Abstract
Abnormal expression of cyclin-dependent kinase 5 (CDK5) has been found in several human cancers, whereas the role of CDK5 in the malignant development of colorectal cancer (CRC) has not been well characterized. Here we investigated the role of CDK5 in CRC and found that its expression was much higher in CRC tissues than that in normal tissues with a higher expression level of CDK5 closely correlating to advanced American Joint Committee on Cancer (AJCC) stage, poor differentiation, increased tumor size and poor prognosis of CRC. Biological function experiments showed that CDK5 regulated CRC cell proliferation and metastasis ability. Whole-genome microarray analysis, co-immunoprecipitation, in vitro kinase assay, western blotting, luciferase reporter assays and electrophoretic mobility shift assay (EMSA) showed that CDK5 could directly phosphorylate ERK5 at threonine (Thr) 732 and finally modulate the oncogenic ERK5–AP-1 axis. Further researches showed that CDK5–ERK5–AP-1 axis could promote progression of CRC carcinogenesis and had a significant correlation in human CRC samples. In summary, this study revealed the functional and mechanistic links between CDK5 and the oncogenic ERK5–AP-1 signaling pathway in the pathogenesis of CRC. These findings suggest that CDK5 has an important role in CRC development and may serve as a potential therapeutic target for CRC.
Highlights
Colorectal cancer (CRC) is one of the most common malignancies in the world involving progressive disruption of epithelial cell proliferation, apoptosis, differentiation and survival mechanisms.[1,2] The CRC carcinogenesis is a multistep and multi-factorial process related to various genetic and epigenetic alterations, including the activation of various oncogenes or inactivation of tumor-suppressor genes.[3,4] the power of many existing biomarkers in early diagnosis or predicting the clinical outcome of individual tumors is limited owing to the great heterogeneity of this cancer
cyclin-dependent kinase 5 (CDK5) and p35 were both upregulated in CRC
The protein levels of CDK5 and its activator p35 varied in seven CRC cell
Summary
Colorectal cancer (CRC) is one of the most common malignancies in the world involving progressive disruption of epithelial cell proliferation, apoptosis, differentiation and survival mechanisms.[1,2] The CRC carcinogenesis is a multistep and multi-factorial process related to various genetic and epigenetic alterations, including the activation of various oncogenes or inactivation of tumor-suppressor genes.[3,4] the power of many existing biomarkers in early diagnosis or predicting the clinical outcome of individual tumors is limited owing to the great heterogeneity of this cancer. Biological function experiments showed that CDK5 regulated CRC cell proliferation and metastasis ability.
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