GJA1

Gene Summary

Gene:GJA1; gap junction protein, alpha 1, 43kDa
Aliases: HSS, CMDR, CX43, EKVP, GJAL, ODDD, AVSD3, HLHS1
Location:6q22.31
Summary:This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:gap junction alpha-1 protein
HPRD
Source:NCBIAccessed: 11 August, 2015

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 (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: GJA1 (cancer-related)

Cheng Y, Ma D, Zhang Y, et al.
Cervical squamous cancer mRNA profiles reveal the key genes of metastasis and invasion.
Eur J Gynaecol Oncol. 2015; 36(3):309-17 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: To investigate mRNA expression profiles associated with cervical squamous carcinoma progression and to identify key genes involved in invasion and metastasis of cervical squamous cancer.
MATERIALS AND METHODS: The authors extracted the mRNA expression profile of eight normal cervical tissues by human whole genome microarray. The main functions of differentially expressed genes were identified by gene ontology (GO) analysis. Gene-networks were established based on bioinformatic approaches. Microarray data of the expressions level of key genes verified by qRT-PCR.
RESULTS: The authors identified 2036 differentially expressed genes between two groups including 1,282 down-regulated genes and 754 up-regulated genes (p < 0.05, FDR < 0.05). Gene-network revealed that PDGFRA, CAV1, and GJA-1 were critical for cervical cancer invasion and metastasis.
CONCLUSIONS: PDGFRA, CAV1, and GJA-1 were revealed as key node genes for cervical cancer invasion and metastasis. The results may provide new evidences and ideas for early diagnosis and prognosis assessment of cervical cancer.

Ghosh S, Kumar A, Chandna S
Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events.
Cancer Lett. 2015; 363(1):46-59 [PubMed] Related Publications
Enrichment of tumour cells in G2/M phases in vitro is known to be associated with low-dose hyper-radiosensitivity (HRS). These cell cycle phases also involve reduced expression of adhesion protein connexin-43 (Cx43). Therefore, we investigated the role of Cx43 in HRS. Asynchronous or G2/M enriched tumour cells (U87, BMG-1, HeLa) and normal primary fibroblasts (HDFn) were γ-irradiated at varying doses, with an asynchronous group separately subjected to Cx43-knockdown prior to irradiation. Cx43 level, gap junctional activity, clonogenic cell survival, cell growth/viability, mitochondrial alterations and other apoptosis-regulating events were studied. G2/M enrichment reduced Cx43 level by ~50% and caused considerable HRS at doses 10 cGy-30 cGy in all tumour cell lines. Cx43-knockdown to the same level (~60%) also elicited prominent HRS response in these cells. Quite important, radiosensitivity of primary HDFn cells remained unaltered by all these treatments. In Cx43-knockdown tumour cells, low-dose irradiation caused significant growth inhibition and apoptosis involving loss of MMP, cytochrome-c release and caspase-3 activation, thereby demonstrating the important cytoprotective role of Cx43. Therefore, this study significantly shows that Cx43 downregulation (a constitutive feature of G2/M phase) selectively renders tumour cells hypersensitive to low-dose radiation, and presents connexins as potential therapeutic targets.

Wang Y, Huang LH, Xu CX, et al.
Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis.
World J Gastroenterol. 2014; 20(33):11770-9 [PubMed] Free Access to Full Article Related Publications
AIM: To explore the mechanism of abnormal Connexin (Cx) 32 and Cx43 expression in the gastric mucosa after Helicobacter pylori (H. pylori) infection.
METHODS: Biopsy specimens of gastric mucosa in different gastric carcinogenesis stages with H. pylori infection, that is, non-atrophic gastritis (NAG; n = 24), chronic atrophic gastritis (CAG; n = 25), intestinal metaplasia (IM; n = 28), dysplasia (DYS; n = 24), and gastric cancer (GC; n = 30), as well as specimens of normal gastric mucosa without H. pylori infection (NGM; n = 25), were confirmed by endoscopy and pathological examination. Cx32 and Cx43 mRNA expression was detected by real-time polymerase chain reaction (PCR). Cx32 and Cx43 promoter CpG island methylation status was determined by methylation-specific PCR (MSP), bisulfite PCR sequencing (BSP) and MassArray methods.
RESULTS: The relative mRNA expression levels in the gastric mucosa of patients with NGM, NAG, CAG, IM, DYS and GC were 0.146 ± 0.011, 0.133 ± 0.026, 0.107 ± 0.035, 0.039 ± 0.032, 0.037 ± 0.01 and 0.03 ± 0.011 for Cx32; and 0.667 ± 0.057, 0.644 ± 0.051, 0.624 ± 0.049, 0.555 ± 0.067, 0.536 ± 0.058 and 0.245 ± 0.121 for Cx43, respectively, which were gradually decreasing and significantly different (GC vs NGM: P < 0.001 for Cx32, P < 0.001 for Cx43). The promoter methylation levels in the gastric mucosa from NGM to GC stages by MSP were 38.8% ± 9.0%, 43.1% ± 9.4%, 56.5% ± 3.1%, 64.4% ± 9.7%, 72.5% ± 4.2% and 79.6% ± 6.8% for Cx32; and 49.0% ± 3.9%, 58.1% ± 5.0%, 66.5% ± 7.9%, 74.0% ± 8.8%, 78.3% ± 3.6% and 88.7% ± 6.2% for Cx43, respectively, which were gradually increasing and significantly different (P = 0.039, P = 0.019). The promoter methylation levels by BSP and MassArray exhibited similar trends. Cx32 and Cx43 mRNA expression was negatively correlated with promoter methylation status and gastric carcinogenesis stages (P < 0.001, P = 0.016).
CONCLUSION: Cx32 and Cx43 mRNA expression decreased gradually during H. pylori infection-associated gastric carcinogenesis, and it is associated with hypermethylation of these genes' promoter.

