|
1
|
Cooreman A, Van Campenhout R, Ballet S, Annaert P, Van Den Bossche B, Colle I, Cogliati B, Vinken M. Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease. Hepatology 2019; 69:1317-1323. [PMID: 30300925 DOI: 10.1002/hep.30306] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/17/2018] [Indexed: 12/20/2022]
Abstract
Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin-like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin-based and pannexin-based channels in noncancerous liver disease.
Collapse
Affiliation(s)
- Axelle Cooreman
- Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Steven Ballet
- Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pieter Annaert
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
| | - Bert Van Den Bossche
- Department of Abdominal Surgery and Hepato-Pancreatico-Biliary Surgery, Algemeen Stedelijk Ziekenhuis Campus Aalst, Aalst, Belgium
| | - Isabelle Colle
- Department of Hepatology and Gastroenterology, Algemeen Stedelijk Ziekenhuis Campus Aalst, Aalst, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of Toxicology, Vrije Universiteit Brussel, Brussels, Belgium
| |
Collapse
|
|
2
|
Cogliati B, Crespo Yanguas S, da Silva TC, Aloia TP, Nogueira MS, Real-Lima MA, Chaible LM, Sanches DS, Willebrords J, Maes M, Pereira IV, de Castro IA, Vinken M, Dagli ML. Connexin32 deficiency exacerbates carbon tetrachloride-induced hepatocellular injury and liver fibrosis in mice. Toxicol Mech Methods 2016; 26:362-370. [PMID: 27268753 PMCID: PMC5417356 DOI: 10.1080/15376516.2016.1190991] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Liver fibrosis results from the perpetuation of the normal wound healing response to several types of injury. Despite the wealth of knowledge regarding the involvement of intracellular and extracellular signaling pathways in liver fibrogenesis, information about the role of intercellular communication mediated by gap junctions is scarce. METHODS In this study, liver fibrosis was chemically induced by carbon tetrachloride in mice lacking connexin32, the major liver gap junction constituent. The manifestation of liver fibrosis was evaluated based on a series of read-outs, including collagen morphometric and mRNA analysis, oxidative stress, apoptotic, proliferative and inflammatory markers. RESULTS More pronounced liver damage and enhanced collagen deposition were observed in connexin32 knockout mice compared to wild-type animals in experimentally triggered induced liver fibrosis. No differences between both groups were noticed in apoptotic signaling nor in inflammation markers. However, connexin32 deficient mice displayed decreased catalase activity and increased malondialdehyde levels. CONCLUSION These findings could suggest that connexin32-based signaling mediates tissue resistance against liver damage by the modulation of the antioxidant capacity. In turn, this could point to a role for connexin32 signaling as a therapeutic target in the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Tereza C. da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Thiago P.A. Aloia
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Marina S. Nogueira
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mirela A. Real-Lima
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Lucas M. Chaible
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Daniel S. Sanches
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Isabel V.A. Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Inar A. de Castro
- Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Maria L.Z. Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| |
Collapse
|
|
3
|
Crespo Yanguas S, Willebrords J, Maes M, da Silva TC, Veloso Alves Pereira I, Cogliati B, Zaidan Dagli ML, Vinken M. Connexins and pannexins in liver damage. EXCLI JOURNAL 2016; 15:177-86. [PMID: 27065778 PMCID: PMC4822047 DOI: 10.17179/excli2016-119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/15/2016] [Indexed: 12/19/2022]
Abstract
Connexins and pannexins are key players in the control of cellular communication and thus in the maintenance of tissue homeostasis. Inherent to this function these proteins are frequently involved in pathological processes. The present paper reviews the role of connexins and pannexins in liver toxicity and disease. As they act both as sensors and effectors in these deleterious events connexins and pannexins could represent a set of novel clinical diagnostic biomarkers and drug targets.
Collapse
Affiliation(s)
- Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Tereza Cristina da Silva
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, São Paulo SP CEP 05508-900, Brazil
| | - Isabel Veloso Alves Pereira
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, São Paulo SP CEP 05508-900, Brazil
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, São Paulo SP CEP 05508-900, Brazil
| | - Maria Lucia Zaidan Dagli
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, São Paulo SP CEP 05508-900, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium
| |
Collapse
|
|
4
|
Maes M, Crespo Yanguas S, Willebrords J, Cogliati B, Vinken M. Connexin and pannexin signaling in gastrointestinal and liver disease. Transl Res 2015; 166:332-43. [PMID: 26051630 PMCID: PMC4570182 DOI: 10.1016/j.trsl.2015.05.005] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 04/29/2015] [Accepted: 05/08/2015] [Indexed: 12/20/2022]
Abstract
Gap junctions, which mediate intercellular communication, are key players in digestive homeostasis. They are also frequently involved in gastrointestinal and liver pathology. This equally holds true for connexin (Cx) hemichannels, the structural precursors of gap junctions, and pannexin (Panx) channels, Cx-like proteins assembled in a hemichannel configuration. Both Cx hemichannels and Panx channels facilitate extracellular communication and drive a number of deteriorative processes, such as cell death and inflammation. Cxs, Panxs, and their channels underlie a wide spectrum of gastrointestinal and liver diseases, including gastritis and peptic ulcer disease, inflammatory intestinal conditions, acute liver failure, cholestasis, hepatitis and steatosis, liver fibrosis and cirrhosis, infectious gastrointestinal pathologies, and gastrointestinal and liver cancer. This could open promising perspectives for the characterization of new targets and biomarkers for therapeutic and diagnostic clinical purposes in the area of gastroenterology and hepatology.
