MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis

Yingmei Wang, Limei Hu, Ping Ji, Fei Teng, Wenyan Tian, Yuexin Liu, David Cogdell, Jinsong Liu, Anil K. Sood, Russell Broaddus, Fengxia Xue, Wei Zhang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Endometrial 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. Methods: Immunohistochemistry 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. Results: We 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. Conclusions: MIIP 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.

Original languageEnglish (US)
Article number112
JournalJournal of Hematology and Oncology
Volume9
Issue number1
DOIs
StatePublished - Oct 19 2016

Fingerprint

rac1 GTP-Binding Protein
Endometrial Neoplasms
Cytoskeleton
Neoplasm Metastasis
Proteins
Cell Movement
Guanosine Triphosphate
Small Interfering RNA

Keywords

  • Endometrial cancer
  • Migration
  • MIIP
  • Rac1/PAK1 pathway
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis. / Wang, Yingmei; Hu, Limei; Ji, Ping; Teng, Fei; Tian, Wenyan; Liu, Yuexin; Cogdell, David; Liu, Jinsong; Sood, Anil K.; Broaddus, Russell; Xue, Fengxia; Zhang, Wei.

In: Journal of Hematology and Oncology, Vol. 9, No. 1, 112, 19.10.2016.

Research output: Contribution to journalArticle

Wang, Y, Hu, L, Ji, P, Teng, F, Tian, W, Liu, Y, Cogdell, D, Liu, J, Sood, AK, Broaddus, R, Xue, F & Zhang, W 2016, 'MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis', Journal of Hematology and Oncology, vol. 9, no. 1, 112. https://doi.org/10.1186/s13045-016-0342-6
Wang, Yingmei ; Hu, Limei ; Ji, Ping ; Teng, Fei ; Tian, Wenyan ; Liu, Yuexin ; Cogdell, David ; Liu, Jinsong ; Sood, Anil K. ; Broaddus, Russell ; Xue, Fengxia ; Zhang, Wei. / MIIP remodels Rac1-mediated cytoskeleton structure in suppression of endometrial cancer metastasis. In: Journal of Hematology and Oncology. 2016 ; Vol. 9, No. 1.
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abstract = "Background: Endometrial 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. Methods: Immunohistochemistry 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. Results: We 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. Conclusions: MIIP 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.",
keywords = "Endometrial cancer, Migration, MIIP, Rac1/PAK1 pathway, Tumor suppressor gene",
author = "Yingmei Wang and Limei Hu and Ping Ji and Fei Teng and Wenyan Tian and Yuexin Liu and David Cogdell and Jinsong Liu and Sood, {Anil K.} and Russell Broaddus and Fengxia Xue and Wei Zhang",
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AU - Wang, Yingmei

AU - Hu, Limei

AU - Ji, Ping

AU - Teng, Fei

AU - Tian, Wenyan

AU - Liu, Yuexin

AU - Cogdell, David

AU - Liu, Jinsong

AU - Sood, Anil K.

AU - Broaddus, Russell

AU - Xue, Fengxia

AU - Zhang, Wei

PY - 2016/10/19

Y1 - 2016/10/19

N2 - Background: Endometrial 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. Methods: Immunohistochemistry 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. Results: We 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. Conclusions: MIIP 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.

AB - Background: Endometrial 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. Methods: Immunohistochemistry 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. Results: We 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. Conclusions: MIIP 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.

KW - Endometrial cancer

KW - Migration

KW - MIIP

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KW - Tumor suppressor gene

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