title: 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.
abstract: 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.
authors.affiliation: General Surgery Center of PLA, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.forename: Zhi-hong
authors.initials: ZH
authors.lastname: Peng
authors.forename: Pei-wu
authors.initials: PW
authors.lastname: Yu
authors.forename: Ge
authors.initials: G
authors.lastname: Yu
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: Dong-zhu
authors.initials: DZ
authors.lastname: Zeng
authors.forename: Yong-liang
authors.initials: YL
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Ying-xue
authors.initials: YX
authors.lastname: Hao
authors.forename: Hua-xing
authors.initials: HX
authors.lastname: Luo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D002450:Cell Communication; D002465:Cell Movement; D018920:Coculture Techniques; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human
references.citation: Cell Calcium. 2008 Nov;44(5):453-64
references.pmid: 18417211
references.citation: Med Sci (Paris). 2004 Feb;20(2):197-206
references.pmid: 14997440
references.citation: J Comp Neurol. 2008 Sep 1;510(1):68-78
references.pmid: 18615537
references.citation: Carcinogenesis. 2004 Apr;25(4):473-82
references.pmid: 14656943
references.citation: Zhonghua Zhong Liu Za Zhi. 2007 Oct;29(10):742-7
references.pmid: 18396685
references.citation: Breast Cancer Res. 2005;7(4):R522-34
references.pmid: 15987459
references.citation: FASEB J. 2011 Jan;25(1):255-64
references.pmid: 20876208
references.citation: Int J Biochem Cell Biol. 2011 Oct;43(10):1459-68
references.pmid: 21718795
references.citation: Circ Res. 2009 Jul 31;105(3):223-30
references.pmid: 19644057
references.citation: Br J Surg. 2011 Sep;98(9):1225-35
references.pmid: 21644239
references.citation: J Clin Pathol. 2006 Apr;59(4):429-33
references.pmid: 16567471
references.citation: J Theor Biol. 2010 Mar 7;263(1):45-58
references.pmid: 20005235
references.citation: J Membr Biol. 2007 Aug;218(1-3):107-21
references.pmid: 17661126
references.citation: Nat Rev Cancer. 2010 Jun;10(6):435-41
references.pmid: 20495577
references.citation: Nat Cell Biol. 2001 Jun;3(6):E145-7
references.pmid: 11389456
references.citation: BMC Med. 2008 Jul 22;6:20
references.pmid: 18647409
references.citation: Mol Cancer. 2005 Aug 09;4(1):31
references.pmid: 16091133
references.citation: Glia. 2007 Nov 15;55(15):1554-64
references.pmid: 17823969
references.citation: Cancer Res. 2010 May 15;70(10):4222-32
references.pmid: 20406988
references.citation: Breast Cancer Res Treat. 2007 Nov;106(1):11-7
references.pmid: 17203385
references.citation: Antioxid Redox Signal. 2009 Feb;11(2):323-38
references.pmid: 18834328
references.citation: Biochim Biophys Acta. 2004 Mar 23;1662(1-2):96-101
references.pmid: 15033581
references.citation: Clin Cancer Res. 2008 Feb 1;14(3):677-84
references.pmid: 18245526
references.citation: Cancer Res. 2006 Oct 15;66(20):9886-94
references.pmid: 17047050
references.citation: J Biol Chem. 2006 Mar 24;281(12):7994-8009
references.pmid: 16407179
references.citation: Med Oncol. 2011 Jun;28(2):502-8
references.pmid: 20373058