Collapse
Affiliation(s)
- Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
| |
Collapse
|
|
5
|
Chen J, Zhao J, Ma R, Lin H, Liang X, Cai X. Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a meta-analysis. PLoS One 2014; 9:e103952. [PMID: 25093414 PMCID: PMC4122395 DOI: 10.1371/journal.pone.0103952] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 07/04/2014] [Indexed: 02/06/2023] Open
Abstract
Backgrounds Hepatocellular Carcinoma (HCC) is one of the most common malignancy of liver and HCC-related morbidity and mortality remains at high level. Researchers had investigated whether and how reduced E-cadherin expression impacted the prognosis of patients with HCC but the results reported by different teams remain inconclusive. Methods A systematic literature search was performed in all available databases to retrieve eligible studies and identify all relevant data, which could be used to evaluate the correlation between reduced E-cadherin expression and clinicopathological features and prognosis for HCC patients. A fixed or random effects model was used in this meta-analysis to calculate the pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (CI). Results Total 2439 patients in thirty studies matched the selection criteria. Aggregation of the data suggested that reduced E-cadherin expression in HCC patients correlated with poor 1-, 3- and 5-year overall survival. The combined ORs were 0.50 (n = 13 studies, 95% CI: 0.37–0.67, Z = 4.49, P<0.00001), 0.39 (n = 13 studies, 95% CI: 0.28–0.56, Z = 5.12, P<0.00001), 0.40 (n = 11 studies, 95% CI: 0.25–0.64, Z = 3.82, P = 0.0001), respectively. Additionally, the pooled analysis denoted that reduced E-cadherin expression negatively impacts recurrence-free survival (RSF) with no significant heterogeneity. The pooled ORs for 1-, 3- and 5- year RSF affected by down-regulated E-cadherin were 0.73 (n = 6 studies, 95% CI: 0.54–1.00, Z = 1.95, P = 0.05), 0.70 (n = 6 studies, 95% CI: 0.52–0.95, Z = 2.32, P = 0.02), 0.66 (n = 5 studies, 95% CI: 0.48–0.90, Z = 2.64, P = 0.008). And what’s more, reduced E-cadherin expression tended to be significantly associated with metastasis (OR = 0.31, 95% CI: 0.16–0.60, Z = 3.50, P = 0.0005), vascular invasion (OR = 0.76, 95% CI: 0.59–0.98, Z = 2.14, P = 0.03), advanced differentiation grade (OR = 0.31, 95% CI: 0.21–0.45, Z = 6.04, P<0.00001) and advanced TMN stage (T3/T4 versus T1/T2) (OR = 0.61,95% CI:0.38–0.98, Z = 2.05, P = 0.04). Conclusions Reduced E-cadherin expression indicates a poor prognosis for patients with HCC, and it may have predictive potential for prognosis of HCC patients.
Collapse
Affiliation(s)
- Jiang Chen
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jie Zhao
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Rui Ma
- Department of Surgery, Zhejiang University Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hui Lin
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiao Liang
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiujun Cai
- Department of General Surgery, Institute of Minimally Invasive Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- * E-mail:
| |
Collapse
|
|
6
|
Abstract
SUMMARY Melanoma cells interact with and depend on seemingly normal cells in their tumour microenvironment to allow the acquisition of the hallmarks of solid cancer. In general, there are three types of interaction of melanoma cells with their microenvironment. First, there is bilateral communication between melanoma cells and the stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix. Second, while under normal conditions keratinocytes control localisation and proliferative behaviour of melanocytes in the epidermis, once this balance is disturbed and a melanoma has developed, melanoma cells may take over the control of their epidermal tumour microenvironment. Finally, there are subcompartments within tumours with different microenvironmental milieu defined by their access to oxygen and nutrients. Therefore, different melanoma cells within a tumour face different microenvironments. Interactions between melanoma cells among each other and with the cell types in their microenvironment happen through endocrine and paracrine communication and/or through direct contact via cell-cell and cell-matrix adhesion, and gap junctional intercellular communication (GJIC). Connexins have been identified as key molecules for direct cell-cell communication and are also thought to be important for the release of signalling molecules from cells to the microenvironment. In this review we provide an update of the alterations in cell-cell communication in melanoma and the tumour microenvironment associated with melanoma development and progression.
