論文 - 詳細
RRC ID | 38287 |
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著者 | Ishikawa M, Nakayama K, Rahman MT, Rahman M, Katagiri A, Iida K, Miyazaki K. |
タイトル | Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer. |
ジャーナル | Oncology |
Abstract |
OBJECTIVE:In the current study, we investigated the mechanism relating downregulation of mitogen-activated protein kinase kinase-4 (MKK4) expression to the development of endometrial cancer. METHODS:MKK4 expression in endometrial cancer was assessed by immunohistochemistry using 87 paraffin-embedded tissue specimens, and clinical data was collected via a retrospective chart review. MKK4 gene knockdown using silencing RNA and an MKK4 gene transfection system was used to assess MKK4 function in tissue samples of endometrial cancer. RESULTS:Lower expression of MKK4 immunointensity was observed in 63.2% (55/87) of the analyzed tumors. High-grade endometrioid adenocarcinoma (G2 and G3) (p = 0.024), postmenopausal status (p = 0.018), and patient age (≥ 60) (p = 0.012) were significantly correlated with lower MKK4 expression. Patients with lower MKK4 expression in endometrial cancer tissues tended to have a shorter overall survival (p = 0.197). Using cell growth and anchorage-independent assays, we determined that both the growth and colony-forming ability of MKK4-transfected HEC1B cells, a line with a low endogenous expression of MKK4, were significantly reduced compared to control vector-transfected cells. Overexpression of the MKK4 gene in HEC1B cells resulted in reduced cell migration activity in a simulated wound healing assay. To confirm that MKK4 expression is related to tumor suppressor function, we used 2 independent but complementary approaches. MKK4 gene knockdown in JHEM1 cells, which overexpressed MKK4, increased proliferation activity. Additionally, the engineered expression of MKK4 in Ishikawa cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of HEC1B. Similar results were produced in tumor xenografts in nude mice. CONCLUSION:These results indicate that MKK4 acts as a tumor suppressor, and reduced expression of MKK4 may contribute to the development of endometrial cancer. |
巻・号 | 79(3-4) |
ページ | 238-46 |
公開日 | 2010-1-1 |
DOI | 10.1159/000322644 |
PII | 000322644 |
PMID | 21372598 |
MeSH | Adult Aged Aged, 80 and over Animals Blotting, Western Carcinoma, Endometrioid / metabolism* Carcinoma, Endometrioid / pathology Cell Adhesion Cell Movement Cell Proliferation Down-Regulation Endometrial Neoplasms / metabolism* Endometrial Neoplasms / pathology Female Genes, Tumor Suppressor Humans Immunoenzyme Techniques Lymphatic Metastasis MAP Kinase Kinase 4 / antagonists & inhibitors MAP Kinase Kinase 4 / genetics MAP Kinase Kinase 4 / metabolism* Mice Mice, Inbred BALB C Mice, Nude Middle Aged Neoplasm Invasiveness Prognosis RNA, Messenger / genetics RNA, Small Interfering / genetics Retrospective Studies Reverse Transcriptase Polymerase Chain Reaction Survival Rate Tumor Cells, Cultured Xenograft Model Antitumor Assays |
IF | 2.642 |
引用数 | 9 |
WOS 分野 | ONCOLOGY |
リソース情報 | |
ヒト・動物細胞 |