Malignant growth is often described as increased cellular proliferation induced by uncontrolled activation of mitogenic signaling pathways [27
]. The MEK5/ERK5 signaling pathway regulates a wide variety of cellular processes during development and also plays an important role in human malignant diseases[28
]. The MEK5/ERK5 signaling pathway is upregulated in many types of cancer, including prostate cancer [11
], breast cancer [16
], and oral squamous cell carcinoma [29
]. In metastatic prostate cancer, strong MEK5 expression is correlated with bony metastases, and less favorable prognosis is caused by upregulated BMK1-induced activator protein-1 (AP-1) activity, a consequent induction of a high level of matrix metallo-protease-9 (MMP-9) and augmented invasive potential [11
]. In oral squamous cell carcinoma, Sticht and colleagues [29
] found that the high pERK5 expression in oral squamous cell carcinoma was associated with an advanced tumor stage and the presentation of lymph node metastases. In breast cancer cells, the activated oncogene STAT3 binds to the promoter regions of MEK5 and induces transcription, conferring a critical survival signal [17
]. Moreover, during chemotherapeutic-induced apoptosis, overexpression of MEK5 in breast cancer cells provides a key survival signal for chemoresistence [30
]. These findings suggested that pMEK5 might be involved in tumor progression and metastatic events.
Our original studies find that activation of MEK5 (pMEK5) was increased in CRC cases. We examined the expression of pMEK5 by immunohistochemistry and western blot, and found that pMEK5 protein expression was increased in CRC compared with adjacent normal mucosa from the same individual. Furthermore, we find that the pMEK5 expression status was significantly correlated with progression of CRC.
In this study, we examined the expression of pMEK5 in 335 cases of CRC by immunohistochemistry. pMEK5 was highly expressed with depth of invasion, especially in T3, T4 carcinomas, but not in T1 and T2 carcinomas (P = 0.001). Therefore, the depth of invasion is a very important prognostic factor, suggesting that pMEK5 can be used as a biomarker to identify subsets of CRC patients with more aggressive feature.
Another interesting finding was that lymph node metastases were detected more frequently in CRC patients with pMEK5 overexpression, when compared with normal cases of pMEK5 expression (P
< 0.001). The same tendency was observed in distant metastases (P
< 0.001), suggesting that the pMEK5 protein may play a role in tumor metastasis, which is consistent with previous studies of prostate cancer [11
]. Consistently, we found that pMEK5 expression in CRC was positive correlation with TNM stage, and pMEK5-overexpression was significantly higher in cases at advanced stage than those at early stage.
One of the greatest challenges in colorectal cancer management is to accurately diagnose the tumor stage and determine proper adjuvant therapy. In early CRC, surgery may be all that is required [31
]. In more advanced cancer, other treatments, such as chemotherapy or radiation therapy, may be required [33
]. So, detection of the tumor stage seemed to be very important. Currently, the TMN staging system of tumors continues to be the gold standard for clinical stages in world wild. However, identifying the lymph node metastasis and distant metastasis with TNM staging system is difficult. For the TNM staging system, the screening of distant metastasis is primarily determined by imaging studies (CT, MRI or PET-CT), ultrasound, and by direct visualization and palpation during operation. These common examination methods have poor detection of early distant metastasis, such as CRC patients with less than 1 cm liver metastasis [35
]. Our study found that pMEK5 could be helpful in the pathological study of CRC, especially for the classification of different stages in CRC and early distant metastasis, which would improve efficacy of multimodal therapy and allocation of resources, sparing patients from unnecessary procedures.
Moreover, Kaplan-Meier analysis of the survival curves showed a significantly worse 5-year disease-free (log-rank test, P = 0.002) and 5-year overall survival rate (log-rank test, P < 0.001) for patients whose tumors overexpressed pMEK5. This suggests that pMEK5 protein is a biomarker identifying a poor prognosis for patients with colorectal cancer. However, multivariate analysis showed that pMEK5 expression is not a biomarker for a worse prognosis (DFS: P = 0.139; OS: P = 0.071). Our results demonstrate that pMEK5 expression was correlated with a worse prognosis, but that pMEK5 was not an independent prognostic factor for CRC. The key reason may be due to the lack of adequate cases.
However, this study is retrospective look at the expression of pMEK5 in the CRC tissue, it is not able to establish if the expression of the pMEK5 is after CRC has occurred. And the mechanism of actions for pMEK5 protein is not known and needs further investigation. Patients with colorectal cancer whose pMEK5 expression is elevated may require a more powerful adjunctive therapy and intensive follow-up. Whether pMEK5 has value clinically as a biomarker for therapeutic approaches in patients with colorectal cancer should be followed up with additional appropriately, designed studies.