Collapse
|
|
7
|
Ableser MJ, Penuela S, Lee J, Shao Q, Laird DW. Connexin43 reduces melanoma growth within a keratinocyte microenvironment and during tumorigenesis in vivo. J Biol Chem 2013; 289:1592-603. [PMID: 24297173 DOI: 10.1074/jbc.m113.507228] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Connexins (Cx) have been identified as tumor suppressors or enhancers, a distinction that appears to be dependent on the type and stage of disease. However, the role of connexins in melanoma tumorigenesis and their status during cancer onset and progression remain controversial and unclear. Here, we show that the aggressive B16-BL6 mouse melanoma cell line expresses low basal levels of Cx26 and Cx43, rendering them gap junctional intercellular communication-deficient as elucidated by immunofluorescence, Western blotting, and dye transfer studies. Following ectopic expression of green fluorescent protein-tagged Cx26 and Cx43 in these connexin-deficient melanomas, punctate gap junction-like plaques were evident at sites of cell-cell apposition, and the incidence of dye transfer was significantly increased similar to connexin-rich keratinocytes. We found that the expression of Cx43, but not Cx26, significantly reduced cellular proliferation and anchorage-independent growth from control melanomas, whereas migration was unaffected. Additionally, melanomas expressing Cx43 displayed significantly reduced growth within the in situ-like microenvironment of keratinocytes, despite a lack of heterocellular gap junctional intercellular communication between the two cell types. Furthermore, when grown in vivo in the chicken chorioallantoic membrane, primary tumors derived from Cx43-expressing melanomas were significantly smaller than controls, whereas Cx26-expressing melanomas produced tumors similar to controls. Collectively, these results suggest that Cx43, and not Cx26, can act as a tumor suppressor during melanoma tumorigenesis.
Collapse
|
|
8
|
Gap junctions and non-neoplastic liver disease. J Hepatol 2012; 57:655-62. [PMID: 22609308 DOI: 10.1016/j.jhep.2012.02.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 02/15/2012] [Accepted: 02/17/2012] [Indexed: 12/30/2022]
Abstract
Because of their critical role as goalkeepers of hepatic homeostasis, gap junctions are frequent targets in liver disease. This concept has been demonstrated on many occasions in the light of hepatocarcinogenesis. Relatively little focus has been put on the fate of gap junctions in other liver pathologies, including hepatitis, liver fibrosis and cirrhosis, cholestasis and hepatic ischemia and reperfusion injury. The present paper provides an in-depth description of the multiple changes in expression, localization and function of connexins, the molecular constituents of gap junctions. The use of connexins as biomarkers and therapeutic targets in liver disease is also illustrated.
Collapse
|
|
9
|
Malaguarnera G, Giordano M, Paladina I, Rando A, Uccello M, Basile F, Biondi A, Carnazzo S, Alessandria I, Mazzarino C. Markers of bile duct tumors. World J Gastrointest Oncol 2011; 3:49-59. [PMID: 21528090 PMCID: PMC3083496 DOI: 10.4251/wjgo.v3.i4.49] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 02/23/2011] [Accepted: 03/02/2011] [Indexed: 02/05/2023] Open
Abstract
Biliary tract carcinomas are relatively rare, representing less than 1% of cancers. However, their incidence has increased in Japan and in industrialized countries like the USA. Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease; therapeutic treatment options are often limited and of minimal utility. Recent studies have shown the importance of serum and molecular markers in the diagnosis and follow up of biliary tract tumors. This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors. Some considerable tumor markers are cancer antigen 125, carbohydrate antigen 19-9, carcinoembryonic antigen, chromogranin A, mucin 1, mucin 5, alpha-fetoprotein, claudins and cytokeratins.
Collapse
Affiliation(s)
- Giulia Malaguarnera
- Giulia Malaguarnera, Clorinda Mazzarino, Department of Biomedical Science, University of Catania, via Androne 83, 95124 Catania, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Cogliati B, Da Silva TC, Aloia TPA, Chaible LM, Real-Lima MA, Sanches DS, Matsuzaki P, Hernandez-Blazquez FJ, Dagli MLZ. Morphological and molecular pathology of CCL4-induced hepatic fibrosis in connexin43-deficient mice. Microsc Res Tech 2010; 74:421-9. [PMID: 20830702 DOI: 10.1002/jemt.20926] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Accepted: 07/22/2010] [Indexed: 12/21/2022]
Abstract
Gap junction channels, formed by connexins (Cx), are involved in the maintenance of tissue homeostasis, cell growth, differentiation, and development. Several studies have shown that Cx43 is involved in the control of wound healing in dermal tissue. However, it remains unknown whether Cx43 plays a role in the control of liver fibrogenesis. Our study investigated the roles of Cx43 heterologous deletion on carbon tetrachloride (CCl(4))-induced hepatic fibrosis in mice. We administered CCl(4) to both Cx43-deficient (Cx43(+/-)) and wild-type mice and examined hepatocellular injury and collagen deposition by histological and ultrastructural analyses. Serum biochemical analysis was performed to quantify liver injury. Hepatocyte proliferation was analyzed immunohistochemically. Protein and messenger RNA (mRNA) expression of liver connexins were evaluated using immunohistochemistry as well as immunoblotting analysis and quantitative real-time PCR. We demonstrated that Cx43(+/-) mice developed excessive liver fibrosis compared with wild-type mice after CCl(4) -induced chronic hepatic injury, with thick and irregular collagen fibers. Histopathological evaluation showed that Cx43(+/-) mice present less necroinflammatory lesions in liver parenchyma and consequent reduction of serum aminotransferase activity. Hepatocyte cell proliferation was reduced in Cx43(+/-) mice. There was no difference in Cx32 and Cx26 protein or mRNA expression in fibrotic mice. Protein expression of Cx43 increased in CCl(4)-treated mice, although with aberrant protein location on cytoplasm of perisinusoidal cells. Our results demonstrate that Cx43 plays an important role in the control and regulation of hepatic fibrogenesis.
