Mps1 is associated with the BRAFV600E mutation and predicts poor outcome in patients with colorectal cancer

Zhang,Yanyan; Dong,Jinyao; Shi,Ruyi; Feng,Liguo; Li,Yike; Cheng,Caixia; Zhang,Ling; Song,Bin; Bi,Yanghui; Huang,He; Kong,Pengzhou; Guo,Jiansheng; Liu,Jing

doi:10.3892/ol.2019.9924

Mps1 is associated with the BRAFV600E mutation and predicts poor outcome in patients with colorectal cancer

Authors:
- Yanyan Zhang
- Jinyao Dong
- Ruyi Shi
- Liguo Feng
- Yike Li
- Caixia Cheng
- Ling Zhang
- Bin Song
- Yanghui Bi
- He Huang
- Pengzhou Kong
- Jiansheng Guo
- Jing Liu
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Affiliations: Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Endoscopy Center, Shanxi Cancer Hospital, Taiyuan, Shanxi 30013, P.R. China, Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of General Surgery, Taiyuan Municipal No. 2 People's Hospital, Taiyuan, Shanxi 030002, P.R. China
Published online on: January 14, 2019 https://doi.org/10.3892/ol.2019.9924
Pages: 2809-2817
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) with the V600E mutation of B‑Raf proto‑oncogene serine/threonine kinase (BRAFV600E) mutation is insensitive to chemotherapy and is indicative of a poor patient prognosis. Although BRAF inhibitors have a marked effect on malignant melanoma harboring the BRAFV600E mutation, they have a limited effect on patients with CRC with the same BRAF mutation. A previous study identified a novel gene, monopolar spindle protein kinase 1 (Mps1), a downstream target of BRAFV600E only, rather than of wild‑type BRAF as well, which contributes to tumorigenesis in melanoma. In the present study, the incidence of BRAFV600E in patients with CRC was identified and the correlation of Mps1, phospho‑extracellular‑signal‑regulated kinase (p‑ERK) and BRAFV600E was investigated. The results indicated that the mutation rate of BRAFV600E was 5.2% in CRC. Poorly differentiated tumors and mucinous tumors have a significantly higher incidence of BRAFV600E compared with well‑differentiated tumors and non‑mucinous tumors (P<0.05). Kaplan‑Meier survival analysis indicated that the survival rate was markedly lower in patients with BRAFV600E compared with in patients with wild‑type BRAF (BRAFWT). The expression of p‑ERK and Mps1 in CRC with BRAFV600E was significantly higher compared with in CRC with BRAFWT (P<0.05), and their expression is associated with cancer classification, degree of differentiation and lymph node transfusion (P<0.05). In addition p‑ERK expression was positively correlated with Mps1 expression, with a contingency coefficient of 0.679 (P=0.002). In conclusion, the results of the present study indicated that Mps1 was significantly associated with BRAFV600E/p‑ERK and may serve a crucial function in the development of CRC. The results of the present study raise the possibility that targeting the oncogenic BRAF and Mps1, particularly when in conjunction, could provide promising therapeutic opportunities for the treatment of CRC.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Brenner H, Kloor M and Pox CP: Colorectal cancer. Lancet. 383:1490–1502. 2014. View Article : Google Scholar : PubMed/NCBI
3	Stintzing S: Recent advances in understanding colorectal cancer. F1000Res. 7:F1000 Faculty Rev–1528. 2018. View Article : Google Scholar
4	Tímár J, Hegedüs B and Rásó E: KRAS mutation testing of colorectal cancer for anti-EGFR therapy: Dogmas versus evidence. Curr Cancer Drug Targets. 10:813–823. 2010. View Article : Google Scholar : PubMed/NCBI
5	Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A and Bernards R: Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 483:100–103. 2012. View Article : Google Scholar : PubMed/NCBI
6	Königsberg R, Hulla W, Klimpfinger M, Reiner-Concin A, Steininger T, Büchler W, Terkola R and Dittrich C: Clinical and economic aspects of KRAS mutational status as predictor for epidermal growth factor receptor inhibitor therapy in metastatic colorectal cancer patients. Oncology. 81:359–364. 2011. View Article : Google Scholar : PubMed/NCBI
