KIFC1, a novel potential prognostic factor and therapeutic target in hepatocellular carcinoma

Fu,Xiaowei; Zhu,Yaqiong; Zheng,Bingbing; Zou,Yeqing; Wang,Chao; Wu,Peng; Wang,Jun; Chen,Haimin; Du,Pengcheng; Liang,Bo; Fang,Lu

doi:10.3892/ijo.2018.4348

KIFC1, a novel potential prognostic factor and therapeutic target in hepatocellular carcinoma

Authors:
- Xiaowei Fu
- Yaqiong Zhu
- Bingbing Zheng
- Yeqing Zou
- Chao Wang
- Peng Wu
- Jun Wang
- Haimin Chen
- Pengcheng Du
- Bo Liang
- Lu Fang
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Affiliations: Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China, Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330000, P.R. China
Published online on: March 29, 2018 https://doi.org/10.3892/ijo.2018.4348
Pages: 1912-1922
Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Kinesin family member C1 (KIFC1, also known as HSET) is a minus end-directed motor protein, which is critical in centrosome clustering. The present study investigated the expression of KIFC1 in paired hepatocellular carcinoma (HCC) tissues and adjacent non-cancerous tissues from 91 patients by immunohistochemical analysis; clinical data were concomitantly collected. KIFC1 was expressed at high levels in HCC tissues, compared with that in peritumoral tissues (54.9 vs. 14.3%; P<0.01), and its expression correlated with tumor emboli, metastasis, recurrence and time of recurrence. Kaplan-Meier analysis showed that the expression of KIFC1 was significantly associated with tumor-free survival rates. In addition, multivariate analyses revealed that the overexpression of KIFC1was an independent predictive marker in patients with HCC. Consistently, data derived from GEPIA was in agreement with the results. In vitro, KIFC1 knockdown effectively decreased HCC cell viability, and induced apoptosis and cell death. KIFC1 knockdown also significantly suppressed tumor cell migration and invasion in vitro. Mechanistically, the apoptosis-related protein, B-cell lymphoma-2 (Bcl-2), was downregulated in KIFC1 small interfering RNA-treated groups, whereas thee levels of Bcl-2-associated X protein and p53 were upregulated. In addition, the expression levels of phosphorylated phosphoinositide 3-kinase and phosphorylated AKT were decreased significantly when KIFC1 was silenced. The epithelial-mesenchymal transition-related proteins, N-cadherin, matrix metalloproteinase-2 (MMP-2), β-catenin, Slug, and Zinc finger E-box-binding homeobox 1, were downregulated, whereas the expression of E-cadherin was upregulated. The overexpression of KIFC1 was correlated closely with the progression of HCC and poor prognosis, and suggested that the expression levels of KIFC1 are a potential prognostic biomarker and therapeutic target in HCC.