Collapse
Affiliation(s)
- Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo 05508-900, Brazil.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Rodrigues ADS, Dagli MLZ, Avanzo JL, Moraes HPD, Mackowiak II, Hernandez-Blazquez FJ. Expression and distribution of connexin 32 in rat liver with experimentally induced fibrosis. PESQUISA VETERINARIA BRASILEIRA 2009. [DOI: 10.1590/s0100-736x2009000400013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The connexin 32 (Cx32) is a protein that forms the channels that promote the gap junction intercellular communication (GJIC) in the liver, allowing the diffusion of small molecules through cytosol from cell-to-cell. Hepatic fibrosis is characterized by a disruption of normal tissue architeture by cellular lesions, and may alter the GJIC. This work aimed to study the expression and distribution of Cx32 in liver fibrosis induced by the oral administration of dimethylnitrosamine in female Wistar rats. The necropsy of the rats was carried out after five weeks of drug administration. They presented a hepatic fibrosis state. Sections from livers with fibrosis and from control livers were submitted to immunohistochemical, Real Time-PCR and Western-Blot analysis to Cx32. In fibrotic livers the Cxs were diffusely scattered in the cytoplasm, contrasting with the control livers, where the Cx32 formed junction plaques at the cell membrane. Also it was found a decrease in the gene expression of Cx32 without reduction in the protein quantity when compared with controls. These results suggest that there the mechanism of intercellular communication between hepatocytes was reduced by the fibrotic process, which may predispose to the occurrence of a neoplastic process, taken in account that connexins are considered tumor suppressing genes.
Collapse
|
|
12
|
Mosnier JF, Kandel C, Cazals-Hatem D, Bou-Hanna C, Gournay J, Jarry A, Laboisse CL. N-cadherin serves as diagnostic biomarker in intrahepatic and perihilar cholangiocarcinomas. Mod Pathol 2009; 22:182-90. [PMID: 18622386 DOI: 10.1038/modpathol.2008.123] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
As a definite immunoprofile of this tumor is missing, the histopathologic diagnosis of intrahepatic cholangiocarcinoma is difficult. The aim of this study was to explore E- and N-cadherin expressions in intrahepatic bile duct tumors, and to determine their potential interest in differential diagnosis. Normal liver tissue, 5 cirrhosis with ductular reaction, 5 focal nodular hyperplasia, 5 bile duct hamartomas, 5 bile duct adenomas, and 45 intrahepatic cholangiocarcinomas from Caucasian patients were studied. Tissue-microarrays including 20 esophageal, 86 gastric, 8 small bowel, 64 colonic, 18 pancreatic, 6 gallbladder, and 7 extrahepatic biliary tract adenocarcinomas, 22 hepatocellular carcinomas, and normal tissues were constructed. Immunohistochemistry was performed using E-cadherin, N-cadherin, NCAM, Hep Par1, and cytokeratins 7, 19 and 20. Immunoblot analysis of frozen liver tissues was performed to control the specificity of E- and N-cadherin antibodies used. In normal liver, epithelial cells of intrahepatic bile ducts, whatever their caliber, as well as hepatocytes, coexpressed E- and N-cadherins at their plasma membranes. In cirrhosis, ductular reactions completely expressed E- and N-cadherins. All the benign lesions and 30 of the 45 intrahepatic cholangiocarcinomas (23/29 peripheral and 7/16 hilar) also expressed N-cadherin. E-cadherin was detected in all the lesions. The expression of N-cadherin at the plasma membrane of tumor cells was significantly more frequent in peripheral than in hilar intrahepatic cholangiocarcinomas (P=0.003). Among noncholangiocarcinomas, only 1% gastric and 66% gallbladder adenocarcinomas and all the hepatocellular carcinomas expressed N-cadherin at the membrane of tumor cells. Finally, for the diagnosis of intrahepatic cholangiocarcinomas, the specificity value of membranous expression of N-cadherin was 88%, whereas that of the combination cytokeratin 7/membranous N-cadherin was 98%. In the gastrointestinal and liver tract, membranous N-cadherin is restricted to the hepatocytes and intrahepatic biliary cells. In combination with cytokeratin 7 and Hep Par1, N-cadherin is a reliable tool for the histopathological diagnosis of primary hepatic tumors.
Collapse
|
|
13
|
Udaka N, Miyagi Y, Ito T. Connexin expression in mouse lung tumor. Cancer Lett 2007; 246:224-9. [PMID: 16580773 DOI: 10.1016/j.canlet.2006.02.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2005] [Revised: 02/24/2006] [Accepted: 02/24/2006] [Indexed: 10/24/2022]
Abstract
Gap junction intercellular communication (GJIC) is considered to play roles in regulation of homeostasis, development and differentiation of many tissues. In the present study, using reverse transcription-polymerase chain reaction (RT-PCR) and in situ RT-PCR, we examined expression of Connexins (Cx26, 32, 37, 40, 43 and 45) in the normal lung and lung tumors of mice to determine whether their expressions change during lung tumorigenesis. Cx26, 32 and 40 were expressed similarly in the normal lung tissue and tumors with smaller size (0.5-1.5mm) though expression of Cx32 and 40 decreased in tumors with larger size (>2.5mm). Cx26 was undetectable in larger size tumors. Cx37 and 45 were expressed in both normal lung and larger size tumors but no expression was seen in smaller size tumors. Cx43 was similarly detectable in normal lung, smaller size tumor and larger size tumor, but western blotting showed that Cx43 was phosphorylated during lung tumorigenesis. Thus, it is likely that alteration of expression of these Cx may be involved in expression of the neoplastic phenotype.
