overview of IL-15 combination therapies that are currently tested in clinical studies to treat patients with hematological or advanced solid tumors.

Rangel MM, Chaible LM, Nagamine MK, et al.
Electroporation transiently decreases GJB2 (connexin 26) expression in B16/BL6 melanoma cell line.
J Membr Biol. 2015; 248(1):47-52 [PubMed] Related Publications
Connexins are proteins that form gap junctions. Perturbations in the cell membrane reportedly promote changes in the expression profile of connexins. Electroporation promotes destabilization by applying electrical pulses, and this procedure is used in electrochemotherapy and gene therapy, among others. This in vitro work aimed to study the interference of electroporation on the expression profile of GJB2 (Cx26 gene) and Connexin 26 in melanoma cell line B16/BL6. The techniques of immunocytochemistry, Western blot, and real-time PCR were used. After electroporation, cells showed a transient decrease in GJB2 mRNA. The immunostaining of Cx26 showed no noticeable change after electroporation at different time points. However, Western blot showed a significant reduction in Cx26 30 min after electroporation. Our results showed that electroporation interferes transiently in the expression of Connexin 26 in melanoma and are consistent with the idea that electroporation is a process of intense stress that promotes cell homeostatic imbalance and results in disruption of cell physiological processes such as transcription and translation.

Sirnes S, Lind GE, Bruun J, et al.
Connexins in colorectal cancer pathogenesis.
Int J Cancer. 2015; 137(1):1-11 [PubMed] Related Publications
The connexins constitute a family of integral membrane proteins that form channels between adjacent cells. These channels are assembled in plasma membrane domains known as gap junctions and enable cells to directly exchange ions and small molecules. Intercellular communication via gap junctions plays important roles in regulating cell growth and differentiation and in maintaining tissue homeostasis. This type of cell communication is often impaired during cancer development, and several members of the connexin protein family have been shown to act as tumor suppressors. Emerging evidence suggests that the connexin protein family has important roles in colorectal cancer development. In the normal colonic epithelial tissue, three connexin isoforms, connexin 26 (Cx26), Cx32 and Cx43, have been shown to be expressed at the protein level. Colorectal cancer development is associated with loss of connexin expression or relocalization of connexins from the plasma membrane to intracellular compartments. Downregulation of connexins in colorectal carcinomas at the transcriptional level involves cancer-specific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfering with the Wnt/β-catenin pathway. There is also increasing evidence that the connexins may have potential as prognostic markers in colorectal cancer. This review discusses the role of connexins in colorectal cancer pathogenesis, as well as their potential as prognostic markers and targets in the prevention and treatment of the disease.

Han SS, Kim WJ, Hong Y, et al.
RNA sequencing identifies novel markers of non-small cell lung cancer.
Lung Cancer. 2014; 84(3):229-35 [PubMed] Related Publications
INTRODUCTION: The development of reliable gene expression profiling technology increasingly impacts our understanding of lung cancer biology. Here, we used RNA sequencing (RNA-Seq) to compare the transcriptomes of non-small cell lung cancer (NSCLC) and normal lung tissues and to investigate expression in lung cancer tissues.
METHODS: We enrolled 88 male patients (mean age, 61.2 years) with NSCLC. RNA-Seq was performed on 88 pairs of NSCLC tumor tissue and non-tumor tissue from 54 patients with adenocarcinoma and 34 patients with squamous cell carcinoma. Immunohistochemistry was performed to validate differential candidate gene expression in a different NSCLC group.
RESULTS: RNA-Seq produced 25.41 × 10(6) (± 8.90 × 10(6)) reads in NSCLC tissues and 24.70×10(6) (± 4.70 × 10(6)) reads in normal lung tissues [mean (± standard deviation)]. Among the genes expressed in both tissues, 335 were upregulated and 728 were downregulated ≥ 2-fold (p < 0.001). Four upregulated genes - CBX3, GJB2, CRABP2, and DSP - not previously reported in lung cancer were studied further. Their altered expression was verified by immunohistochemistry in a different set of NSCLC tissues (n = 154). CBX3 was positive in 90.3% (139 cases) of the samples; GJB2, in 22.7% (35 cases); CRABP2, in 72.1% (111 cases); and DSP, in 17.5% (27 cases). The positive rate of CRABP2 was higher in adenocarcinoma than squamous cell carcinoma (p < 0.01).
CONCLUSIONS: CBX3 and CRABP2 expression was markedly increased in lung cancer tissues and especially CRABP2 may be promising candidate genes in lung adenocarcinoma.