Wu D, Chen K, Bai Y, et al.
Screening of diagnostic markers for osteosarcoma.
Mol Med Rep. 2014; 10(5):2415-20 [PubMed] Related Publications
Osteosarcoma, which is the most common type of highly malignant bone tumor in children and adolescents, has poor diagnosis and 2-year survival rates of 15-20% following surgery or radiotherapy, and has therefore generated marked attention. In order to investigate the potential biomarkers for diagnosing osteosarcoma, the expression profiling data from normal and disease tissues were compared, respectively, and the differentially‑expressed genes were analyzed by three different statistical tests. Interacting proteins were determined and an interaction network was constructed by Search Tool for the Retrieval of Interacting Genes database. Subsequently, the protein interaction network was decomposed and Gene Otology annotation using Cytoscape, Mcode and Bingo, was conducted on the function modules. Finally, three differentially‑expressed genes GJA1, COL1A2 and COL5A2 were identified, and an interaction network was successfully generated with COL1A2 and COL5A2 at the core. From the results, it was observed that COL1A2 and COL5A2 interact with a number of genes of the matrix metalloprotease (MMP) family, including MMP1, MMP2, MMP3 and MMP14, TGFβ and RUNX2. Furthermore, these genes have been confirmed to be important in the tumorigenesis of osteosarcoma. It was hypothesized that the upregulation of the COL gene family may be considered as a diagnostic marker for osteosarcoma and collagen may be administered as a therapy.

Yu M, Zhang C, Li L, et al.
Cx43 reverses the resistance of A549 lung adenocarcinoma cells to cisplatin by inhibiting EMT.
Oncol Rep. 2014; 31(6):2751-8 [PubMed] Related Publications
Cisplatin (CDDP) is one of the standard first-line chemotherapeutic agents for advanced non-small cell lung cancer (NSCLC). Unfortunately, prolonged exposure to CDDP results in acquired resistance which prevents the successful treatment of lung cancer patients. Thus, it is necessary to explore the mechanism underlying the resistance of NSCLC to CDDP. In the present study, a CDDP-resistant human lung cancer cell line A549/CDDP was established from the parental cell line A549. The results demonstrated that A549/CDDP cells acquired an epithelial-mesenchymal transition (EMT) phenotype, with morphological changes including acquisition of a spindle-like fibroblastic phenotype, downregulation of E-cadherin, upregulation of mesenchymal markers (vimentin, Snail and Slug), and increased capability of invasion and migration. Compared with A549 cells, the A549/CDDP cells showed decreased connexin43 (Cx43) expression. Overexpression of Cx43 reversed EMT and CDDP resistance in the A549/CDDP cells. Conversely, knockdown of Cx43 expression by siRNA-Cx43 initiated EMT and induced CDDP insensitivity in A549 cells. In summary, Cx43 reverses CDDP resistance in A549 CDDP-resistant cells by preventing EMT, making Cx43 a possible therapeutic target for lung cancer.

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.

Mostafavi H, Khaksarian M, Joghataei MT, et al.
Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac.
Mol Med Rep. 2014; 9(6):2405-10 [PubMed] Related Publications
It has been demonstrated that connexin 43 (Cx43) and microRNAs have significant roles in glioma. Cyclic adenosine monophosphate (cAMP) is suggested to be a regulator of connexins and microRNAs. However, it remains elusive whether cAMP and exchange protein directly activated by cAMP (Epac2), have a regulatory effect on Cx43 and microRNA-451 (miR-451) in astrocytoma cells. We treated 1321N1 astrocytoma cells with a selective β2 adrenergic agonist and a selective Epac activator with and without adenyl cyclase and protein kinase A inhibition. Cx43 and miR-451 expression were measured. Next, we evaluated the effect of miR-451 overexpression on Cx43 expression. Cell proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that cAMP-Epac2 increased Cx43 and miR-451 expression. However, the alteration of miR-451 expression required a higher dose of drugs. Overexpression of miR-451 had no significant effect on Cx43 expression. The MTT assay showed that cAMP-Epac stimulation and miR-451 overexpression had a synergic inhibitory effect on cell proliferation. These findings may expand our understanding of the molecular biology of glioma and provide new potential therapeutic targets.

