Oncotarget

Research Papers:

Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity

Hae Sook Noh, Young-Sool Hah, Ji Hye Ha, Min Young Kang, Sahib Zada, Sun Young Rha, Sang Soo Kang, Hyun Joon Kim, Jae-Yong Park, June-Ho Byun, Jong Ryeal Hahm, Jeong Kyu Shin, Sang-Ho Jeong, Young-Joon Lee and Deok Ryong Kim _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:4632-4646. https://doi.org/10.18632/oncotarget.6728

Metrics: PDF 1549 views  |   HTML 1845 views  |   ?  


Abstract

Hae Sook Noh1,*, Young-Sool Hah2,*, Ji Hye Ha1, Min Young Kang3, Sahib Zada1, Sun Young Rha4, Sang Soo Kang5, Hyun Joon Kim5, Jae-Yong Park6, June-Ho Byun7, Jong Ryeal Hahm8, Jeong Kyu Shin3, Sang-Ho Jeong9, Young-Joon Lee9, Deok Ryong Kim1

1Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

2Biomedical Research Institute of Gyeongsang National Hospital, Gyeongsang National University, JinJu, Republic of Korea

3Department of Obstetrics and Gynecology, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

4Department of Internal Medicine, Yonsei Cancer Center, Songang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea

5Department of Anatomy and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

6School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea

7Department of Oral and Maxillofacial Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

8Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

9Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea

*These authors contributed equally to this work

Correspondence to:

Deok Ryong Kim, e-mail: drkim@gnu.ac.kr

Keywords: RKIP, EMT, metastasis, Notch1, ERK

Received: September 02, 2015     Accepted: November 26, 2015     Published: December 22, 2015

ABSTRACT

Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and a prognostic marker in cancers. However, how RKIP acts as a suppressor during metastasis is not fully understood. Here, we show that RKIP activity in cervical and stomach cancer is inversely correlated with endogenous levels of the Notch1 intracellular domain (NICD), which stimulates the epithelial to mesenchymal transition (EMT) and metastasis. The levels of RKIP were significantly decreased in tumor tissues compared to normal tissues, whereas NICD levels were increased. Overexpression of RKIP in several cell lines resulted in a dramatic decrease of NICD and subsequent inhibition of several mesenchymal markers, such as vimentin, N-cadherin, and Snail. In contrast, knockdown of RKIP exhibited opposite results both in vitro and in vivo using mouse models. Nevertheless, knockdown of Notch1 in cancer cells had no effect on the expression of RKIP, suggesting that RKIP is likely an upstream regulator of the Notch1 pathway. We also found that RKIP directly interacts with Notch1 but has no influence on the intracellular level of the γ-secretase complex that is necessary for Notch1 activation. These data suggest that RKIP plays a distinct role in activation of Notch1 during EMT and metastasis, providing a new target for cancer treatment.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 6728