Journal
TUMOR BIOLOGY
Volume 37, Issue 5, Pages 5979-5990Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1007/s13277-015-4433-8
Keywords
NIBP; NF-kappa B; MMP; Colorectal cancer; Metastasis
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Funding
- National Natural Science Foundation of China [81260365]
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme
- Guangzhou Pilot Project of Clinical and Translational Research Center (Early Gastrointestinal Cancers) [7415696196402]
- Guangdong Province Universities and Colleges Major National Training Project [2014GKXM026]
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The nuclear factor (NF)-kappa B pathway has been implicated in colorectal cancer (CRC) tumorigenesis. Here, we investigated the role of a novel NIK- and IKK beta-binding protein (NIBP) in CRC metastasis through activation of the canonical NF-kappa B 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-kappa B pathway, MMP expression, and the metastatic potential of HT-29 cells overexpressing NIBP after treatment with the NF-kappa B 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-kappa B 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-kappa B pathway and increasing MMP-2 and MMP-9 expression. In addition, NIBP overexpression, at least in part, may reduce inhibition of the canonical NF-kappa B pathway and MMPs caused by PDTC treatment.
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