Munoz JL, Rodriguez-Cruz V, Greco SJ, et al.
Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43.
Cell Death Dis. 2014; 5:e1145 [PubMed] Free Access to Full Article Related Publications
Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM.

Grek CL, Rhett JM, Ghatnekar GS
Cardiac to cancer: connecting connexins to clinical opportunity.
FEBS Lett. 2014; 588(8):1349-64 [PubMed] Free Access to Full Article Related Publications
Gap junctions and their connexin components are indispensable in mediating the cellular coordination required for tissue and organ homeostasis. The critical nature of their existence mandates a connection to disease while at the same time offering therapeutic potential. Therapeutic intervention may be offered through the pharmacological and molecular disruption of the pathways involved in connexin biosynthesis, gap junction assembly, stabilization, or degradation. Chemical inhibitors aimed at closing connexin channels, peptide mimetics corresponding to short connexin sequences, and gene therapy approaches have been incredibly useful molecular tools in deciphering the complexities associated with connexin biology. Recently, therapeutic potential in targeting connexins has evolved from basic research in cell-based models to clinical opportunity in the form of human trials. Clinical promise is particularly evident with regards to targeting connexin43 in the context of wound healing. The following review is aimed at highlighting novel advances where the pharmacological manipulation of connexin biology has proven beneficial in animals or humans.

Davidson B, Abeler VM, Førsund M, et al.
Gene expression signatures of primary and metastatic uterine leiomyosarcoma.
Hum Pathol. 2014; 45(4):691-700 [PubMed] Free Access to Full Article Related Publications
Leiomyosarcoma (LMS) is the most common uterine sarcoma. Although the disease is relatively rare, it is responsible for considerable mortality due to frequent metastasis and chemoresistance. The molecular events related to LMS metastasis are unknown to date. The present study compared the global gene expression patterns of primary uterine LMSs and LMS metastases. Gene expression profiles of 13 primary and 15 metastatic uterine LMSs were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. To identify differently expressed genes between primary and metastatic tumors, we performed one-way analysis of variance with Benjamini-Hochberg correction. This led to identification of 203 unique probes that were significantly differentially expressed in the 2 tumor groups by greater than 1.58-fold with P < .01, of which 94 and 109 were overexpressed in primary and metastatic LMSs, respectively. Genes overexpressed in primary uterine LMSs included OSTN, NLGN4X, NLGN1, SLITRK4, MASP1, XRN2, ASS1, RORB, HRASLS, and TSPAN7. Genes overexpressed in LMS metastases included TNNT1, FOLR3, TDO2, CRYM, GJA1, TSPAN10, THBS1, SGK1, SHMT1, EGR2, and AGT. Quantitative real-time PCR confirmed significant anatomical site-related differences in FOLR3, OSTN, and NLGN4X levels; and immunohistochemistry showed significant differences in TDO2 expression. Gene expression profiling differentiates primary uterine LMSs from LMS metastases. The molecular signatures unique to primary and metastatic LMSs may aid in understanding tumor progression in this cancer and in providing a molecular basis for prognostic studies and therapeutic target discovery.

Sato T, Neschadim A, Lavie A, et al.
The engineered thymidylate kinase (TMPK)/AZT enzyme-prodrug axis offers efficient bystander cell killing for suicide gene therapy of cancer.
PLoS One. 2013; 8(10):e78711 [PubMed] Free Access to Full Article Related Publications
We previously described a novel suicide (or 'cell fate control') gene therapy enzyme/prodrug system based on an engineered variant of human thymidylate kinase (TMPK) that potentiates azidothymidine (AZT) activation. Delivery of a suicide gene sequence into tumors by lentiviral transduction embodies a cancer gene therapy that could employ bystander cell killing as a mechanism driving significant tumor regression in vivo. Here we present evidence of a significant bystander cell killing in vitro and in vivo mediated by the TMPK/AZT suicide gene axis that is reliant on the formation of functional gap-junctional intercellular communications (GJICs). Potentiation of AZT activation by the engineered TMPK expressed in the human prostate cancer cell line, PC-3, resulted in effective bystander killing of PC-3 cells lacking TMPK expression--an effect that could be blocked by the GJIC inhibitor, carbenoxolone. Although GJICs are mainly formed by connexins, a new family of GJIC molecules designated pannexins has been recently identified. PC-3 cells expressed both connexin43 (Cx43) and Pannexin1 (Panx1), but Panx1 expression predominated at the plasma membrane, whereas Cx43 expression was primarily localized to the cytosol. The contribution of bystander effects to the reduction of solid tumor xenografts established by the PC-3 cell line was evaluated in an animal model. We demonstrate the contribution of bystander cell killing to tumor regression in a xenograft model relying on the delivery of expression of the TMPK suicide gene into tumors via direct intratumoral injection of recombinant therapeutic lentivirus. Taken together, our data underscore that the TMPK/AZT enzyme-prodrug axis can be effectively utilized in suicide gene therapy of solid tumors, wherein significant tumor regression can be achieved via bystander effects mediated by GJICs.

