NIBP impacts on the expression of E-cadherin, CD44 and vimentin in colon cancer via the NF-κB pathway

Xu,Chun‑Yan; Qin,Meng‑Bin; Tan,Lin; Liu,Shi‑Quan; Huang,Jie‑An

doi:10.3892/mmr.2016.5165

NIBP impacts on the expression of E-cadherin, CD44 and vimentin in colon cancer via the NF-κB pathway

Authors:
- Chun‑Yan Xu
- Meng‑Bin Qin
- Lin Tan
- Shi‑Quan Liu
- Jie‑An Huang
View Affiliations

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: April 22, 2016 https://doi.org/10.3892/mmr.2016.5165
Pages: 5379-5385

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

NIBP, a novel nuclear factor-κB (NF-κB)-inducing kinase (NIK) and IκB kinase β (IKKβ) binding protein, directly interacts with NIK and IKKβ, and acts as the ʻbridgeʼ of the NF‑κB classical and alternative signaling pathways. However, its influence on epithelial‑mesenchymal transition markers in colon cancer remains to be fully elucidated. The aim of the present study was to investigate the roles of NIBP impacting on the expression of E‑cadherin, CD44 and vimentin. In the present study, the associations between NIBP and E‑cadherin, CD44 and vimentin in clinical samples were analyzed by making pairwise comparisons between normal colon tissue, non‑metastatic colon cancer tissue and metastatic colon cancer tissue. In in vitro experiments, after changing the expression of NIBP in cells, the protein expression levels of CD44, vimentin, E‑cadherin were analyzed by western blot analysis. The results revealed that the protein expression levels of NIBP, CD44 and vimentin were markedly increased, and E‑cadherin was markedly decreased, in metastatic colon cancer tissue compared with normal colon tissue and non‑metastatic colon cancer tissue. Upregulation of NIBP expression decreased the levels of E‑cadherin, whereas the downregulation of NIBP increased E‑cadherin levels, while no significant differences were observed in the levels of CD44 and vimentin. In addition, cells that were treated with the NF‑κB inhibitor, pyrrolidine dithiocarbamate (PDTC), also tended to exhibit increased levels of CD44 and vimentin expression in the NIBP upregulated expression group (29‑NIBP group) compared with the mock group, whereas the expression levels of E‑cadherin, CD44 and vimentin were similar in the NIBP downregulated expression group (116‑NIBPmir group) and the HCT116 blank control group (116‑mock group) on treatment of the cells with tumor necrosis factor‑α. These findings indicated that NIBP, E‑cadherin, CD44 and vimentin are possibly associated with metastasis in colon cancer. When the NF‑κB pathway is not subjected to any interventions, NIBP may predominantly regulate the NF‑κB classical pathway, rather than the alternative pathway. When the classical pathway was completely inhibited, NIBP was able to activate the NF‑κB alternative pathway. NIBP is therefore necessary for the interaction between the NF‑κB classical and alternative pathways. In conclusion, NIBP impacts on the expression levels of E‑cadherin, CD44 and vimentin via the NF‑κB classical and alternative pathways. Therapeutic regimens for patients with colorectal cancer may comprise NIBP inhibitors in the future.

