title: MKK4 acts as a potential tumor suppressor in ovarian cancer.
abstract: Our previous studies indicate that loss of MKK4 expression is associated with the progression of ovarian cancer. However, direct evidence that MKK4 inhibits the malignant phenotype of ovarian cancer cells is limited. In the current study, we investigated the mechanism relating loss of MKK4 expression to the development of ovarian cancer. Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected TOV-21G cells, a line with a homozygous deletion of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in TOV-21G cells resulted in reduced proliferative activity and increased apoptosis. To confirm that MKK4 expression related to tumor suppress function, we used two independent but complementary approaches. MKK4 gene knockdown in OVK18#2 and MDAH2774 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOV-21G. Similar results were produced in tumor xenografts in nude mice. These results indicated that MKK4 acts as a tumor suppressor and may represent an important therapeutic target for the treatment of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Shimane University School of Medicine, Enyacho 89-1, Izumo, Shimane, 6938501, Japan.
authors.forename: Shamima
authors.initials: S
authors.lastname: Yeasmin
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Mohammed Tanjimur
authors.initials: MT
authors.lastname: Rahman
authors.forename: Munmun
authors.initials: M
authors.lastname: Rahman
authors.forename: Masako
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Atsuko
authors.initials: A
authors.lastname: Katagiri
authors.forename: Kouji
authors.initials: K
authors.lastname: Iida
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakayama
authors.forename: Kohji
authors.initials: K
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human