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1	Llovet JM and Bruix J: Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 48:1312–1327. 2008. View Article : Google Scholar : PubMed/NCBI
2	Feo F, Pascale RM, Simile MM, De Miglio MR, Muroni MR and Calvisi D: Genetic alterations in liver carcinogenesis: Implications for new preventive and therapeutic strategies. Crit Rev Oncog. 11:19–62. 2000. View Article : Google Scholar
3	Michielsen PP, Francque SM and van Dongen JL: Viral hepatitis and hepatocellular carcinoma. World J Surg Oncol. 3:272005. View Article : Google Scholar : PubMed/NCBI
4	Sun W, Xing B, Sun Y, Du X, Lu M, Hao C, Lu Z, Mi W, Wu S, Wei H, et al: Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: Novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteomics. 6:1798–1808. 2007. View Article : Google Scholar : PubMed/NCBI
5	Tang ZY: Hepatocellular carcinoma - cause, treatment and metastasis. World J Gastroenterol. 7:445–454. 2001. View Article : Google Scholar
6	Sherman M: Modern approach to hepatocellular carcinoma. Curr Gastroenterol Rep. 13:49–55. 2011. View Article : Google Scholar
7	Calvisi DF, Pascale RM and Feo F: Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. Rev Recent Clin Trials. 2:217–236. 2007. View Article : Google Scholar
8	Fukasawa K: Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 7:911–924. 2007. View Article : Google Scholar : PubMed/NCBI
9	Ogden A, Rida PC and Aneja R: Let's huddle to prevent a muddle: Centrosome declustering as an attractive anticancer strategy. Cell Death Differ. 19:1255–1267. 2012. View Article : Google Scholar : PubMed/NCBI
10	Anderhub SJ, Krämer A and Maier B: Centrosome amplification in tumorigenesis. Cancer Lett. 322:8–17. 2012. View Article : Google Scholar : PubMed/NCBI
11	Ogden A, Rida PC and Aneja R: Heading off with the herd: How cancer cells might maneuver supernumerary centrosomes for directional migration. Cancer Metastasis Rev. 32:269–287. 2013. View Article : Google Scholar :
12	Pannu V, Rida PC, Ogden A, Clewley R, Cheng A, Karna P, Lopus M, Mishra RC, Zhou J and Aneja R: Induction of robust de novo centrosome amplification, high-grade spindle multipolarity and metaphase catastrophe: A novel chemotherapeutic approach. Cell Death Dis. 3:e3462012. View Article : Google Scholar : PubMed/NCBI
13	Ando A, Kikuti YY, Kawata H, Okamoto N, Imai T, Eki T, Yokoyama K, Soeda E, Ikemura T, Abe K, et al: Cloning of a new kinesin-related gene located at the centromeric end of the human MHC region. Immunogenetics. 39:194–200. 1994. View Article : Google Scholar : PubMed/NCBI
14	DeLuca JG, Newton CN, Himes RH, Jordan MA and Wilson L: Purification and characterization of native conventional kinesin, HSET, and CENP-E from mitotic hela cells. J Biol Chem. 276:28014–28021. 2001. View Article : Google Scholar : PubMed/NCBI
15	Kleylein-Sohn J, Pöllinger B, Ohmer M, Hofmann F, Nigg EA, Hemmings BA and Wartmann M: Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET. J Cell Sci. 125:5391–5402. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nath S, Bananis E, Sarkar S, Stockert RJ, Sperry AO, Murray JW and Wolkoff AW: Kif5B and Kifc1 interact and are required for motility and fission of early endocytic vesicles in mouse liver. Mol Biol Cell. 18:1839–1849. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hall VJ, Compton D, Stojkovic P, Nesbitt M, Herbert M, Murdoch A and Stojkovic M: Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer. Hum Reprod. 22:52–62. 2007. View Article : Google Scholar
18	Yang WX and Sperry AO: C-terminal kinesin motor KIFC1 participates in acrosome biogenesis and vesicle transport. Biol Reprod. 69:1719–1729. 2003. View Article : Google Scholar : PubMed/NCBI
19	Yang WX, Jefferson H and Sperry AO: The molecular motor KIFC1 associates with a complex containing nucleoporin NUP62 that is regulated during development and by the small GTPase RAN. Biol Reprod. 74:684–690. 2006. View Article : Google Scholar
