Abstract
Background
Hepatocellular carcinoma (HCC) is one of the malignant tumors and leads to the highly death in the solid tumors, but its mechanism remains unclear. KPNβ1 is one of the soluble nuclear transport receptors, has been reported to act as an important role in the occurrence and development of tumor, such as cervical cancer, head and neck and lung cancer. However, the expression mechanisms and physiological significance of KPNβ1 in HCC is still unclear.
Aim
The expression of KPNβ1 and its involvement in HCC was studied.
Methods
The expression of KPNβ1 protein was measured by Western blot and immunohistochemistry in HCC. We analyzed the effects of growth and interference of KPNβ1 in the cell cycle process by CCK8 and flow cytometrical analysis.
Results
KPNβ1 protein level was up-regulated in HCC tissue samples. The KPNβ1 expression was significantly associated with histological differentiation. The levels of KPNβ1 were significantly correlated with histological grade (P = 0.03), metastasis (P = 0.01), vein invasion (P = 0.04) and tumor size (P = 0.01) in HCC samples. Serum starvation assay proved that KPNβ1 was arrested in G1 phase and was gradually reduced by refeeding serum. Moreover, the knockdown of KPNβ1 induced cell proliferation arrest in HepG2 cell. Western blot analyses showed that KPNβ1 was correlated with NF-кB signaling pathway.
Conclusions
Our datum showed that KPNβ1 expression was up-regulated in HCC tissue samples and increasing HCC cells growth and the KPNβ1 expression was associated with poor survival. KPNβ1 may take part in the pathogenesis of hepatocellular carcinoma via NF-кB signaling pathway and serve as an independent prognostic indicator and a novel therapeutic target for HCC.
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.
Tsochatzis EA, Meyer T, Burroughs AK. Hepatocellular carcinoma. N Engl J Med. 2012;366(1):92.
Xia L, Huang W, Tian D, Zhu H, Qi X, Chen Z, et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 2013;57(2):610–24.
Malek NP, Schmidt S, Huber P, Manns MP, Greten TF. The diagnosis and treatment of hepatocellular carcinoma. Dtsch Arztebl Int. 2014;111(7):101–6.
Moudgil V, Redhu D, Dhanda S, Singh J. A review of molecular mechanisms in the development of hepatocellular carcinoma by aflatoxin and hepatitis B and C viruses. J Environ Pathol Toxicol Oncol. 2013;32(2):165–75.
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9(3):153–66.
Coleman WB. Mechanisms of human hepatocarcinogenesis. Curr Mol Med. 2003;3(6):573–88.
Zhao ZK, Dong P, Gu J, Chen L, Zhuang M, Lu WJ, et al. Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. Tumor Biol. 2013;34(1):173–80.
Nakielny S, Dreyfuss G. Transport of proteins and RNAs in and out of the nucleus. Cell. 1999;99(7):677–90.
Mosammaparast N, Pemberton LF. Karyopherins: from nuclear-transport mediators to nuclear-function regulators. Trends Cell Biol. 2004;14(10):547–56.
Chook YM, Blobel G. Karyopherins and nuclear import. Curr Opin Struct Biol. 2001;11(6):703–15.
Kohler M, Speck C, Christiansen M, Bischoff FR, Prehn S, Haller H, et al. Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Mol Cell Biol. 1999;19(11):7782–91.
Kau TR, Silver PA. Nuclear transport as a target for cell growth. Drug Discov Today. 2003;8(2):78–85.
van der Watt PJ, Stowell CL, Leaner VD. The nuclear import receptor Kpnbeta1 and its potential as an anticancer therapeutic target. Crit Rev Eukaryot Gene Expr. 2013;23(1):1–10.
Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4(2):106–17.
Zhang P, Garnett J, Creighton CJ, Al Sannaa GA, Igram DR, Lazar A, et al. EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis. J Pathol. 2014;232(3):308–18.
Angus L, van der Watt PJ, Leaner VD. Inhibition of the nuclear transporter, Kpnbeta1, results in prolonged mitotic arrest and activation of the intrinsic apoptotic pathway in cervical cancer cells. Carcinogenesis. 2014;35(5):1121–31.
Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, et al. Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer. Clin Cancer Res. 2013;19(8):1994–2003.
Edick MJ, Cheng C, Yang W, Cheok M, Wilkinson MR, Pei D, et al. Lymphoid gene expression as a predictor of risk of secondary brain tumors. Genes Chromosom Cancer. 2005;42(2):107–16.
Liang P, Zhang H, Wang G, Li S, Cong S, Luo Y, et al. KPNB1, XPO7 and IPO8 mediate the translocation of NF-kappaB/P65 into the nucleus. Traffic. 2013;14(11):1132–43.
Rahbari NN, Mehrabi A, Mollberg NM, Muller SA, Koch M, Buchler MW, et al. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 2011;253(3):453–69.
Olsen SK, Brown RS, Siegel AB. Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies. Ther Adv Gastroenterol. 2010;3(1):55–66.
Chan SL, Yeo W. Targeted therapy of hepatocellular carcinoma: present and future. J Gastroenterol Hepatol. 2012;27(5):862–72.
Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB. 2012;14(9):635–45.
Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485–91.
Giannini EG, Marenco S, Borgonovo G, Savarino V, Farinati F, Del Poggio P, et al. Alpha-fetoprotein has no prognostic role in small hepatocellular carcinoma identified during surveillance in compensated cirrhosis. Hepatology. 2012;56(4):1371–9.
Zhu Y, Liu Y, Qian Y, Dai X, Yang L, Chen J, et al. Research on the efficacy of Celastrus Orbiculatus in suppressing TGF-beta1-induced epithelial-mesenchymal transition by inhibiting HSP27 and TNF-alpha-induced NF-kappaB/Snail signaling pathway in human gastric adenocarcinoma. BMC Complement Altern Med. 2014;14:433.
Tsao SM, Hsia TC, Yin MC. Protocatechuic acid inhibits lung cancer cells by modulating FAK, MAPK, and NF-kappaB pathways. Nutr Cancer. 2014;66(8):1331–41.
Gao X, Liu Y, Deeb D, Arbab AS, Gautam SC. Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-kappaB/mTOR signaling. J Exp Ther Oncol. 2014;10(4):275–83.
Song R, Song H, Liang Y, Yin D, Zhang H, Zheng T, et al. Reciprocal activation between ATPase inhibitory factor 1 and NF-kappaB drives hepatocellular carcinoma angiogenesis and metastasis. Hepatology. 2014;60(5):1659–73.
Baldwin AS Jr. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu Rev Immunol. 1996;14:649–83.
Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225–60.
Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000;18:621–63.
Acknowledgments
This work was supported by the China Postdoctoral Science Foundation (NO: 2013M541563) and the peak of six personnel Foundation in Jiangsu Province.
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Linlin Yang and Baoying Hu have contributed equally to this work.
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Yang, L., Hu, B., Zhang, Y. et al. Suppression of the nuclear transporter-KPNβ1 expression inhibits tumor proliferation in hepatocellular carcinoma. Med Oncol 32, 128 (2015). https://doi.org/10.1007/s12032-015-0559-1
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DOI: https://doi.org/10.1007/s12032-015-0559-1