View Figures

View References

1	Cancer Facts & Figures 2015. American Cancer Society; 2015
2	Wang F, Yang JL, Yu KK, Xu M, Xu YZ, Chen L, Lu YM, Fang HS, Wang XY, Hu ZQ, et al: Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma. Mol Cancer. 14:102015. View Article : Google Scholar
3	Zhao Z, Wu MS, Zou C, Tang Q, Lu J, Liu D, Wu Y, Yin J, Xie X, Shen J, et al: Downregulation of MCT1 inhibits tumor growth, metastasis and enhances chemotherapeutic efficacy in osteosarcoma through regulation of the NF-κB pathway. Cancer Lett. 342:150–158. 2014. View Article : Google Scholar
4	Zhang LL, Liu J, Lei S, Zhang J, Zhou W and Yu HG: PTEN inhibits the invasion and metastasis of gastric cancer via down-regulation of FAK expression. Cell Signal. 26:1011–1020. 2014. View Article : Google Scholar : PubMed/NCBI
5	Perkins ND: Oncogenes, tumor suppressors and p52 NF-kappaB. Oncogene. 22:7553–7556. 2003. View Article : Google Scholar : PubMed/NCBI
6	Bonizzi G and Karin M: The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25:280–288. 2004. View Article : Google Scholar : PubMed/NCBI
7	Patke A, Mecklenbräuker I and Tarakhovsky A: Survival signaling in resting B cells. Curr Opin Immunol. 16:251–255. 2004. View Article : Google Scholar : PubMed/NCBI
8	Demchenko YN, Glebov OK, Zingone A, Keats JJ, Bergsagel PL and Kuehl WM: Classical and/or alternative NF-kappaB pathway activation in multiple myeloma. Blood. 115:3541–3552. 2010. View Article : Google Scholar : PubMed/NCBI
9	Hu WH, Pendergast JS, Mo XM, Brambilla R, Bracchi-Ricard V, Li F, Walters WM, Blits B, He L, Schaal SM and Bethea JR: NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. J Biol Chem. 280:29233–29241. 2005. View Article : Google Scholar : PubMed/NCBI
10	Zhang Y, Bitner D, Pontes Filho AA, Li F, Liu S, Wang H, Yang F, Adhikari S, Gordon J, Srinivasan S and Hu W: Expression and function of NIK- and IKK2-binding protein (NIBP) in mouse enteric nervous system. Neurogastroenterol Motil. 26:77–97. 2014. View Article : Google Scholar :
11	Qin M and Liu S, Li A, Xu C, Tan L, Huang J and Liu S: NIK- and IKKbeta-binding protein promotes colon cancer metastasis by activating the classical NF-kappaB pathway and MMPs. Tumour Biol. Nov 23–2015.Epub ahead of print.
12	Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2:442–454. 2002. View Article : Google Scholar : PubMed/NCBI
13	Thompson EW, Newgreen DF and Tarin D: Carcinoma invasion and metastasis: A role for epithelial-mesenchymal transition? Cancer Res. 65:5991–5995; discussion 5995. 2005. View Article : Google Scholar : PubMed/NCBI
14	Gujral TS, Chan M, Peshkin L, Sorger PK, Kirschner MW and MacBeath G: A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell. 159:844–856. 2014. View Article : Google Scholar : PubMed/NCBI
15	Tong W, Sun D, Wang Q and Suo J: Sorcin enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Cell Biochem Biophys. 2015 Jan 8;Epub ahead of print. View Article : Google Scholar
16	Wang X, Wang H, Li G, Song Y, Wang S, Zhu F, Guo C, Zhang L and Shi Y: Activated macrophages down-regulate expression of E-cadherin in hepatocellular carcinoma cells via NF-kappaB/Slug pathway. Tumour Biol. 35:8893–8901. 2014. View Article : Google Scholar : PubMed/NCBI
17	Cheng ZX, Wang DW, Liu T, Liu WX, Xia WB, Xu J, Zhang YH, Qu YK, Guo LQ, Ding L, et al: Effects of the HIF-1α and NF-κB loop on epithelial-mesenchymal transition and chemoresistance induced by hypoxia in pancreatic cancer cells. Oncol Rep. 31:1891–1898. 2014.PubMed/NCBI
18	Li SY: NIBP expression in colorectal cancer tissues and its impact on colon cancer cell proliferation (unpublished PhD thesis). Guangxi Medical University; 2015
19	Tan L: The research of NIBP protein expression and its relationship with the transformation of epithelial-mesenchymal in colorectal cancer tissue (unpublished PhD thesis). Guangxi Medical University; 2015
20	Zheng L, Fu Y, Zhuang L, Gai R, Ma J, Lou J, Zhu H, He Q and Yang B: Simultaneous NF-κB inhibition and E-cadherin upregulation mediate mutually synergistic anticancer activity of celastrol and SAHA in vitro and in vivo. Int J Cancer. 135:1721–1732. 2014. View Article : Google Scholar : PubMed/NCBI
21	Strippoli R, Benedicto I, Foronda M, Perez-Lozano ML, Sánchez-Perales S, López-Cabrera M and Del Pozo MÁ: p38 maintains E-cadherin expression by modulating TAK1-NF-kappaB during epithelial-to-mesenchymal transition. J Cell Sci. 123:4321–4331. 2010. View Article : Google Scholar : PubMed/NCBI
