BUB1 promotes proliferation of liver cancer cells by activating SMAD2 phosphorylation

Zhu,Li‑Jing; Pan,Yan; Chen,Xiao‑Ying; Hou,Pan‑Fei

doi:10.3892/ol.2020.11445

BUB1 promotes proliferation of liver cancer cells by activating SMAD2 phosphorylation

Authors:
- Li‑Jing Zhu
- Yan Pan
- Xiao‑Ying Chen
- Pan‑Fei Hou
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Affiliations: Department of Radiation Oncology, Lianshui County People's Hospital, Huaian, Jiangsu 223400, P.R. China, Department of Clinical Laboratory, Lianshui County People's Hospital, Huaian, Jiangsu 223400, P.R. China, Clinical Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
Published online on: March 5, 2020 https://doi.org/10.3892/ol.2020.11445
Pages: 3506-3512
Copyright : © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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Abstract

Budding uninhibited by benzimidazoles 1 (BUB1) is a mitotic checkpoint serine/threonine kinase that has been reported as an oncogene or tumor suppressor gene in various types of cancer, including breast cancer, pancreatic ductal adenocarcinoma, prostate and gastric cancers. However, its role in liver cancer remains unclear. The present study aimed to explore the biological function of BUB1 in liver cancer. The present study demonstrated that BUB1 mRNA expression levels and the intensity of immunohistochemical staining were significantly increased in liver cancer tissues compared with normal tissues. The role of BUB1 in cell proliferation was also determined. Overexpression of BUB1 significantly promoted cell proliferation, whereas knockdown of BUB1 expression inhibited the proliferation of liver cancer cell lines. In experiments investigating the underlying mechanism, overexpression of BUB1 increased the levels of SMAD2 phosphorylation, whereas knockdown of BUB1 reduced the levels of SMAD2 phosphorylation. Therefore, BUB1 may promote proliferation of liver cancer cells by activating phosphorylation of SMAD2, and BUB1 may serve as a potential target in the diagnosis and/or treatment of liver cancer.