Li C, Zhan C, Chen Y, et al.
Analysis report for osteosarcoma expression profile.
Eur Rev Med Pharmacol Sci. 2013; 17(20):2804-9 [PubMed] Related Publications
BACKGROUND: Osteosarcoma is a kind of highly malignant primary bone tumor which most common in the teenage, and holds strong aggressive, earlier organs metastases mainly to lung, prone to postoperative recur. Therefore for osteosarcoma, invasion and transfer mechanism and related factors' interaction remains to be a key research subject.
AIM: We aim to find biological molecules marker can be used for osteosarcoma diagnosis through contrast of osteosarcoma sample and normal tissue samples.
MATERIALS AND METHODS: This analysis using human osteosarcoma expression profile data and three lesions normal tissue samples (liver, kidneys, lymph) expression data and compare them, and find significant specifically expressed genes, according to their function.
RESULTS: Research shows that the cancer cell proliferation, invasion, transfer and recurrent process involve many factors interaction, of which angiogenesis is the necessary condition of tumor growth, transfer and the recurrence.
CONCLUSIONS: Now the most important positive regulatory factor of angiogenesis is VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor). Both of them are with a wide variety and close relationship of tumor angiogenesis and progress.

Talhouk RS, Fares MB, Rahme GJ, et al.
Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: role of β-catenin/connexin43 association.
Exp Cell Res. 2013; 319(20):3065-80 [PubMed] Related Publications
Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures. C-terminus truncated Cx43 did not alter proliferation. Untransfected MCF-7 cells formed spherical aggregates in 3D cultures, and MDA-MB-231 cells formed stellar aggregates. However, MCF-7 cells over-expressing Cx43 formed smaller sized clusters and Cx43 expressing MDA-MB-231 cells lost their stellar morphology. Extravasation ability of both MCF-7 and MDA-MB-231 cells was reduced by 60% and 30% respectively. On the other hand, silencing Cx43 in MCF10A cells, nonneoplastic human mammary cell line, increased proliferation in both 2D and 3D cultures, and disrupted acinar morphology. Although Cx43 over-expression did not affect total levels of β-catenin, α-catenin and ZO-2, it decreased nuclear levels of β-catenin in 2D and 3D cultures of MCF-7 cells, and in 3D cultures of MDA-MB-231 cells. Cx43 associated at the membrane with α-catenin, β-catenin and ZO-2 in 2D and 3D cultures of MCF-7 cells, and only in 3D conditions in MDA-MB-231 cells. This study suggests that Cx43 exerts tumor suppressive effects in a context-dependent manner where GJ assembly with α-catenin, β-catenin and ZO-2 may be implicated in reducing growth rate, invasiveness, and, malignant phenotype of 2D and 3D cultures of MCF-7 cells, and 3D cultures of MDA-MB-231 cells, by sequestering β-catenin away from nucleus.

Jin Z, Xu S, Yu H, et al.
miR-125b inhibits Connexin43 and promotes glioma growth.
Cell Mol Neurobiol. 2013; 33(8):1143-8 [PubMed] Related Publications
MicroRNA is strongly associated with tumor growth and development. This study examined the potential roles of miR-125b in glioma growth. We found that miR-125b promotes glioma cell line growth and clone formation, and protects the glioma cells from apoptosis in vitro. The miR-125b-transfected glioma cells also demonstrated increased growth after in vivo transplantation. We further identified that miR-125b inhibits Connexin43 expression, and the overexpression of Connexin43 antagonizes the effects of miR-125b in cell growth and anti-apoptosis. We conclude that miR-125b regulates glioma growth partly through Connexin43 protein.

Tang B, Peng ZH, Yu PW, et al.
Aberrant expression of Cx43 is associated with the peritoneal metastasis of gastric cancer and Cx43-mediated gap junction enhances gastric cancer cell diapedesis from peritoneal mesothelium.
PLoS One. 2013; 8(9):e74527 [PubMed] Free Access to Full Article Related Publications
The process of peritoneal metastasis involves the diapedesis of intra-abdominal exfoliated gastric cancer cells through the mesothelial cell monolayers; however, the related molecular mechanisms for this process are still unclear. Heterocellular gap-junctional intercellular communication (GJIC) between gastric cancer cells and mesothelial cells may play an active role during diapedesis. In this study we detected the expression of connexin 43 (Cx43) in primary gastric cancer tissues, intra-abdominal exfoliated cancer cells, and matched metastatic peritoneal tissues. We found that the expression of Cx43 in primary gastric cancer tissues was significantly decreased; the intra-abdominal exfoliated cancer cells and matched metastatic peritoneal tissues exhibited increasing expression compared with primary gastric cancer tissues. BGC-823 and SGC-7901 human gastric cancer cells were engineered to express Cx43 or Cx43T154A (a mutant protein that only couples gap junctions but provides no intercellular communication) and were co-cultured with human peritoneal mesothelial cells (HPMCs). Heterocellular GJIC and diapedesis through HPMC monolayers on matrigel-coated coverslips were investigated. We found that BGC-823 and SGC-7901 gastric cancer cells expressing Cx43 formed functional heterocellular gap junctions with HPMC monolayers within one hour. A significant increase in diapedesis was observed in engineered Cx43-expressing cells compared with Cx43T154A and control group cells, which suggested that the observed upregulation of diapedesis in Cx43-expressing cells required heterocellular GJIC. Further study revealed that the gastric cancer cells transmigrated through the intercellular space between the mesothelial cells via a paracellular route. Our results suggest that the abnormal expression of Cx43 plays an essential role in peritoneal metastasis and that Cx43-mediated heterocellular GJIC between gastric cancer cells and mesothelial cells may be an important regulatory step during metastasis. Finally, we observed that the diapedesis of exfoliated gastric cancer cells through mesothelial barriers is a viable route of paracellular migration.