22	Zhang J, Yamada O, Kida S, Matsushita Y, Yamaoka S, Chagan-Yasutan H and Hattori T: Identification of CD44 as a downstream target of noncanonical NF-κB pathway activated by human T-cell leukemia virus type 1-encoded Tax protein. Virology. 413:244–252. 2011. View Article : Google Scholar : PubMed/NCBI
23	Päll T, Pink A, Kasak L, Turkina M, Anderson W, Valkna A and Kogerman P: Soluble CD44 interacts with intermediate filament protein vimentin on endothelial cell surface. PLoS One. 6:e293052011. View Article : Google Scholar
24	Steinmetz NF, Maurer J, Sheng H, Bensussan A, Maricic I, Kumar V and Braciak TA: Two domains of vimentin are expressed on the surface of lymph node, bone and brain metastatic prostate cancer lines along with the putative stem cell marker proteins CD44 and CD133. Cancers (Basel). 3:2870–2885. 2011. View Article : Google Scholar
25	Mashita N, Yamada S, Nakayama G, Tanaka C, Iwata N, Kanda M, Kobayashi D, Fujii T, Sugimoto H, Koike M, et al: Epithelial to mesenchymal transition might be induced via CD44 isoform switching in colorectal cancer. J Surg Oncol. 110:745–751. 2014. View Article : Google Scholar : PubMed/NCBI
26	Suzuki Y, Yamaguchi T, Matsumoto H, Nakano D, Honda G, Shinoura N, Karasawa K and Takahashi K: Prognostic factors and treatment effects in patients with curatively resected brain metastasis from colorectal cancer. Dis Colon Rectum. 57:56–63. 2014. View Article : Google Scholar
27	Wein A, Emmert M, Merkel S, Harich HD, Siebler J, Thiemann R, Lamberti C, Göttler B, Fries S, Kiani A, et al: Palliative treatment of colorectal cancer with secondary metastasis resection in Germany-impact of the multidis-ciplinary treatment approach on prognosis and cost: The Northern Bavaria IVOPAK I Project. Oncology. 88:103–121. 2015.
28	Chaw SY, Majeed AA, Dalley AJ, Chan A, Stein S and Farah CS: Epithelial to mesenchymal transition (EMT) biomarkers-E-cadherin, beta-catenin, APC and Vimentin-in oral squamous cell carcinogenesis and transformation. Oral Oncol. 48:997–1006. 2012. View Article : Google Scholar : PubMed/NCBI
29	Zhai X, Zhu H, Wang W, Zhang S, Zhang Y and Mao G: Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. Med Oncol. 31:9702014. View Article : Google Scholar : PubMed/NCBI
30	Takahashi Y, Sawada G, Kurashige J, Uchi R, Matsumura T, Ueo H, Takano Y, Akiyoshi S, Eguchi H, Sudo T, et al: Paired related homoeobox 1, a new EMT inducer, is involved in metastasis and poor prognosis in colorectal cancer. Br J Cancer. 109:307–311. 2013. View Article : Google Scholar : PubMed/NCBI
31	Rokavec M, Öner MG, Li H, Jackstadt R, Jiang L, Lodygin D, Kaller M, Horst D, Ziegler PK, Schwitalla S, et al: IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 124:1853–1867. 2014. View Article : Google Scholar : PubMed/NCBI
32	Zhang L, Shao L, Creighton CJ, Zhang Y, Xin L, Ittmann M and Wang J: Function of phosphorylation of NF-kB p65 ser536 in prostate cancer oncogenesis. Oncotarget. 6:6281–6294. 2015. View Article : Google Scholar : PubMed/NCBI
33	Yu H, Shen Y, Hong J, Xia Q, Zhou F and Liu X: The contribution of TGF-β in epithelial-mesenchymal transition (EMT): Down-regulation of E-cadherin via snail. Neoplasma. 62:1–15. 2015. View Article : Google Scholar
34	Ji Q, Liu X, Han Z, Zhou L, Sui H, Yan L, Jiang H, Ren J, Cai J and Li Q: Resveratrol suppresses epithelial-to-mesenchymal transition in colorectal cancer through TGF-beta1/Smads signaling pathway mediated Snail/E-cadherin expression. BMC Cancer. 15:972015. View Article : Google Scholar
35	Du L, Rao G, Wang H, Li B, Tian W, Cui J, He L, Laffin B, Tian X, Hao C, et al: CD44-positive cancer stem cells expressing cellular prion protein contribute to metastatic capacity in colorectal cancer. Cancer Res. 73:2682–2694. 2013. View Article : Google Scholar : PubMed/NCBI
36	Li C, Chen S, Yue P, Deng X, Lonial S, Khuri FR and Sun SY: Proteasome inhibitor PS-341 (bortezomib) induces calpain-dependent IkappaB(alpha) degradation. J Biol Chem. 285:16096–16104. 2010. View Article : Google Scholar : PubMed/NCBI
37	Hideshima T, Chauhan D, Kiziltepe T, Ikeda H, Okawa Y, Podar K, Raje N, Protopopov A, Munshi NC, Richardson PG, et al: Biologic sequelae of IkappaB kinase (IKK) inhibition in multiple myeloma: Therapeutic implications. Blood. 113:5228–5236. 2009. View Article : Google Scholar : PubMed/NCBI