Abstract
BackgroundEndometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system. Migration and invasion inhibitory protein (MIIP) gene was recently discovered candidate tumor suppress gene which located at chromosome 1p36.22. 1p36 deletion was found in many types of tumor including EC. In the present study, we will determine the role and mechanism of MIIP in EC metastasis.MethodsImmunohistochemistry was used to measure MIIP expression in normal and EC tissue. Both gain-of-function (infection) and loss-of-function (siRNA) assays were used to alter MIIP expression levels. The effect of MIIP on cell migration and invasion was measured by transwell assay. F-actin immunofluorescence staining was used to observe the cell morphology. The activation of GTP-loaded Rac1 was evaluated by Rac activity assay kit. Immunoprecipitation/WB was used to measure the interaction between MIIP and PAK1.ResultsWe demonstrate that MIIP expression was significantly decreased in EC patients comparing to the normal ones, and decreased MIIP expression in EC tissues is associated with deep myometrial invasion, advanced stage, and the presence of lymph node metastasis. Using both gain-of-function (infection) and loss-of-function (siRNA) assays, we show that MIIP markedly blocked EC cell migration, whereas loss of MIIP led to increase in EC cell migration. We demonstrate that elevated expression of MIIP resulted in cytoskeleton reorganization with decreased formation of lamellipodia. We also provide evidence that MIIP is a key molecule in directing Rac1 signaling cascades in EC. Ectopically expressed MIIP consistently competed with Rac1-GTP for binding with the PAK1 p21-binding domain. Our data show that MIIP and PAK1 bind each other and that a C-terminal polyproline domain of MIIP is required for PAK1 binding. Deletion of the PAK1-binding domain of MIIP reduced cell migration-inhibiting activity.ConclusionsMIIP may function as a tumor suppressor gene for endometrial carcinoma. MIIP attenuates Rac1 signaling through a protein interaction network, and loss of this regulator may contribute to EC metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0342-6) contains supplementary material, which is available to authorized users.
Highlights
Endometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system
We demonstrate that Migration and invasion inhibitory protein (MIIP) inhibited EC cell migration through blocking of the Ras-related C3 botulinum toxin substrate 1 (Rac1) signal transduction pathway by directly binding to its downstream effector p21-Activating kinase 1 (PAK1), and a C-terminal polyproline domain of MIIP is required for PAK1 binding
Decreased MIIP expression is associated with tumorigenesis and progression of EC To investigate MIIP’s role in EC tumorigenesis and progression, we first evaluated MIIP protein expression in normal endometrium (NE), atypical hyperplasia endometrium (AHE), and EC using an immunohistochemical analysis on tissue microarrays (TMAs)
Summary
Endometrial carcinoma (EC) is one of the most common malignancies of the female reproductive system. Previous studies have shown that MIIP inhibits glioma cell migration and invasion through two mechanisms: (1) attenuating insulin-like growth factor-binding protein 2 (IGFBP2)mediated cell migration [10] and (2) blocking HDAC6 activity and increasing acetylated α-tubulin, which stabilizes microtubules [11]. The activation of Rac and its downstream effectors has been associated with tumor cell migration, invasion, and/or metastasis in breast, ovarian, lung, colorectal, bladder, and ECs [13,14,15,16,17,18,19]. It is not clear how MIIP modulates the Rho GTPase family members
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