7	Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al: Mutations of the BRAF gene in human cancer. Nature. 417:949–954. 2002. View Article : Google Scholar : PubMed/NCBI
8	Dizdar L, Werner TA, Drusenheimer JC, Möhlendick B, Raba K, Boeck I, Anlauf M, Schott M, Göring W, Esposito I, et al: BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma. Int J Cancer. 2018:
9	Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, et al: Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol. 33:4032–4038. 2015. View Article : Google Scholar : PubMed/NCBI
10	Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, et al: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 366:207–215. 2012. View Article : Google Scholar : PubMed/NCBI
11	Cui Y and Guadagno TM: B-Raf(V600E) signaling deregulates the mitotic spindle checkpoint through stabilizing Mps1 levels in melanoma cells. Oncogene. 27:3122–3133. 2008. View Article : Google Scholar : PubMed/NCBI
12	Cui Y, Borysova MK, Johnson JO and Guadagno TM: Oncogenic B-Raf(V600E) induces spindle abnormalities, supernumerary centrosomes, an aneuploidy in human melanocytic cells. Cancer Res. 70:675–684. 2010. View Article : Google Scholar : PubMed/NCBI
13	Liu J, Cheng X, Zhang Y, Li S, Cui H, Zhang L, Shi R, Zhao Z, He C, Wang C, et al: Phosphorylation of Mps1 by BRAFV600E prevents Mps1 degradation and contributes to chromosome instability in melanoma. Oncogene. 32:713–723. 2012. View Article : Google Scholar : PubMed/NCBI
14	Zhang L, Shi R, He C, Cheng C, Song B, Cui H, Zhang Y, Zhao Z, Bi Y, Yang X, et al: Oncogenic B-Raf(V600E) abrogates the AKT/B-Raf/Mps1 interaction in melanoma cells. Cancer Lett. 337:125–132. 2013. View Article : Google Scholar : PubMed/NCBI
15	NCCN Guidelines version 2.2015 Staging Colon Cancer. https://www.nccn.org/professionals/physician_gls/default.aspx#site
16	Fu X, Huang Y, Fan X, Deng Y, Liu H, Zou H, Wu P, Chen Z, Huang J, Wang J, et al: Demographic trends and KRAS/BRAF^V600E mutations in colorectal cancer patients of South China: A single-site report. Int J Cancer. 2018 Nov 10;Doi: 10.1002/ijc.31973. View Article : Google Scholar
17	Sawada K, Nakamura Y, Yamanaka T, Kuboki Y, Yamaguchi D, Yuki S, Yoshino T, Komatsu Y, Sakamoto N, Okamoto W and Fujii S: Prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 17:198–205. 2018. View Article : Google Scholar : PubMed/NCBI
18	Bläker H, Alwers E, Arnold A, Herpel E, Tagscherer KE, Roth W, Jansen L, Walter V, Kloor M, Chang-Claude J, et al: The association between mutations in BRAF and colorectal cancer-specific survival depends on microsatellite status and tumor stage. Clin Gastroenterol Hepatol. S1542-3565(18)30371-9. 2018.
19	Tie J, Gibbs P, Lipton L, Christie M, Jorissen RN, Burgess AW, Croxford M, Jones I, Langland R, Kosmider S, et al: Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer. 128:2075–2084. 2011. View Article : Google Scholar : PubMed/NCBI
20	Pinheiro M, Ahlquist T, Danielsen SA, Lind GE, Veiga I, Pinto C, Costa V, Afonso L, Sousa O, Fragoso M, et al: Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin. BMC Cancer. 10:5872010. View Article : Google Scholar : PubMed/NCBI
21	Shaukat A, Arain M, Thaygarajan B, Bond JH and Sawhney M: Is BRAF mutation associated with interval colorectal cancers? Dig Dis Sci. 55:2352–2356. 2010. View Article : Google Scholar : PubMed/NCBI
22	Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M, Giovannucci EL and Fuchs CS: CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 58:90–96. 2009. View Article : Google Scholar : PubMed/NCBI
23	Rozek LS, Herron CM, Greenson JK, Moreno V, Capella G, Rennert G and Gruber SB: Smoking, gender, and ethnicity predict somatic BRAF mutations in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 19:838–843. 2010. View Article : Google Scholar : PubMed/NCBI
24	Fariña-Sarasqueta A, van Lijnschoten G, Moerland E, Creemers GJ, Lemmens VE, Rutten HJ and van den Brule AJ: The BRAF^V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann Oncol. 21:2396–2402. 2010. View Article : Google Scholar : PubMed/NCBI
