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

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6728

1949-2553

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, Deok Ryong Kim,

Mechanisms of cancer metastasis

// Hae Sook Noh 1, * , Young-Sool Hah 2, * , Ji Hye Ha 1 , Min Young Kang 3 , Sahib Zada 1 , Sun Young Rha 4 , Sang Soo Kang 5 , Hyun Joon Kim 5 , Jae-Yong Park 6 , June-Ho Byun 7 , Jong Ryeal Hahm 8 , Jeong Kyu Shin 3 , Sang-Ho Jeong 9 , Young-Joon Lee 9 , Deok Ryong Kim 1 1 Department of Biochemistry and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea 2 Biomedical Research Institute of Gyeongsang National Hospital, Gyeongsang National University, JinJu, Republic of Korea 3 Department of Obstetrics and Gynecology, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea 4 Department of Internal Medicine, Yonsei Cancer Center, Songang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea 5 Department of Anatomy and Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea 6 School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Republic of Korea 7 Department of Oral and Maxillofacial Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea 8 Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, Republic of Korea 9 Department 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.