Collapse
Affiliation(s)
- Naoko Udaka
- Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto, Japan.
| | | | | |
Collapse
|
|
14
|
Christiansen H, Koenig S, Krause P, Hermann RM, Rave-Frank M, Proehl T, Becker H, Hess CF, Schmidberger H. External-beam radiotherapy as preparative regimen for hepatocyte transplantation after partial hepatectomy. Int J Radiat Oncol Biol Phys 2006; 65:509-16. [PMID: 16690433 DOI: 10.1016/j.ijrobp.2006.01.040] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2005] [Revised: 01/11/2006] [Accepted: 01/23/2006] [Indexed: 12/25/2022]
Abstract
PURPOSE The transplantation of donor hepatocytes is considered a promising option to correct chronic liver failure through repopulation of the diseased organ. This study describes a novel selective external-beam irradiation technique as a preparative regimen for hepatocyte transplantation. METHODS AND MATERIALS Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were preconditioned with external-beam single-dose irradiation (25 Gy) delivered to two thirds of the liver. Four days later, a one-third partial hepatectomy (PH) was performed to resect the untreated liver section, and 15 million wild-type (DPPIV+) hepatocytes were transplanted via the spleen into the recipient livers. The degree of donor-cell integration and growth was studied 8 h, 3 days, and 5 and 12 weeks after transplantation. RESULTS Transplanted hepatocytes integrated rapidly into the irradiated liver and proliferated as clusters, finally repopulating the host liver to approximately 20% hepatocyte mass. After 12 weeks, donor cells and their numerous descendents were fully integrated and expressed functional markers to the same extent as host hepatocytes. CONCLUSIONS We demonstrate that external-beam liver irradiation is sufficient to achieve partial repopulation of the host liver after hepatocyte transplantation, under the additional stimulus of one-third PH. The method described has potentially good prospects for its application in a clinically viable form of treatment.
Collapse
Affiliation(s)
- Hans Christiansen
- Department of Radiotherapy, University Hospital Goettingen, Goettingen, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Mesnil M, Crespin S, Avanzo JL, Zaidan-Dagli ML. Defective gap junctional intercellular communication in the carcinogenic process. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2005; 1719:125-45. [PMID: 16359943 DOI: 10.1016/j.bbamem.2005.11.004] [Citation(s) in RCA: 248] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2005] [Revised: 11/07/2005] [Accepted: 11/10/2005] [Indexed: 01/07/2023]
Abstract
Gap junctions are membrane structures made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules. Nearly 40 years ago, the loss of functional gap junctions has been described in cancer cells and led to the hypothesis that such type of intercellular communication is involved in the carcinogenesis process. From this time, a lot of data has been accumulated confirming that gap junctions are frequently decreased or absent in cancer cells whatever their tissue and species origins. Here, we review such data by insisting on the possible links existing between altered gap-junctional intercellular communication capacity (or the altered expression of their constitutive proteins, the connexins) and the stages of cancer progression in various cancer models. Then, we analyse particular aspects of the disturbance of connexin-mediated communication in cancer such as the cytoplasmic localization of connexins, the lack of heterologous communication between cancer cells and normal cells, the role of connexin gene mutations in cancer. In a separate part of the review, we also analyse the disturbance of gap-junctional intercellular communication during the late stages of cancer (invasion and metastasis processes).
Collapse
Affiliation(s)
- Marc Mesnil
- Equipe Interactions et Communications Cellulaires, Institut de Physiologie et Biologie Cellulaires, CNRS-UMR 6187, Université de Poitiers, 40 avenue du Recteur Pineau, 86022 Poitiers cedex, France.
| | | | | | | |
Collapse
|
|
16
|
Sheen IS, Jeng KS, Shih SC, Kao CR, Wang PC, Chen CZ, Chang WH, Wang HY, Shyung LR. Do the expressions of gap junction gene connexin messenger RNA in noncancerous liver remnants of patients with hepatocellular carcinoma correlate with postoperative recurrences? World J Gastroenterol 2005; 11:171-5. [PMID: 15633210 PMCID: PMC4205396 DOI: 10.3748/wjg.v11.i2.171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether the changes of gap junction gene connexin messenger RNA in the noncancerous liver tissue of patients with hepatocellular carcinoma (HCC) could play a significant role in its postresection recurrence.
METHODS: Seventy-nine consecutive patients having undergone curative resection for HCC entered this study. Using a reverse-transcription polymerase chain reaction (RT-PCR)-based assay, connexin (Cx) 26, connexin (Cx) 32 and connexin (Cx) 43 mRNAs were determined prospectively in noncancerous liver tissues from these 79 patients and in the liver tissues from 15 controls. The correlations between connexin mRNA expression and the clinicopathological variables and outcomes (tumor recurrence and recurrence related mortality) were studied.