Li JY, Berger MF, Marghoob A, et al.
Combined melanocytic and sweat gland neoplasm: cell subsets harbor an identical HRAS mutation in phacomatosis pigmentokeratotica.
J Cutan Pathol. 2014; 41(8):663-71 [PubMed] Free Access to Full Article Related Publications
Phacomatosis pigmentokeratotica (PPK) is characterized by the co-existence of epidermal nevi and large segmental speckled lentiginous nevi of the papulosa type. PPK, previously explained as 'twin spot' mosaicism due to the postzygotic crossing-over of two homozygous recessive mutations, has recently been shown to derive from one postzygotic activating RAS mutation. Epidermal nevi, including those in PPK, are known to give rise to neoplasms such as trichoblastoma and basal cell carcinoma. Within speckled lentiginous nevi, Spitz nevi and melanoma have been well documented. We report a case of PPK with a combined melanocytic and adnexal neoplasm presenting where the nevi conjoined. Using next-generation sequencing techniques, we were able to identify the same HRAS G13R mutation within both components of the tumor, and to show the absence of additional mutated modifier genes in a panel of 300 cancer-related genes. Given the genetic findings in this rare tumor-type, we suggest that this case may be used as a model for understanding the development of biphenotypic neoplasia or intratumoral heterogeneity in some cases.

Xiao J, Zhang G, Qiu P, et al.
Tanshinone IIA increases the bystander effect of herpes simplex virus thymidine kinase/ganciclovir gene therapy via enhanced gap junctional intercellular communication.
PLoS One. 2013; 8(7):e67662 [PubMed] Free Access to Full Article Related Publications
The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy.

Li X, Su Y, Pan J, et al.
Connexin 26 is down-regulated by KDM5B in the progression of bladder cancer.
Int J Mol Sci. 2013; 14(4):7866-79 [PubMed] Free Access to Full Article Related Publications
Connexin 26 (Cx26) expression is down-regulated and KDM5B (H3K4 demethylase) is up-regulated in the progression of bladder cancer, suggesting that Cx26 expression may be down-regulated by KDM5B in bladder cancer. To test the hypothesis, the HT1376 and T24 human bladder carcinoma cells were transfected with the plasmids pcDNA3.1-KDM5B, and caused the down-regulation of Cx26 expression. In contrast, the HT1376 and T24 cells transfected with the plasmids pTZU6+1-shRNA-KDM5B1 and pTZU6+1-shRNA-KDM5B2 caused the up-regulation of Cx26 expression. Immunohistochemistry and Spearman's rank correlation analysis showed that the immunohistochemical expression of KDM5B and Cx26 was inversely related in bladder carcinoma tissues but no relationship in benign tissues. Taken together, these results indicate that KDM5B represses Cx26 expression in the bladder cancer development. Thus, a negative value to Cx26 immunohistochemical expression and a positive value to KDM5B immunohistochemical expression could be an ancillary diagnosis of primary bladder malignancy.

Coggshall K, Farsani T, Ruben B, et al.
Keratitis, ichthyosis, and deafness syndrome: a review of infectious and neoplastic complications.
J Am Acad Dermatol. 2013; 69(1):127-34 [PubMed] Related Publications
Keratitis, ichthyosis, and deafness (KID) syndrome is a rare genodermatosis associated with mutations in the connexin 26 gene. Although characterized by this clinical triad, KID syndrome predisposes to a heterogeneous spectrum of cutaneous manifestations and complications, both infectious and neoplastic in nature. Chronic mucocutaneous candidiasis and/or superinfection of skin lesions commonly occur and warrant aggressive therapeutic intervention. Benign neoplasms, namely trichilemmal tumors, have also been reported and can herald malignant growth and invasive disease. Squamous cell carcinoma of both mucosa and skin, especially acral sites, occurs in approximately 15% of patients. The pathogenesis of KID syndrome can be at least partially explained by the role of connexin 26 in intercellular communication and carcinogenesis, but the precise mechanism of disease remains unclear. Treatment strategies, which have ranged from antifungals and antibiotics to systemic retinoids, pose an ongoing challenge given the spectrum of disease. A review of the literature, with a particular focus on infection and malignancy associated with KID syndrome, and updates on the pathogenesis of disease, is discussed.