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1	Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, Schirmacher P and Vilgrain V; European Association for the Study of the Liver, : EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 69:182–236. 2018. View Article : Google Scholar : PubMed/NCBI
2	Lu XJ, Shi Y, Chen JL and Ma S: Krüppel-like factors in hepatocellular carcinoma. Tumour Biol. 36:533–541. 2015. View Article : Google Scholar : PubMed/NCBI
3	Forner A, Reig M and Bruix J: Hepatocellular carcinoma. Lancet. 391:1301–1314. 2018. View Article : Google Scholar : PubMed/NCBI
4	Yu WB, Rao A, Vu V, Xu L, Rao JY and Wu JX: Management of centrally located hepatocellular carcinoma: Update 2016. World J Hepatol. 9:627–634. 2017. View Article : Google Scholar : PubMed/NCBI
5	Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA and Giulini SM: Early and late recurrence after liver resection for hepatocellular carcinoma: Prognostic and therapeutic implications. Ann Surg. 243:229–235. 2006. View Article : Google Scholar : PubMed/NCBI
6	Hu J and Gao DZ: Distinction immune genes of hepatitis-induced heptatocellular carcinoma. Bioinformatics. 28:3191–3194. 2012. View Article : Google Scholar : PubMed/NCBI
7	Marquardt JU, Galle PR and Teufel A: Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): An emerging field for advanced technologies. J Hepatol. 56:267–275. 2012. View Article : Google Scholar : PubMed/NCBI
8	Bolanos-Garcia VM and Blundell TL: BUB1 and BUBR1: Multifaceted kinases of the cell cycle. Trends Biochem Sci. 36:141–150. 2011. View Article : Google Scholar : PubMed/NCBI
9	Johnson VL, Scott MI, Holt SV, Hussein D and Taylor SS: Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 117:1577–1589. 2004. View Article : Google Scholar : PubMed/NCBI
10	Yu H and Tang Z: Bub1 multitasking in mitosis. Cell Cycle. 4:262–265. 2005. View Article : Google Scholar : PubMed/NCBI
11	Ricke RM, Jeganathan KB and van Deursen JM: Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol. 193:1049–1064. 2011. View Article : Google Scholar : PubMed/NCBI
12	Fu X, Chen G, Cai ZD, Wang C, Liu ZZ, Lin ZY, Wu YD, Liang YX, Han ZD, Liu JC, et al: Overexpression of BUB1B contributes to progression of prostate cancer and predicts poor outcome in patients with prostate cancer. Onco Targets Ther. 9:2211–2220. 2016.PubMed/NCBI
13	Piao J, Zhu L, Sun J, Li N, Dong B, Yang Y and Chen L: High expression of CDK1 and BUB1 predicts poor prognosis of pancreatic ductal adenocarcinoma. Gene. 701:15–22. 2019. View Article : Google Scholar : PubMed/NCBI
14	Han JY, Han YK, Park GY, Kim SD and Lee CG: Bub1 is required for maintaining cancer stem cells in breast cancer cell lines. Sci Rep. 5:159932015. View Article : Google Scholar : PubMed/NCBI
15	Stahl D, Braun M, Gentles AJ, Lingohr P, Walter A, Kristiansen G and Gütgemann I: Low BUB1 expression is an adverse prognostic marker in gastric adenocarcinoma. Oncotarget. 8:76329–76339. 2017. View Article : Google Scholar : PubMed/NCBI
16	Chen QF, Xia JG, Li W, Shen LJ, Huang T and Wu P: Examining the key genes and pathways in hepatocellular carcinoma development from hepatitis B virus-positive cirrhosis. Mol Med Rep. 18:4940–4950. 2018.PubMed/NCBI
17	Zhang L, Huang Y, Ling J, Zhuo W, Yu Z, Shao M, Luo Y and Zhu Y: Screening and function analysis of hub genes and pathways in hepatocellular carcinoma via bioinformatics approaches. Cancer Biomark. 22:511–521. 2018. View Article : Google Scholar : PubMed/NCBI
18	Wen DY, Lin P, Pang YY, Chen G, He Y, Dang YW and Yang H: Expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma using the Cancer Genome Atlas, the Gene Expression Omnibus, and Quantitative Real-Time Polymerase Chain Reaction. Med Sci Monit. 24:2786–2808. 2018. View Article : Google Scholar : PubMed/NCBI
19	Wang Y, Liu DP, Chen PP, Koeffler HP, Tong XJ and Xie D: Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. Cancer Res. 67:2535–2543. 2007. View Article : Google Scholar : PubMed/NCBI
20	Williams GL, Roberts TM and Gjoerup OV: Bub1: Escapades in a cellular world. Cell Cycle. 6:1699–1704. 2007. View Article : Google Scholar : PubMed/NCBI
21	Li L, Xu DB, Zhao XL and Hao TY: Combination analysis of Bub1 and Mad2 expression in endometrial cancer: Act as a prognostic factor in endometrial cancer. Arch Gynecol Obstet. 288:155–165. 2013. View Article : Google Scholar : PubMed/NCBI
22	Mukherjee A, Joseph C, Craze M, Chrysanthou E and Ellis IO: The role of BUB and CDC proteins in low-grade breast cancers. Lancet. 385 (Suppl 1):S722015. View Article : Google Scholar : PubMed/NCBI
23	Takagi K, Miki Y, Shibahara Y, Nakamura Y, Ebata A, Watanabe M, Ishida T, Sasano H and Suzuki T: BUB1 immunolocalization in breast carcinoma: Its nuclear localization as a potent prognostic factor of the patients. Horm Cancer. 4:92–102. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ocaña A, Pérez-Peña J, Alcaraz-Sanabria A, Sánchez-Corrales V, Nieto-Jiménez C, Templeton AJ, Seruga B, Pandiella A and Amir E: In silico analyses identify gene-sets, associated with clinical outcome in ovarian cancer: Role of mitotic kinases. Oncotarget. 7:22865–22872. 2016. View Article : Google Scholar : PubMed/NCBI
25	Dituri F, Mancarella S, Cigliano A, Chieti A and Giannelli G: TGF-β as multifaceted orchestrator in HCC progression: signaling, EMT, immune microenvironment, and novel therapeutic perspectives. Semin Liver Dis. 39:53–69. 2019. View Article : Google Scholar : PubMed/NCBI
26	Derynck R and Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 425:577–584. 2003. View Article : Google Scholar : PubMed/NCBI
27	Wrana JL, Attisano L, Wieser R, Ventura F and Massagué J: Mechanism of activation of the TGF-beta receptor. Nature. 370:341–347. 1994. View Article : Google Scholar : PubMed/NCBI
28	Shi Y and Massagué J: Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 113:685–700. 2003. View Article : Google Scholar : PubMed/NCBI
29	Massagué J: TGFbeta in Cancer. Cell. 134:215–230. 2008. View Article : Google Scholar : PubMed/NCBI