RESULTS: Compared with liver tissues of control patients, the expression of Cx 32 mRNA in noncancerous liver tissues was significantly lower (mean: 0.715 vs control 1.225, P<0.01), whereas the decreased Cx 26 mRNA (mean: 0.700 vs of control 1.205, P>0.05) and increased Cx 43 mRNA (mean: 0.241 vs control 0.100, P>0.05) had no statistical significance. We defined the value of Cx 32 mRNA or Cx 26 mRNA below 0.800 as a lower value. By multivariate analysis for noncancerous livers, a lower value of Cx 32 mRNA correlated significantly with a risk of HCC recurrence and recurrence-related mortality. The lower value of Cx 26 mRNA did not correlate with recurrence and mortality. The increased value of Cx43 mRNA also did not correlate with postoperative recurrence and recurrence-related mortality. By multivariate analysis, other significant predictors of HCC recurrence included vascular permeation, cellular dedifferentiation, and less encaps-ulation. The other significant parameter of recurrence related mortality was vascular permeation.
CONCLUSION: The decreased expression of Cx 32 mRNA in noncancerous liver tissues plays a significant role in the prediction of postoperative recurrence of HCC.
Collapse
Affiliation(s)
- I-Shyan Sheen
- Division of Hepatogastroenterology, Chang Gung Memorial Hospital, Taipei, Taiwan, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
Under normal homeostasis, melanocyte growth and behaviour is tightly controlled by the surrounding keratinocytes. Keratinocytes regulate melanocyte behaviour through a complex system of paracrine growth factors and cell-cell adhesion molecules. Pathological changes, leading to development of malignant melanoma, upset this delicate homeostatic balance and can lead to altered expression of cell-cell adhesion and cell-cell communication molecules. In particular, there is a switch from the E-cadherin-mediated keratinocyte-melanocyte partnership to the N-cadherin-mediated melanoma-melanoma and melanoma-fibroblast interaction. Other changes include the alteration in the gap junctions formed between the melanocyte and keratinocyte. Changes in the connexin expression, in particular the loss of connexin 43, may result in a reduction or a loss of gap junctional activity, which is thought to contribute towards tumour progression. In the current review we describe the alterations in cell-cell adhesion and communication associated with melanoma development and progression, and discuss how a greater understanding of these processes may aid the future therapy of this disease.
Collapse
Affiliation(s)
- Nikolas K Haass
- The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | | | | |
Collapse
|
|
18
|
Koenig S, Stoesser C, Krause P, Becker H, Markus PM. Liver repopulation after hepatocellular transplantation: integration and interaction of transplanted hepatocytes in the host. Cell Transplant 2005; 14:31-40. [PMID: 15789660 DOI: 10.3727/000000005783983322] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The mechanisms of donor hepatocyte integration into recipient liver are not fully understood. We investigated mechanisms of both the integration and interaction of transplanted hepatocytes with host liver cells as well as the repopulation of the host organ following intraportal transplantation. Mature hepatocytes were injected into the portal vein of dipeptidylpeptidase IV (DPPIV)-deficient rats pretreated with retrorsine and subjected to 30% partial hepatectomy to ensure selective donor growth. The degree of integration and proliferation was studied by colocalizing transplanted cells (DPPIV positive) with connexin 32, MMP-2, and OX-43 (multilayer immunofluorescence imaging). FACS analysis was established to assess the extent of repopulation quantitatively. Transplanted hepatocytes reached the distal portal spaces and sinusoids within 1 h after injection. A small proportion of cells succeeded in traversing the endothelial barrier through mechanical disruption in both locations. Transplanted hepatocytes lost their membrane-bound gap junctions (connexin 32) during this process. Successful integration of the donor cells required up to 5 days, heralded by gap junction reconstitution and the specific basolateral membrane expression of DPPIV. MMP-2 degraded the extracellular matrix in close proximity to donor cells, providing space for cell division. FACS analysis revealed that more than 37% of the liver was repopulated by cells derived from donors at 2 months after transplantation. Our data demonstrate a high degree of donor cell repopulation of the host organ and provide valuable insight into the specific mechanisms of donor cell integration. Connexin 32 expression in transplanted hepatocytes may serve as an indicator of their effective incorporation and communication within the recipient liver. FACS analysis reveals an accurate method to determine quantitatively the extent of liver repopulation.
Collapse
Affiliation(s)
- Sarah Koenig
- Department of General Surgery, Georg-August-University Goettingen, 37099 Germany.