Groesser L, Herschberger E, Sagrera A, et al.
Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell.
J Invest Dermatol. 2013; 133(8):1998-2003 [PubMed] Related Publications
Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy.

Stoletov K, Strnadel J, Zardouzian E, et al.
Role of connexins in metastatic breast cancer and melanoma brain colonization.
J Cell Sci. 2013; 126(Pt 4):904-13 [PubMed] Free Access to Full Article Related Publications
Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell-cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease.

Bijnsdorp IV, Rozendaal L, van Moorselaar RJ, Geldof AA
A predictive role for noncancerous prostate cells: low connexin-26 expression in radical prostatectomy tissues predicts metastasis.
Br J Cancer. 2012; 107(12):1963-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It is important to identify markers that predict whether prostate cancer will metastasise. The adjacent noncancerous cells (influenced by the tumour cells) may also express potential markers. The objective of this study was to determine the influence of cancer cells on noncancerous cells and to assess the value of the cell-communication protein connexin-26 (Cx26) as a marker to predict the development of metastasis.
METHODS: The effect of conditioned medium (CM) from PrCa cells on in vitro noncancerous cell proliferation, migration and invasion and Cx26 expression was determined. Connexin-26 expression was investigated in prostatectomy tissues from 51 PrCa patients by immunohistochemistry and compared with various clinicopathological parameters.
RESULTS: Proliferation, migration and invasion of noncancerous cells were influenced by CM from the PrCa cell lines. Importantly, a clear relation was found between low Cx26 expression in the noncancerous tissue in prostatectomy sections and the risk of development of metastasis (P<0.0002). Kaplan-Meier analysis showed a relation between low Cx26 expression in noncancerous tissues and time to biochemical recurrence (P=0.0002).
CONCLUSION: Measuring Cx26 expression in the adjacent noncancerous tissues (rather than cancer tissues) of prostatectomy sections could help to identify high-risk patients who may benefit from adjuvant therapy to decrease the risk of metastasis.

Li BX, Yamanaka K, Xiao X
Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription.
Bioorg Med Chem. 2012; 20(23):6811-20 [PubMed] Free Access to Full Article Related Publications
CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure-activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX-KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX-KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action.

Pushpavalli SN, Ramaiah MJ, Lavanya A, et al.
Imidazo-benzothiazoles a potent microRNA modulator involved in cell proliferation.
Bioorg Med Chem Lett. 2012; 22(20):6418-24 [PubMed] Related Publications
MicroRNAs are endogenously expressed tiny non-coding RNAs that control gene expression at the post-transcriptional level and regulate processes of cell growth, differentiation, proliferation and apoptosis. Aberrant expression of microRNAs correlates with various cancers. Our experiments demonstrated that imidazo-benzothiazole conjugates caused apoptosis in colon cancer cells by modulating the expression of microRNAs. In vivo study in Drosophila melanogaster has exhibited inhibitory action on bantam microRNA, the homolog of human miR-542-5p that is involved in deciding the cellular cues that regulate the balance between proliferation and apoptosis. The expression of direct targets of bantam such as Hid and HDAC-6 were affected upon compound treatment. Interestingly, these conjugates downregulate the genes involved in microRNA biogenesis such as Drosha, Pasha and Dicer-1. Our findings have elucidated the microRNA inhibitory role of imidazo-benzothiazole conjugates.

Wang Y, Wang Z, Joshi BH, et al.
The tumor suppressor Caliban regulates DNA damage-induced apoptosis through p53-dependent and -independent activity.
Oncogene. 2013; 32(33):3857-66 [PubMed] Related Publications
We previously identified Caliban (Clbn) as the Drosophila homolog of human Serologically defined colon cancer antigen 1 gene and demonstrated that it could function as a tumor suppressor in human non-small-cell lung cancer (NSCLC) cells, although its mode of action was unknown. Herein, we identify roles for Clbn in DNA damage response. We generate clbn knockout flies using homologous recombination and demonstrate that they have a heightened sensitivity to irradiation. We show that normal Clbn function facilitates both p53-dependent and -independent DNA damage-induced apoptosis. Clbn coordinates different apoptosis pathways, showing a two-stage upregulation following DNA damage. Clbn has proapoptotic functions, working with both caspase and the proapoptotic gene Hid. Finally, ecotopic expression of clbn(+) in NSCLC cells suppresses tumor formation in athymic nude mice. We conclude that Caliban is a regulator of DNA damage-induced apoptosis, functioning as a tumor suppressor in both p53-dependent and -independent pathways.