Khan Z, Yaiw KC, Wilhelmi V, et al.
Human cytomegalovirus immediate early proteins promote degradation of connexin 43 and disrupt gap junction communication: implications for a role in gliomagenesis.
Carcinogenesis. 2014; 35(1):145-54 [PubMed] Related Publications
A lack of gap junctional intercellular communication (GJIC) is common in cancer. Many oncogenic viruses have been shown to downregulate the junctional protein connexin 43 (Cx43) and reduce GJIC. Human cytomegalovirus (HCMV) is a ubiquitous, species-specific betaherpesvirus that establishes life-long latency after primary infection. It encodes two viral gene products, immediate early (IE) proteins IE1 and IE2, which are crucial in viral replication and pathogenesis of many diseases. Emerging evidence demonstrates that HCMV DNA and proteins are highly prevalent in glioblastoma multiforme (GBM) and in other tumors, but HCMV's role in tumorigenesis remains obscure. In the present study, we examined the effects of HCMV infection on Cx43 expression and GJIC as well as the viral mechanism mediating the effects in human GBM cells and tissue samples. We found that HCMV downregulated Cx43 protein, resulting in disruption of functional GJIC as assayed by fluorescent dye transfer assay. We show that both HCMV-IE72 and IE86 mediate downregulation of Cx43 by silencing RNA targeting either IE72 or IE86 coupled with ganciclovir. This finding was further validated by transfection with expression vectors encoding IE72 or IE86, and we show that viral-mediated Cx43 depletion involved proteasomal degradation. Importantly, we also observed that the Cx43 protein levels and IE staining correlated inversely in 10 human GBM tissue specimens. Thus, HCMV regulates Cx43 expression and GJIC, which may contribute to gliomagenesis.

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.

Takahashi E, Nakamura S
Histiocytic sarcoma : an updated literature review based on the 2008 WHO classification.
J Clin Exp Hematop. 2013; 53(1):1-8 [PubMed] Related Publications
Histiocytic sarcoma (HS) is an extremely rare malignant neoplasm showing morphologic and immunophenotypic evidence of histiocytic differentiation. The vast majority of previously reported HSs are now generally recognized to be misdiagnosed examples of non-Hodgkin lymphomas, predominantly diffuse large B-cell lymphoma or anaplastic large cell lymphoma. The recognition of such tumors parallels the development and widespread use of immunohistochemical techniques, along with the development of molecular genetic methods to detect immunoglobulin (IG) or T-cell receptor (TCR) gene rearrangement. The 2001 World Health Organization (WHO) definition of HS requires the absence of clonal B/T-cell receptor gene rearrangements. However, the 2008 WHO classification no longer strictly requires the absence of clonal immunoglobulin heavy chain (IGH) or TCR gene rearrangement for the diagnosis of HS. Recent studies demonstrated that HSs that occur subsequent to or concurrent with B- or T-lymphoblastic lymphoma/leukemia or mature B-cell neoplasms generally show clonal IgH and/or TCR gene rearrangement. These findings suggest the possibility of transdifferentiation of the two otherwise morphologically and immunohistochemically distinctive neoplasms. In addition, a recent study suggested clonal IG gene rearrangements may be detected at a high frequency in sporadic HS, indicating that a large subset of sporadic HSs may inherit the B-lymphocyte genotype. These findings provide new insights into the pathogenesis of HS, although the etiology of HS is still unknown. HS is a diagnosis of exclusion. It is necessary to rule out other diseases that could be misdiagnosed as HS with extensive immunophenotypical analysis before diagnosing HS.

Osgood RS, Upham BL, Hill T, et al.
Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure.
PLoS One. 2014; 8(6):e65150 [PubMed] Free Access to Full Article Related Publications
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1-Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs.

Benlalam H, Carré T, Jalil A, et al.
Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1-specific CD8⁺ T lymphocyte emergence.
J Mol Med (Berl). 2013; 91(10):1207-20 [PubMed] Related Publications
UNLABELLED: Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-γ) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag-specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-γ secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.
KEY MESSAGE: GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.