| | | | | | | | | |
Collapse
|
|
19
|
Sheen IS, Jeng KS, Wang PC, Shih SC, Chang WH, Wang HY, Chen CC, Shyung LR. Are gap junction gene connexins 26, 32 and 43 of prognostic values in hepatocellular carcinoma? A prospective study. World J Gastroenterol 2004; 10:2785-90. [PMID: 15334670 PMCID: PMC4572102 DOI: 10.3748/wjg.v10.i19.2785] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2004] [Revised: 02/16/2004] [Accepted: 02/23/2004] [Indexed: 12/15/2022] Open
Abstract
AIM To investigate the prognostic value of the expression of connexin (Cx) 26, 32 and 43 messenger RNA (mRNA) in hepatocellular carcinoma (HCC) tissues. METHODS Using a reverse-transcriptase polymerase chain reaction (RT-PCR), Cx 26, Cx 32 and Cx 43 mRNAs were determined in the liver tissues of 15 controls and in HCC tissues of 25 patients undergoing curative hepatic resection. The patients were followed up clinically. RESULTS Cx 26 and Cx 32 mRNAs were significantly lower in HCC tissues compared with controls (both P<0.01). By multivariate analysis, a lower level of Cx 26 and Cx 32 mRNA correlated significantly with a risk of HCC recurrence (P = 0.033) and recurrence-related mortality (P = 0.031, P = 0.031). Cx 43 mRNA was higher in HCC tissues compared with controls but did not correlate with postoperative recurrence or recurrence-related mortality. Other significant predictors of HCC recurrence included cellular dedifferentiation (P = 0.033), less encapsulation (P = 0.050), vascular permeation (P = 0.046), and daughter nodules (P = 0.046). Significant variables related to recurrence-related mortality consisted of cell dedifferentiation (P = 0.031), vascular permeation (P = 0.048), and daughter nodules (P = 0.048). The levels of Cx 26 and Cx 32 mRNAs correlated significantly with cell differentiation (P = 0.031). CONCLUSION A low expression of Cx 26 and Cx 32 mRNAs in HCC tissues is predictive of postoperative recurrence of HCCs.
Collapse
Affiliation(s)
- I-Shyan Sheen
- Department of Surgery, Mackay Memorial Hospital, No.92, Sec 2,Chung-San North Road, Taipei, Taiwan, China.
| | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Bode HP, Wang L, Cassio D, Leite MF, St-Pierre MV, Hirata K, Okazaki K, Sears ML, Meda P, Nathanson MH, Dufour JF. Expression and regulation of gap junctions in rat cholangiocytes. Hepatology 2002; 36:631-40. [PMID: 12198655 DOI: 10.1053/jhep.2002.35274] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocytes and other digestive epithelia exchange second messengers and coordinate their functions by communicating through gap junctions. However, little is known about intercellular communication in cholangiocytes. The aim of this study was to examine expression and regulation of gap junctions in cholangiocytes. Connexin expression was determined by confocal immunofluorescence in rat bile ducts and in normal rat cholangiocyte (NRC) cells, a polarized cholangiocyte cell line. Intercellular Ca(2+) signaling was monitored by fluorescent microscopy. Microinjection studies assessed regulation of gap junction permeability in NRC cells and in SKHep1 cells, a liver-derived cell line engineered to express connexin 43. Immunochemistry showed that cholangiocytes from normal rat liver as well as the NRC cells express connexin 43. Localization of apical, basolateral, and tight junction proteins confirmed that NRC cells are well polarized. Apical exposure to ATP induced Ca(2+) oscillations that were coordinated among neighboring NRC cells, and inhibition of gap junction conductance desynchronized the Ca(2+) oscillations. NRC cells transfected with a connexin 43 antisense were significantly less coupled. Transcellular dye spreading was inhibited by activation of protein kinase A or protein kinase C. The same was observed in transfected SKHep1 cells, which expressed only connexin 43. Rat cholangiocytes and NRC cells express connexin 43, which permits synchronization of Ca(2+) signals among cells. Permeability of connexin 43-gap junctions is negatively regulated by protein kinases A and C. In conclusion, cholangiocytes have the capacity for intercellular communication of second messenger signals via gap junctions in a fashion that is under hormonal control.
Collapse
Affiliation(s)
- Hans-Peter Bode
- Department of Gastroenterology, University of Bern, Bern, Switzerland
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Hsu M, Andl T, Li G, Meinkoth JL, Herlyn M. Cadherin repertoire determines partner-specific gap junctional communication during melanoma progression. J Cell Sci 2000; 113 ( Pt 9):1535-42. [PMID: 10751145 DOI: 10.1242/jcs.113.9.1535] [Citation(s) in RCA: 121] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Reduced gap junction activity has long been implicated in tumorigenesis. To elucidate the potential role of intercellular communication in melanoma development, we examined gap junctional capability of melanocytic cells from various stages of tumor progression in coculture models using dye transfer assays. Normal melanocytes coupled with keratinocytes by gap junctional formation, whereas melanoma cells did not. Instead, melanoma cells communicated among themselves and with fibroblasts. This switch in communication partners coincided with a shift from E-cadherin to N-cadherin expression during melanoma development. Forced expression of E-cadherin by adenoviral gene transfer in N-cadherin-expressing melanoma cells restored gap junctional compatibility with keratinocytes. Our data suggest that (1) melanocyte transformation is associated with loss of the pre-existing gap junctional activity with keratinocytes but a concomitant gain of communication with a newly juxtaposed cell type, the fibroblasts, (2) the specificity of gap junctional formation during melanoma development is determined by the cadherin profile on the melanocytic cells and (3) the overall gap junctional activity of melanocytic cells is not reduced with transformation.
