RRC ID 59671
Author Akizuki R, Eguchi H, Endo S, Matsunaga T, Ikari A.
Title ZO-2 Suppresses Cell Migration Mediated by a Reduction in Matrix Metalloproteinase 2 in Claudin-18-Expressing Lung Adenocarcinoma A549 Cells.
Journal Biol Pharm Bull
Abstract Abnormal expression of the tight junctional components claudins (CLDNs) is observed in various malignant tissues. We reported recently that CLDN18 expression is down-regulated in human lung adenocarcinoma tissues. In the present study, we investigated the biological functions of CLDN18 using lung adenocarcinoma A549 cells. Microarray analysis showed that CLDN18 increases zonula occludens (ZO)-2 expression in A549 cells. The ectopic expression of CLDN18 increased nuclear ZO-2 levels, which were inhibited by N-[2-[[3-(4-bromophenyl)-2-propen-1-yl]amino]ethyl]5-isoquinolinesulfonamide (H-89), a nonspecific protein kinase A (PKA) inhibitor, but not by a PKA inhibitor 14-22 amide. In addition, dibutyryl cyclic adenosine monophosphate, an analogue of PKA, did not increase ZO-2 levels. These results suggest that H-89 sensitive factors without PKA are involved in the CLDN18-induced elevation of ZO-2. The cell cycle was affected by neither ZO-2 knockdown in CLDN18-expresssing A549 (CLDN18/A549) cells nor ZO-2 overexpression in A549 cells, suggesting that ZO-2 does not play an important role in the regulation of cell proliferation. The introduction of ZO-2 small interfering RNA (siRNA) into CLDN18/A549 cells increased migration, the expression and activity of matrix metalloproteinase 2 (MMP2), and the reporter activity of an MMP2 promoter construct. Furthermore, H-89 enhanced both mRNA levels and reporter activity of MMP2 in CLDN18/A549 cells. These results suggested that a reduction in CLDN18-dependent ZO-2 expression enhances MMP2 expression in lung adenocarcinoma cells, resulting in the promotion of the cell migration. CLDN18 may be a novel marker for metastasis in lung adenocarcinoma.
Volume 42(2)
Pages 247-254
Published 2019-1-1
DOI 10.1248/bpb.b18-00670
PMID 30713254
MeSH A549 Cells Adenocarcinoma of Lung / metabolism* Adenocarcinoma of Lung / pathology Cell Line, Tumor Cell Movement / physiology Cell Proliferation / physiology Chromones / pharmacology Claudins / genetics Claudins / metabolism* Cyclic AMP Response Element-Binding Protein / metabolism Humans Isoquinolines / pharmacology Matrix Metalloproteinase 2 / metabolism* Morpholines / pharmacology Oligonucleotide Array Sequence Analysis Oncogene Protein v-akt Phosphorylation Protein Kinase Inhibitors / pharmacology Sulfonamides / pharmacology Zonula Occludens-2 Protein / antagonists & inhibitors Zonula Occludens-2 Protein / biosynthesis* Zonula Occludens-2 Protein / genetics Zonula Occludens-2 Protein / metabolism
IF 1.54
Times Cited 0
Human and Animal Cells A549