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
Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Oncol Lett. 2019 Mar;17(3):2809-2817. doi: 10.3892/ol.2019.9924. Epub 2019 Jan 14.
Colorectal cancer (CRC) with the V600E mutation of B-Raf proto-oncogene serine/threonine kinase (BRAF) 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 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 only, rather than of wild-type BRAF as well, which contributes to tumorigenesis in melanoma. In the present study, the incidence of BRAF in patients with CRC was identified and the correlation of Mps1, phospho-extracellular-signal-regulated kinase (p-ERK) and BRAF was investigated. The results indicated that the mutation rate of BRAF was 5.2% in CRC. Poorly differentiated tumors and mucinous tumors have a significantly higher incidence of BRAF 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 compared with in patients with wild-type BRAF (BRAF). The expression of p-ERK and Mps1 in CRC with BRAF was significantly higher compared with in CRC with BRAF (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/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.
具有B-Raf原癌基因丝氨酸/苏氨酸激酶（BRAF）V600E突变的结直肠癌（CRC）对化疗不敏感，提示患者预后不良。尽管BRAF抑制剂对携带BRAF突变的恶性黑色素瘤有显著疗效，但对具有相同BRAF突变的CRC患者疗效有限。先前的一项研究发现了一个新基因，单极纺锤体蛋白激酶1（Mps1），它仅是BRAF的下游靶点，而非野生型BRAF的下游靶点，其在黑色素瘤的肿瘤发生中起作用。在本研究中，确定了CRC患者中BRAF的发生率，并研究了Mps1、磷酸化细胞外信号调节激酶（p-ERK）与BRAF的相关性。结果表明，CRC中BRAF的突变率为5.2%。与高分化肿瘤和非黏液性肿瘤相比，低分化肿瘤和黏液性肿瘤中BRAF的发生率显著更高（P<0.05）。Kaplan-Meier生存分析表明，与野生型BRAF患者相比，BRAF患者的生存率显著更低。与BRAF野生型的CRC相比，BRAF突变的CRC中p-ERK和Mps1的表达显著更高（P<0.05），且它们的表达与癌症分类、分化程度和淋巴结转移相关（P<0.05）。此外，p-ERK表达与Mps1表达呈正相关，列联系数为0.679（P=0.002）。总之，本研究结果表明，Mps1与BRAF/p-ERK显著相关，可能在CRC的发生发展中起关键作用。本研究结果提示，靶向致癌性BRAF和Mps1，尤其是联合靶向，可能为CRC的治疗提供有前景的治疗机会。