Collapse
Affiliation(s)
- M Hsu
- The Wistar Institute, Philadelphia, PA 19104, USA
| | | | | | | | | |
Collapse
|
|
22
|
Endo K, Ueda T, Ueyama J, Ohta T, Terada T. Immunoreactive E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin proteins in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, and patients' survival. Hum Pathol 2000; 31:558-65. [PMID: 10836294 DOI: 10.1053/hp.2000.6683] [Citation(s) in RCA: 122] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
We evaluated the immunohistochemical expression status of E-cadherin, alpha-catenin, beta-catenin, and gamma-catenin, and the relationship with tumor grade, clinicopathologic parameters, and patients' survival, in 107 surgically resected hepatocellular carcinoma (HCC), using a semiquantitative scoring system. These molecules were largely located at the cell membrane of HCC cells. Compared with expression in nontumorous liver, E-cadherin showed underexpression, whereas alpha-, beta-, and gamma-catenins showed overexpression in most HCC. E-cadherin expression significantly correlated inversely with HCC histological grade, being the highest in well-differentiated HCC. In contrast, alpha-, beta-, and gamma-catenins' expression significantly correlated positively with HCC grade, being the highest in poorly differentiated HCC. Significant positive correlations were found between gamma-catenin high expression and capsular invasion or presence of satellite nodules, and between beta-catenin high expression and vascular invasion. Kaplan-Meier examination of patients' survival indicated that HCC patients with underexpression of E-cadherin, alpha-catenin, and gamma-catenin, and patients with overexpression of beta-catenin, had poor survival rates. These results suggest that E-cadherin is downregulated while the 3 catenins are upregulated in HCC, that E-cadherin expression inversely correlates with HCC grade while the 3 catenins' expression positively correlates with HCC grade, and that HCC patients with downregulation of E-cadherin, alpha-catenin, and gamma-catenin and HCC patients with upregulation of beta-catenin have poor prognosis.
Collapse
Affiliation(s)
- K Endo
- Second Department of Pathology, Tottori University, Faculty of Medicine, Yonago, Japan
| | | | | | | | | |
Collapse
|
|
23
|
Jinn Y, Ichioka M, Marumo F. Expression of connexin32 and connexin43 gap junction proteins and E-cadherin in human lung cancer. Cancer Lett 1998; 127:161-9. [PMID: 9619873 DOI: 10.1016/s0304-3835(98)00032-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We used immunohistochemical staining to examine the expression of the gap junction proteins connexin32 and connexin43 and of the intercellular adhesion molecule, E-cadherin, that is thought to be a prerequisite for gap junctional intercellular communication (GJIC), in 24 specimens of human lung cancer. Connexin32 was not found in cancer tissue and there were significantly fewer spots of connexin43 in the poorly differentiated versus the well differentiated (P = 0.0005) and moderately differentiated (P = 0.0002) adenocarcinomas and in the poorly differentiated versus the well differentiated (P = 0.0182) and moderately differentiated (P = 0.004) squamous cell carcinomas of the lung. E-Cadherin was expressed in all but three cases of poorly differentiated non-small cell lung cancer that showed a heterogeneously decreased expression of E-cadherin. These findings suggest that GJIC is decreased in poorly differentiated non-small cell lung cancer.
Collapse
Affiliation(s)
- Y Jinn
- Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, Japan
| | | | | |
Collapse
|
|
24
|
Nakata Y, Iwai M, Kimura S, Shimazu T. Prolonged decrease in hepatic connexin32 in chronic liver injury induced by carbon tetrachloride in rats. J Hepatol 1996; 25:529-37. [PMID: 8912153 DOI: 10.1016/s0168-8278(96)80213-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND/AIMS Our previous study indicated that the amount of connexin32, the major gap-junctional protein of rat liver, is transiently reduced in acute liver injury after single administration of hepatotoxic chemicals. This study was designed to examine alteration in the expression of connexin32 in chronic liver injury, unassociated with hepatocyte proliferation. METHODS Rats were injected with carbon tetrachloride (CCI4, 0.5 ml/kg) twice a week for 12 weeks. After cessation of CCI4 injection, hepatic contents of connexin32 and its mRNA levels were measured by immunoblotting as well as immunohistochemical examination and by Northern-blot analysis. RESULTS The plasma alanine-aminotransferase activity was increased from 30 U/I to about 1000 U/l after 12 weeks of CCI4 injections, but recovered nearly to normal level in 7 days after cessation of the injection. Liver specimens 12 days after the last CCI4 injection appeared cirrhotic with a marked increase in fibrosis. Connexin32 contents in these livers decreased to about 37% of controls. The significant decrease in connexin32 content was sustained for at least 30 days and recovered to the control level by 60 days. The alteration of connexin32 content in chronically injured liver was confirmed immunohistochemically. The level of connexin32-mRNA, however, was not reduced, but rather increased by chronic injection of CCI4. CONCLUSION The results suggest that intercellular communication is disturbed in chronic liver injury, lasting even after recovery from the acute phase of injury. Since the mRNA levels of connexin32 were sustained, the prolonged decrease in connexin32 contents in these livers might be due to a post-transcriptional change that causes decrease in protein synthesis or a derangement of post-translational controls.
Collapse
Affiliation(s)
- Y Nakata
- Department of Medical Biochemistry, Ehime University School of Medicine, Japan
| | | | | | | |
Collapse
|