Easton JA, Donnelly S, Kamps MA, et al.
Porokeratotic eccrine nevus may be caused by somatic connexin26 mutations.
J Invest Dermatol. 2012; 132(9):2184-91 [PubMed] Free Access to Full Article Related Publications
Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.

Li FR, Jiao P, Yao ST, et al.
Paris polyphylla Smith extract induces apoptosis and activates cancer suppressor gene connexin26 expression.
Asian Pac J Cancer Prev. 2012; 13(1):205-9 [PubMed] Related Publications
BACKGROUND: The inhibition of tumor cell growth without toxicity to normal cells is an important target in cancer therapy. One possible way to increase the efficacy of anticancer drugs and to decrease toxicity or side effects is to develop traditional natural products, especially from medicinal plants. Paris polyphylla Smith has shown anti-tumour effects by inhibition of tumor promotion and inducement of tumor cell apoptosis, but mechanisms are still not well understood. The present study was to explore the effect of Paris polyphylla Smith extract (PPSE) on connexin26 and growth control in human esophageal cancer ECA109 cells.
METHODS: The effects of PPSE on Connexin26 were examined by RT-PCR, western blot and immunofluorescence; cell growth and proliferation were examined by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay.
RESULTS: PPSE inhibited the growth and proliferation on esophageal cancer ECA109 cells, while increasing the expression of connexin26 mRNA and protein; conversely, PPSE decreased Bcl-2 and increased Bad.
CONCLUSION: This study firstly shows that PPSE can increase connexin26 expression at mRNA and protein level, exerting anti-tumour effects on esophageal cacner ECA109 cells via inhibiting cell proliferation and inducing cell apoptosis.

Lazic T, Li Q, Frank M, et al.
Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: report of a patient with GJB2 (G12R) Connexin 26 mutation and unusual clinical findings.
Pediatr Dermatol. 2012 May-Jun; 29(3):349-57 [PubMed] Related Publications
Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia, characterized mainly by the presence of hyperkeratotic skin lesions, neurosensory hearing loss, and vascularizing keratitis. Most mutations that have been discovered as a cause of KID syndrome are autosomal dominant, found in exon 2 of the Connexin (Cx) 26 gene. A G12R (p.Gly12Arg) is a GJB2 mutation reported in only two patients with KID syndrome to date. This article describes a patient with the G12R mutation and KID syndrome with interesting additional features, which include a porokeratotic eccrine ostial and dermal duct nevus, follicular occlusion triad, and unusual persistent oral mucosal papules. We compare this patient's phenotype with the only two other patients described with the same (G12R) mutation. The phenotypic heterogeneity of KID syndrome, inexplicable according to our current understanding of these proteins, speaks to the complexity of the connexin system and its overlapping expression patterns in different tissues.

Liu LM, Yan MG, Yang DH, et al.
The expression of protein inhibitor of activated signal transducers and activators of transcription 3 in the evolutionary process of gastric cancer.
Eur J Intern Med. 2011; 22(5):e31-5 [PubMed] Related Publications
OBJECTIVE: To study the expression of PIAS3 (protein inhibitor of activated signal transducers and activators of transcription 3) in the evolutionary process of gastric cancer.
METHODS: Samples were taken from the endoscopic biopsy specimens of 125 patients. Gastric mucosal lesions were diagnosed in HE staining, and chronic atrophic gastritis (CAG) with intestinal metaplasia (IM) were distinguished in AB-PAS and HID-AB staining. The expressions of PIAS3 gene in different types of gastric mucosal lesions were detected by immunocytochemistry and in situ hybridization. The results were analyzed using IPP 6.0 image analysis system, from which the average optical density was obtained of positive cells.
RESULTS: There were 25 patients with chronic superficial gastritis (CSG), 87 CAG (30 with complete intestinal IM, 27 with incomplete intestinal IM, 21 with complete colonic IM, 9 with incomplete colonic IM), 8 dysplasia (DYS) and 5 gastric cancer (GC). In the expressions of PIAS3 mRNA and protein, a difference was not found between the patients with CSG and those with CAG with complete or incomplete intestinal IM; however, a significant difference was statistically found among patients with CSG (or intestinal IM), complete colonic IM, incomplete colonic IM, DYS and GC, expression levels of which stepped down one by one.
CONCLUSIONS: There are differences in the PIAS3 expression from different stages of gastric precancerous conditions/lesions to GC, which may reveal a close relationship between expression reduction or loss of PIAS3 and gastric tumorigenesis.