20	Farina F, Pierobon P, Delevoye C, Monnet J, Dingli F, Loew D, Quanz M, Dutreix M and Cappello G: Kinesin KIFC1 actively transports bare double-stranded DNA. Nucleic Acids Res. 41:4926–4937. 2013. View Article : Google Scholar : PubMed/NCBI
21	Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M and Pellman D: Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 22:2189–2203. 2008. View Article : Google Scholar : PubMed/NCBI
22	Pawar S, Donthamsetty S, Pannu V, Rida P, Ogden A, Bowen N, Osan R, Cantuaria G and Aneja R: KIFCI, a novel putative prognostic biomarker for ovarian adenocarcinomas: Delineating protein interaction networks and signaling circuitries. J Ovarian Res. 7:532014. View Article : Google Scholar : PubMed/NCBI
23	Grinberg-Rashi H, Ofek E, Perelman M, Skarda J, Yaron P, Hajdúch M, Jacob-Hirsch J, Amariglio N, Krupsky M, Simansky DA, et al: The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain. Clin Cancer Res. 15:1755–1761. 2009. View Article : Google Scholar : PubMed/NCBI
24	Li Y, Lu W, Chen D, Boohaker RJ, Zhai L, Padmalayam I, Wennerberg K, Xu B and Zhang W: KIFC1 is a novel potential therapeutic target for breast cancer. Cancer Biol Ther. 16:1316–1322. 2015. View Article : Google Scholar : PubMed/NCBI
25	De S, Cipriano R, Jackson MW and Stark GR: Overexpression of kinesins mediates docetaxel resistance in breast cancer cells. Cancer Res. 69:8035–8042. 2009. View Article : Google Scholar : PubMed/NCBI
26	Chun YH, Kim SU, Park JY, Kim DY, Han KH, Chon CY, Kim BK, Choi GH, Kim KS, Choi JS, et al: Prognostic value of the 7th edition of the AJCC staging system as a clinical staging system in patients with hepatocellular carcinoma. Eur J Cancer. 47:2568–2575. 2011. View Article : Google Scholar : PubMed/NCBI
27	Tang Z, Li C, Kang B, Gao G, Li C and Zhang Z: GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 45:W98–W102. 2017. View Article : Google Scholar : PubMed/NCBI
28	Liang B, Zheng W, Fang L, Wu L, Zhou F, Yin X, Yu X and Zou Z: Overexpressed targeting protein for Xklp2 (TPX2) serves as a promising prognostic marker and therapeutic target for gastric cancer. Cancer Biol Ther. 17:824–832. 2016. View Article : Google Scholar : PubMed/NCBI
29	Huitzil-Melendez FD, Capanu M, O'Reilly EM, Duffy A, Gansukh B, Saltz LL and Abou-Alfa GK: Advanced hepatocellular carcinoma: Which staging systems best predict prognosis? J Clin Oncol. 28:2889–2895. 2010. View Article : Google Scholar : PubMed/NCBI
30	Hao J, Yang Z, Wang L, Zhang Y, Shu Y, Jiang L, Hu Y, Lv W, Dong P and Liu Y: Downregulation of BRD4 inhibits gallbladder cancer proliferation and metastasis and induces apoptosis via PI3K/AKT pathway. Int J Oncol. 51:823–831. 2017. View Article : Google Scholar :
31	Estaquier J, Vallette F, Vayssiere JL and Mignotte B: The mitochondrial pathways of apoptosis. Adv Exp Med Biol. 942:157–183. 2012. View Article : Google Scholar : PubMed/NCBI
32	Fabregat I: Dysregulation of apoptosis in hepatocellular carcinoma cells. World J Gastroenterol. 15:513–520. 2009. View Article : Google Scholar : PubMed/NCBI
33	Lin HL, Yang MH, Wu CW, Chen PM, Yang YP, Chu YR, Kao CL, Ku HH, Lo JF, Liou JP, et al: 2-Methoxyestradiol attenuates phosphatidylinositol 3-kinase/Akt pathway-mediated metastasis of gastric cancer. Int J Cancer. 121:2547–2555. 2007. View Article : Google Scholar : PubMed/NCBI
34	Rudmik LR and Magliocco AM: Molecular mechanisms of hepatic metastasis in colorectal cancer. J Surg Oncol. 92:347–359. 2005. View Article : Google Scholar : PubMed/NCBI
35	Kumar S and Weaver VM: Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer Metastasis Rev. 28:113–127. 2009. View Article : Google Scholar : PubMed/NCBI
36	El-Nahas AM: Plasticity of kidney cells: Role in kidney remodeling and scarring. Kidney Int. 64:1553–1563. 2003. View Article : Google Scholar : PubMed/NCBI
37	Sato M, Shames DS and Hasegawa Y: Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. Respirology. 17:1048–1059. 2012. View Article : Google Scholar : PubMed/NCBI