Zhao JQ, Sun FJ, Liu SS, et al.
Expression of connexin 43 and E-cadherin protein and mRNA in non-small cell lung cancers in Chinese patients.
Asian Pac J Cancer Prev. 2013; 14(2):639-43 [PubMed] Related Publications
AIM: Connexin 43 (Cx43) and E-cadherin are important biomarkers related with cancer. Their expression at protein and mRNA levels was here investigated in 50 primary lung carcinoma tissues and 20 samples of adjacent normal tissue of Chinese patients with non-small cell lung cancer (NSCLC).
METHODS: Protein and mRNA expression were evaluated by ABC immunohistochemistry and RT-PCR.
RESULTS: (1) The positive expression rates of Cx43 and E-cadherin protein were higher in the adjacent normal tissues than those in the primary lung carcinoma tissues; (2) the positive expression rates of Cx43 and E-cadherin protein decreased with NSCLC progression; (3) the expression of E-cadherin protein was not related with the pathological type of NSCLC; and (4) the relative quantity of the Cx43 or E-cadherin mRNA expression was correlated with the the histological type, clinical stage, cancer cell differentiation and the lymph node metastasis.
CONCLUSION: The data suggested that the Cx43 and E-cadherin are reduced with NSCLC progression, and might be important biomarkers for judging the metastasis and prognosis.

Wang J, Dai Y, Huang Y, et al.
All-trans retinoic acid restores gap junctional intercellular communication between oral cancer cells with upregulation of Cx32 and Cx43 expressions in vitro.
Med Oral Patol Oral Cir Bucal. 2013; 18(4):e569-77 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: All-trans retinoic acid (ATRA) has been demonstrated to inhibit tumor growth by restoration of gap junctional intercellular communication (GJIC) via upregulation of connexin (Cx) expression in some solid tumors. However, the relationship between ATRA and GJIC remains unclear in oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the effect of ATRA on the GJIC function of OSCC.
STUDY DESIGN: We measured the effects of ATRA on the viability and cell cycle distribution of SCC9 and Tca8113 OSCC cells. The GJIC function was observed using the scrape-loading dye transfer technique, and the mRNA and protein levels of Cx32 and Cx43 were detected by qRT-PCR, Western blot, and immunofluorescence assays.
RESULTS: ATRA inhibited the growth of OSCC cells in a dose- and time-dependent manner (P <0.05) and caused cell cycle arrest. ATRA-treated cells showed a 2.69-fold and 2.06-fold enhancement of GJIC in SCC9 and Tca8113 cells, respectively (P <0.05). Moreover, ATRA induced upregulation of Cx32 and Cx43 at both the mRNA and protein levels in OSCC cells.
CONCLUSION: Our results indicated that restoration of GJIC via enhanced Cx32 and Cx43 expression might serve as a novel mechanism for the anti-tumor effect of ATRA in OSCC.

Stelkovics E, Kiszner G, Meggyeshazi N, et al.
Selective in situ protein expression profiles correlate with distinct phenotypes of basal cell carcinoma and squamous cell carcinoma of the skin.
Histol Histopathol. 2013; 28(7):941-54 [PubMed] Related Publications
Non-melanoma skin cancer is the most common malignancy that shows increasing incidence due to our cumulative exposure to ultraviolet irradiation. Its major subtypes, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) differ in pathobiology, phenotype and clinical behavior, which must be reflected at the molecular level. In this study, protein expression profiles of BCC and SCC were tested in tissue microarrays and correlated with that of actinic keratosis, Bowen's disease, seborrheic keratosis and normal epidermis by detecting 22 proteins involved in cell interactions, growth, cell cycle regulation or apoptosis. The significantly more reduced collagen XVII, CD44v6, pan-Desmoglein levels and more evident E-Cadherin delocalization in BCC compared to SCC correlated with the de novo dermal invasion of BCC against the progressive invasion from in situ lesions in SCC development. EGFR was also expressed at a significantly higher level in SCC than in BCC. The upregulated cell communication protein connexin43 in BCC could contribute to the protection of BCC from metastatic invasion. Elevated cell replication in BCC was underlined by the increased topoisomerase IIα and reduced p21(waf1) and p27(kip1) positive cells fractions compared to SCC. Compared to differentiated keratinocytes, caspase-8 and -9 were equally upregulated in skin carcinoma subtypes for either mediating apoptosis induction or immune escape of tumor cells. Hierarchical cluster analysis grouped SCC and actinic keratosis cases exclusively together in support of their common origin and malignant phenotype. BCC cases were also clustered fully together. Differentially expressed proteins reflect the distinct pathobiology of skin carcinoma subtypes and can serve as surrogate markers in doubtful cases.

