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NIK- and IKKβ-binding protein promotes colon cancer metastasis by activating the classical NF-κB pathway and MMPs

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Tumor Biology

Abstract

The nuclear factor (NF)-κB pathway has been implicated in colorectal cancer (CRC) tumorigenesis. Here, we investigated the role of a novel NIK- and IKKβ-binding protein (NIBP) in CRC metastasis through activation of the canonical NF-κB pathway. NIBP, p-p65, and matrix metalloproteases (MMPs) were assessed by immunohistochemistry in 114 CRC tissues, and the time to metastasis was recorded after surgery. Furthermore, the activity of the NF-κB pathway, MMP expression, and the metastatic potential of HT-29 cells overexpressing NIBP after treatment with the NF-κB inhibitor pyrrolidinecarbodithioic acid (PDTC) were examined in vitro and in vivo. NIBP-positive CRC exhibited a higher rate of metastasis, and the time to metastasis of NIBP-positive patients was shorter in the early tumor, lymph node, metastasis (TNM) stages (I and II), while NIBP and p-p65 expression was higher in later TNM stages (III and IV). However, there was no difference in terms of the positive rate of NIBP, p-p65, MMP-2, and serum carcinoembryonic antigen (CEA) level was no difference in the pathological type, gender, tumor location, or size. The NF-κB pathway, MMP-2 and MMP-9 activity, and cell motility and invasion were increased in NIBP-overexpressing cells, even after PDTC treatment. Moreover, these cells exhibited high metastasis in mice, and p-p65, MMP-2, and MMP-9 expression levels were elevated in the primary tumor and liver metastases. In conclusion, NIBP overexpression increases the CRC metastatic potential through activation of the NF-κB pathway and increasing MMP-2 and MMP-9 expression. In addition, NIBP overexpression, at least in part, may reduce inhibition of the canonical NF-κB pathway and MMPs caused by PDTC treatment.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 81260365), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2011), Guangzhou Pilot Project of Clinical and Translational Research Center (Early Gastrointestinal Cancers, No. 7415696196402), and Guangdong Province Universities and Colleges Major National Training Project (No. 2014GKXM026).

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Authors and Affiliations

  1. Department of Gastroenterology, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510000, China

    Mengbin Qin, Aimin Li & Side Liu

  2. Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning, 530000, China

    Mengbin Qin, Shiquan Liu, Chunyan Xu, Lin Tan & Jiean Huang

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  1. Mengbin Qin
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  2. Shiquan Liu
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  3. Aimin Li
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  7. Side Liu
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Correspondence to Jiean Huang or Side Liu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Qin, M., Liu, S., Li, A. et al. NIK- and IKKβ-binding protein promotes colon cancer metastasis by activating the classical NF-κB pathway and MMPs. Tumor Biol. 37, 5979–5990 (2016). https://doi.org/10.1007/s13277-015-4433-8

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  • DOI: https://doi.org/10.1007/s13277-015-4433-8

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