Loss of MKK4 expression in ovarian cancer: a potential role for the epithelial to mesenchymal transition.

In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase 4 (MKK4) expression to development of ovarian cancer. Over-expression of the MKK4 gene in TOV-21 G cells, a line with homozygous deletion of MKK4, resulted in morphologic changes in which cells growing in a scattered, fibroblast-like pattern formed tightly packed colonies. Based on a wound healing assay and a Matrigel invasion assay, we determined that both motility and invasiveness of MKK4-transfected TOV-21G cells were significantly reduced compared to control vector-transfected cells. To confirm that MKK4 expression related to tumor invasion resulted from an epithelial to mesenchymal transition (EMT)-like morphological change, we used 2 independent but complementary approaches. MKK4 gene knockdown in MDAH 2774 cells over-expressing MKK4 increased invasion activity. Additionally, engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOVG-21G. Interestingly, we found that MKK4 upregulation caused downregulation of phosphorylated NF-κB and Twist, as well as upregulation of E-cadherin, in TOVG-21G and SKOV3 cells. Reciprocal results were obtained in MDAH 2774 cells with MKK4 knockdown. Our results suggest that MKK4 downregulation causes increased phosphorylation NF-κB. This promotes Twist over-expression, resulting in E-cadherin downregulation that induces EMT in ovarian cancer.
AuthorsShamima Yeasmin, Kentaro Nakayama, Mohammed Tanjimur Rahman, Munmun Rahman, Masako Ishikawa, Atsuko Katagiri, Kouji Iida, Naomi Nakayama, Kohji Miyazaki
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 128 Issue 1 Pg. 94-104 (Jan 1 2011) ISSN: 1097-0215 [Electronic] United States
PMID20309881 (Publication Type: Journal Article)
CopyrightCopyright © 2010 UICC.
Chemical References
  • NF-kappa B
  • RNA, Small Interfering
  • MAP2K4 protein, human
  • MAP Kinase Kinase 4
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement (genetics)
  • Disease Progression
  • Epithelial-Mesenchymal Transition (genetics)
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Hybridization, Fluorescence
  • MAP Kinase Kinase 4 (genetics, metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B (metabolism)
  • Neoplasms, Experimental (enzymology, genetics, pathology)
  • Ovarian Neoplasms (enzymology, genetics, pathology)
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering (genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • Transplantation, Heterologous

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