25	Yoon HH, Shi Q, Alberts SR, Goldberg RM, Thibodeau SN, Sargent DJ and Sinicrope FA; Alliance for Clinical Trials in Oncology, : Racial differences in BRAF/KRAS mutation rates and survival in stage III colon cancer patients. J Natl Cancer Inst. 107:djv1862015. View Article : Google Scholar : PubMed/NCBI
26	Barras D, Missiaglia E, Wirapati P, Sieber OM, Jorissen RN, Love C, Molloy PL, Jones IT, McLaughlin S, Gibbs P, et al: BRAFV600E mutant colorectal cancer subtypes based on gene expression. Clin Cancer Res. 23:104–115. 2017. View Article : Google Scholar : PubMed/NCBI
27	Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M and Koralewski P: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first line treatment for metastatic colorectal cancer: The OPUS study. Ann Oncol. 22:1535–1546. 2011. View Article : Google Scholar : PubMed/NCBI
28	Strub T, Ghiraldini FG, Carcamo S, Li M, Wroblewska A, Singh R, Goldberg MS, Hasson D, Wang Z, Gallagher SJ, et al: SIRT6 haploinsufficiency induces BRAF^V600E melanoma cell resistance to MAPK inhibitors via IGF signalling. Nat Commun. 9:34402018. View Article : Google Scholar : PubMed/NCBI
29	Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S, Chae YC, Xu X, Choi H, Dimwamwa E, et al: Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J Clin Invest. 126:1834–1856. 2016. View Article : Google Scholar : PubMed/NCBI
30	Knauf JA, Luckett KA, Chen KY, Voza F, Socci ND, Ghossein R and Fagin JA: Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J Clin Invest. 128:4086–4097. 2018. View Article : Google Scholar : PubMed/NCBI
31	Korphaisarn K and Kopetz S: BRAF-directed therapy in metastatic colorectal cancer. Cancer J. 22:175–178. 2016. View Article : Google Scholar : PubMed/NCBI
32	Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, et al: Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAFV600-mutant colorectal cancer. J Clin Oncol. 33:4023–4031. 2015. View Article : Google Scholar : PubMed/NCBI
33	Kasbek C, Yang CH and Fisk HA: Mps1 as a link between centrosomes and genomic instability. Environ Mol Mutagen. 50:654–665. 2009. View Article : Google Scholar : PubMed/NCBI
34	Restuccia A, Yang F, Chen C, Lu L and Dai W: Mps1 is SUMO-modified during the cell cycle. Oncotarget. 7:3158–3170. 2016. View Article : Google Scholar : PubMed/NCBI
35	Gorbsky GJ: The spindle checkpoint and chromosome segregation in meiosis. FEBS J. 282:2471–2487. 2015. View Article : Google Scholar : PubMed/NCBI
36	Edelmann MJ, Nicholson B and Kessler BM: Pharmacological targets in the ubiquitin system offer new ways of treating cancer, neurodegenerative disorders and infectious diseases. Expert Rev Mol Med. 13:e352011. View Article : Google Scholar : PubMed/NCBI
37	Hiruma Y, Sacristan C, Pachis ST, Adamopoulos A, Kuijt T, Ubbink M, von Castelmur E, Perrakis A and Kops GJ: CELL DIVISION CYCLE. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling. Science. 348:1264–1267. 2015. View Article : Google Scholar : PubMed/NCBI
38	Daniel J, Coulter J, Woo JH, Wilsbach K and Gabrielson E: High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc Natl Acad Sci USA. 108:5384–5389. 2011. View Article : Google Scholar : PubMed/NCBI
39	Shankavaram U, Maachani UB, Zhao S, Camphausen K and Tandle A: Molecular profiling of MPS1 gene silencing in U251 glioma cell line. Genom Data. 6:36–39. 2015. View Article : Google Scholar : PubMed/NCBI
40	Ling Y, Zhang X, Bai Y, Li P, Wei C, Song T, Zheng Z, Guan K, Zhang Y, Zhang B, et al: Overexpression of Mps1 in colon cancer cells attenuates the spindle assembly checkpoint and increases aneuploidy. Biochem Biophys Res Commun. 450:1690–1695. 2014. View Article : Google Scholar : PubMed/NCBI
41	Dominguez-Brauer C, Thu KL, Mason JM, Blaser H, Bray MR and Mak TW: Targeting mitosis in cancer: Emerging strategies. Mol Cell. 60:524–536. 2015. View Article : Google Scholar : PubMed/NCBI
42	Martinez R, Blasina A, Hallin JF, Hu W, Rymer I, Fan J, Hoffman RL, Murphy S, Marx M, Yanochko G, et al: Mitotic checkpoint kinase Mps1 has a role in normal physiology which impacts clinical utility. PLoS One. 10:e01386162015. View Article : Google Scholar : PubMed/NCBI