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

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

doi:10.3892/ol.2019.9924

Mps1 is associated with the BRAF^V600E mutation and predicts poor outcome in patients with colorectal cancer

Oncol Lett. 2019 Mar;17(3):2809-2817. doi: 10.3892/ol.2019.9924. Epub 2019 Jan 14.

Authors

Yanyan Zhang^{1

2

3}, Jinyao Dong⁴, Ruyi Shi^{2

3

5}, Liguo Feng⁶, Yike Li^{1

2

3}, Caixia Cheng^{2

3

7}, Ling Zhang^{2

3

8}, Bin Song^{2

3

9}, Yanghui Bi^{2

3}, He Huang¹, Pengzhou Kong^{2

3}, Jiansheng Guo¹, Jing Liu^{1

2

3}

Affiliations

¹ Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
² Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
³ Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
⁴ Endoscopy Center, Shanxi Cancer Hospital, Taiyuan, Shanxi 30013, P.R. China.
⁵ Department of Cell Biology and Genetics, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
⁶ Department of General Surgery, Taiyuan Municipal No. 2 People's Hospital, Taiyuan, Shanxi 030002, P.R. China.
⁷ Department of Pathology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
⁸ Department of Pathology, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
⁹ Department of Oncology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.

Abstract

Colorectal cancer (CRC) with the V600E mutation of B-Raf proto-oncogene serine/threonine kinase (BRAF^V600E) 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 BRAF^V600E 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 BRAF^V600E only, rather than of wild-type BRAF as well, which contributes to tumorigenesis in melanoma. In the present study, the incidence of BRAF^V600E in patients with CRC was identified and the correlation of Mps1, phospho-extracellular-signal-regulated kinase (p-ERK) and BRAF^V600E was investigated. The results indicated that the mutation rate of BRAF^V600E was 5.2% in CRC. Poorly differentiated tumors and mucinous tumors have a significantly higher incidence of BRAF^V600E 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 BRAF^V600E compared with in patients with wild-type BRAF (BRAF^WT). The expression of p-ERK and Mps1 in CRC with BRAF^V600E was significantly higher compared with in CRC with BRAF^WT (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 BRAF^V600E/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.

Keywords: B-Raf proto-oncogene serine/threonine kinase V600E mutation; colorectal cancer; monopolar spindle protein kinase 1.