Yulyana Y, Endaya BB, Ng WH, et al.
Carbenoxolone enhances TRAIL-induced apoptosis through the upregulation of death receptor 5 and inhibition of gap junction intercellular communication in human glioma.
Stem Cells Dev. 2013; 22(13):1870-82 [PubMed] Free Access to Full Article Related Publications
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been used extensively in cancer therapy. However, more than half of glioblastoma multiforme are insensitive to the apoptotic effect of TRAIL. Improvement in therapeutic modalities that enhances the efficacy of TRAIL in glioma is much sought after. In this study, we combined the tumor selectivity of TRAIL and tumor-homing properties of mesenchymal stem cells (MSC) with gap junction (GJ) inhibitory effect of carbenoxolone (CBX) to target orthotopic glioma. MSC were engineered to express TRAIL (MSC-TRAIL) by incorporating the secretable trimeric form of TRAIL into a Herpes Simplex Virus (HSV) type I amplicon vector. Our results showed that combined treatment of MSC-TRAIL and CBX enhanced glioma cell death, especially in three primary human glioma isolates, of which two of those are marginally sensitive to TRAIL. CBX enhanced TRAIL-induced apoptosis through upregulation of death receptor 5, blockade of GJ intercellular communication, and downregulation of connexin 43. Dual arm therapy using TRAIL and CBX prolonged the survival of treated mice by ~27% when compared with the controls in an intracranial glioma model. The enhanced efficacy of TRAIL in combination with CBX coupled with the minimal cytotoxic nature of CBX suggested a favorable clinical usage of this treatment regimen.

Chen WS, Chen CC, Chen LL, et al.
Secreted heat shock protein 90α (HSP90α) induces nuclear factor-κB-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion.
J Biol Chem. 2013; 288(13):9001-10 [PubMed] Free Access to Full Article Related Publications
Secreted levels of HSP90α and overexpression of TCF12 have been associated with the enhancement of colorectal cancer (CRC) cell migration and invasion. In this study, we observed that CRC patients with tumor TCF12 overexpression exhibited both a higher rate of metastatic occurrence and a higher average serum HSP90α level compared with patients without TCF12 overexpression. Therefore, we studied the relationship between the actions of secreted HSP90α and TCF12. Like overexpressed TCF12, secreted HSP90α or recombinant HSP90α (rHSP90α) induced fibronectin expression and repressed E-cadherin, connexin-26, connexin-43, and gap junction levels in CRC cells. Consistently, rHSP90α stimulated invasive outgrowths of CRC cells from spherical structures during three-dimensional culture. rHSP90α also induced TCF12 expression in CRC cells. Its effects on CRC cell epithelial-mesenchymal transition, migration, and invasion were drastically prevented when TCF12 was knocked down. This suggests that TCF12 expression is required for secreted HSP90α to enhance CRC cell spreading. Through the cellular receptor CD91, rHSP90α facilitated the complex formation of CD91 with IκB kinases (IKKs) α and β and increased the levels of phosphorylated (active) IKKα/β and NF-κB. Use of an IKKα/β inhibitor or ectopic overexpression of dominant-negative IκBα efficiently repressed rHSP90α-induced TCF12 expression. Moreover, κB motifs were recognized in the gene sequence of the TCF12 promoter, and a physical association between NF-κB and the TCF12 promoter was detected in rHSP90α-treated CRC cells. Together, these results suggest that the CD91/IKK/NF-κB signaling cascade is involved in secreted HSP90α-induced TCF12 expression, leading to E-cadherin down-regulation and enhanced CRC cell migration/invasion.

Mauro V, Carette D, Pontier-Bres R, et al.
The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism.
Apoptosis. 2013; 18(4):480-91 [PubMed] Related Publications
Griseofulvin, a widely used antifungal antimitotic drug has been proposed as an anti-tumoral treatment by way of in vitro experiments. Recently, in vivo demonstration of griseofulvin efficacy against multiple myeloma in mice argues for its potential as therapeutics for cancer. Nevertheless, the molecular mechanisms by which griseofulvin disrupts cancerous cell progression are far from being understood. In the present study, we found that griseofulvin inhibits human germ cell tumor cell growth through activation of mitochondrial caspase pathway (caspase 9 and 3) leading to the activation of apoptosis rather than an alteration of cell proliferation. Strikingly, we demonstrated that griseofulvin triggered the expression level of connexin 43 (mRNA and protein), a well described tumor-suppressor gene, known to participate in apoptosis regulation. Consistently, together with microtubule instability, a mechanism classically associated with cell death in response to griseofulvin, we observed a disruption of connexin 43/tubulin association concomitant of an enhanced translocation of connexin 43, or an immunoreactive fragment of the protein, from the cytoplasm to the nucleus. Finally, by using siRNA approaches we demonstrated the requirement of connexin 43 in the apoptotic induction of griseofulvin on our tumor cell model. Altogether, these results described a new molecular mechanism connexin 43-dependent targeted by griseofulvin leading to apoptosis of human germ cell tumor cells.

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.