Bennàssar A, Ferrando J, Grimalt R
Congenital atrichia and hypotrichosis.
World J Pediatr. 2011; 7(2):111-7 [PubMed] Related Publications
BACKGROUND: Alopecia present from birth includes a broad differential diagnosis and often represents a diagnostic and therapeutic challenge for the involved physician.
DATA SOURCES: An initial correct diagnosis and classification is essential because structural hair defects may be the expression of a genetic disorder affecting hair growth, part of a congenital syndrome with accompanying hair malformations, or a marker for an underlying metabolic disorder and may impact the mental and physical development of a child. Pathological hair loss rarely occurs in the first year of life; however, it may be a leading symptom of many congenital diseases.
RESULTS: In recent years, the clinical and microscopic features of hereditary hair shaft disorders have been characterized and classified. Furthermore, significant progress has been made in our knowledge of genes that control the normal development and differentiation of hair follicles, and thus the research is to define and classify the hair disorders within a genetic basis.
CONCLUSIONS: In this article we discuss several types of genotrichosis and provide a practical classification based on their clinical features.

Natsuga K, Akiyama M, Shimizu H
Malignant skin tumours in patients with inherited ichthyosis.
Br J Dermatol. 2011; 165(2):263-8 [PubMed] Related Publications
Inherited ichthyoses are rare genodermatoses caused by mutations in the genes involved in epidermal development. Although there have been case reports on patients with ichthyosis who developed skin malignancies, it is still unknown whether or not patients with ichthyosis have an increased risk of skin malignancies. Here, we review case series of skin malignancies in patients with ichthyosis and show biological findings which might lead to cancer susceptibility. A survey of the literature revealed 28 cases of inherited ichthyoses with skin malignancy, including 12 cases of keratitis-ichthyosis-deafness (KID) syndrome, seven of autosomal recessive congenital ichthyosis, three of Netherton syndrome and six of miscellaneous ichthyosis. Twenty-four of the 28 cases developed single or multiple squamous cell carcinomas (SCCs). The age at diagnosis of the first skin malignancy ranged from 15 to 54 years. As patients with these particular subtypes of ichthyosis seem to be prone to skin malignancies, including SCC, at an unusually young age, routine cancer surveillance of these patients is strongly recommended.

Sirnes S, Honne H, Ahmed D, et al.
DNA methylation analyses of the connexin gene family reveal silencing of GJC1 (Connexin45) by promoter hypermethylation in colorectal cancer.
Epigenetics. 2011; 6(5):602-9 [PubMed] Related Publications
Gap junctions are specialized plasma membrane domains consisting of channels formed by members of the connexin protein family. Gap junctional intercellular communication is often lost in cancers due to aberrant localization or downregulation of connexins, and connexins are therefore suggested to act as tumor suppressor genes in various tissues. The aim of this study was to investigate the expression pattern and DNA promoter methylation status of connexins in colorectal cancer. Expression of six (GJA1, GJA9, GJB1, GJB2, GJC1 and GJD3) connexin genes was detected in normal colonic tissue samples. GJC1 expression was reduced in colorectal carcinomas compared to normal tissue samples. All analyzed connexins were hypermethylated in colon cancer cell lines, although at various frequencies. GJA4, GJB6 and GJD2 were hypermethylated in 60% (29/48), 25% (12/48) and 96% (46/48) of primary colorectal carcinomas, respectively. However, the methylation status was not associated with gene expression. GJC1 has two alternative promoters, which were methylated in 42% (32/76) and 38% (25/65) of colorectal tumors, and in none of the normal mucosa samples. Expression of GJC1 was significantly lower in methylated compared with unmethylated samples (p < 0.01) and was restored in cell lines treated with the demethylating drug 5-aza-2'deoxycytidine. Taken together, DNA hypermethylation of the promoter region of GJC1, encoding connexin45, is an important mechanism in silencing gene expression in colorectal cancer.

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