Talbot J, Brion R, Picarda G, et al.
Loss of connexin43 expression in Ewing's sarcoma cells favors the development of the primary tumor and the associated bone osteolysis.
Biochim Biophys Acta. 2013; 1832(4):553-64 [PubMed] Related Publications
Ewing's sarcoma (ES) is a primary bone tumor characterized by a chromosomic translocation between the EWS gene and a member of the ETS gene family, mainly FLI1, which leads to an aberrant transcription factor EWS-FLI1 that promotes tumorigenicity. Gap junctions are intercellular channels composed of transmembrane proteins (connexin: Cx), that allow direct intercellular communication between adjacent cells. Numerous studies have shown that tumorigenesis may be associated with a loss of gap junctional intercellular communication (GJIC). Loss of Cx43 expression was observed at the protein and mRNA levels in ES cell lines compared to those measured in human mesenchymal stem cells. A673 ES cells stably transfected with an shRNA targeting EWS-FLI1 showed an increase in Cx43 expression (at the mRNA, protein and transcriptional levels) and GJIC. In an osteolytic murine model of ES, the overexpression of Cx43 in ES cells dramatically reduced tumor growth, leading to a significant increase in animal survival. In vitro assays showed that Cx43 overexpression increases the p27 level with an associated marked decrease of Rb phosphorylation, consistent with the observed blockade of the cell cycle in G0/G1 phase. In addition, the bone microarchitectural parameters, assessed by micro-CT analysis, showed an increased bone volume when Cx43 expression was enhanced. Histological analysis demonstrated that the overexpression of Cx43 in ES tumor cells inhibits osteoclast activity and therefore bone resorption. Our study demonstrated that the loss of Cx43 expression in ES cells plays a crucial role in the development of the primary tumor and the associated bone osteolysis.

Park JM, Munoz JL, Won BW, et al.
Exogenous CXCL12 activates protein kinase C to phosphorylate connexin 43 for gap junctional intercellular communication among confluent breast cancer cells.
Cancer Lett. 2013; 331(1):84-91 [PubMed] Related Publications
Despite ongoing attempts to improve the overall breast cancer (BC) survival rate, BC cells' (BCCs) predilection for metastasizing to the bone marrow has enabled BCCs to not only remain dormant, but also evade detection. BCCs are able to acquire quiescence by establishing gap junctional intercellular communication (GJIC) with the stroma through the assembly of connexins (Cxs). The chemoattractant CXCL12 also appears to play a role in GJIC based on its tendency to decrease when GJIC is formed between BCCs and bone marrow stroma. This study investigates the role CXCL12 has on Cx43 expression and PKC-mediated Cx43 phosphorylation. Cx43 gene reporter assays revealed that as the BCCs come in contact with each other and establish GJIC, there is an inverse relationship between CXCL12 level and Cx43 expression. Immunoblot analyses confirmed this relationship at the level of protein, showing decreased Cx43 and reduced Cx43 phosphorylation at higher CXCL12 concentrations. However, real-time PCR studies revealed little change in Cx43 mRNA levels, despite stimulation with different concentrations of CXCL12, indicating CXCL12's effect on Cx43 is post-translational, through phosphorylation. Immunoblot analyses and functional dye exchange studies showed activation of PKC by exogenous CXCL12 in the phosphorylation, which in turn, increased intercellular communication. These findings elucidate the importance of considering the microenvironment's role in micrometastasis in clinical studies pertaining to prospective breast cancer treatment.

Dovzhanskiy DI, Hartwig W, Lázár NG, et al.
Growth inhibition of pancreatic cancer by experimental treatment with 4-phenylbutyrate is associated with increased expression of Connexin 43.
Oncol Res. 2012; 20(2-3):103-11 [PubMed] Related Publications
Histone deacetylase inhibitors are a new and promising drug family with a strong anticancer activity and potent modulation of connexin expression. The restoration of connexins in cancer cells has been suggested as a possible mechanism to control tumor progression. The aim of this study was to investigate the effects of 4-phenylbutyrate (4-PB) on the growth of human pancreatic cell lines in vitro and in vivo with a focus on connexin modulation. The proliferation of tumor cells was determined using an MTT assay, and the effect of 4-PB in vivo was studied in a chimeric mouse model. The expression and localization of connexin 43 (Cx43) were assessed by Western blot, immunofluorescence microscopy, and immunohistochemistry. Antitumoral activity was assessed by immunohistochemistry for Ki-67 and histone H4. Treatment with 4-PB resulted in the significant in vitro and in vivo growth inhibition of pancreatic tumor cells. The reduction of the xenograft tumor volume was associated with the inhibition of histone deacetylation and decrease in cell proliferation. Treatment with 4-PB caused a significant increase in the Cx43 expression in T3M4 cells (up to 2.8-fold). The newly synthesized Cx43 was localized in the cytoplasm but not on the cell membrane. Treatment with 4-PB inhibited the proliferation of human pancreatic tumor cells in vitro and in vivo and increased the expression of Cx43. Therefore, 4-PB might be useful in the therapy of pancreatic cancer.

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