Abstract
Cancer is a complex disease process that evolves as a consequence of multiple malfunctions in key regulatory molecular networks. Understanding these networks will be essential to combat cancer. In this study, we focussed on central players in such networks. In a series of colon and breast cancer cell lines, we found that CD24 activates Src, and induces the activation of c-Jun and expression of c-Jun and c-Fos. Thereby CD24 increases the promoter activity and expression of miR-21, which in turn suppresses expression of Pdcd4 and PTEN. Co-transfection of a CD24 expression construct and an siRNA that silences Src showed that CD24-dependent upregulation of miR-21 is mediated by Src. Additionally, we found that miR-34a post-transcriptionally downregulates CD24 and Src expression, leading to the deactivation of c-Jun, reduced expression of c-Jun and c-Fos, inhibition of miR-21, and upregulation of Pdcd4 and PTEN. Furthermore, miR-34a-mediated inhibition of Src expression reduced migration and invasion of colorectal cancer cells. Resected tumor tissues from 26 colorectal patients showed significantly lower expression of Pdcd4 and miR-34a, and higher expression of CD24, Src and miR-21 compared to the corresponding normal tissues. Moreover, CD24 positively correlated with the amount of Src protein in tumor tissues, and a trend towards an inverse correlation between miR-34a and Src protein levels was also observed. Our results reveal essential players in the complex networks that regulate the progression of solid tumors such as colorectal cancer. These findings therefore identify novel therapeutic approaches for combating tumor growth and progression.
Highlights
Tumorigenesis is a multistep process that is regulated by complex molecular networks whose activity is perturbed by sequential alterations in a variety of oncogenes, tumor-suppressor genes and microRNA genes [1]
To investigate further the signalling pathways addressed by CD24 and their possible implications for cancer progression, we first investigated whether ectopic expression of CD24 is able to increase the activity of Src and its downstream signalling axis in a panel of colorectal cancer cell lines
We screened for miR-21 expression following CD24-overexpression or knockdown, because we and others have shown that miR-21 is regulated by AP-1 family members [22,23]
Summary
Tumorigenesis is a multistep process that is regulated by complex molecular networks whose activity is perturbed by sequential alterations in a variety of oncogenes, tumor-suppressor genes and microRNA genes [1]. These alterations are usually somatic events, germ-line mutations can predispose a person to heritable or familial cancer. CD24 may act in several ways to exert these effects It can support rolling of tumor cells on endothelial monolayers due to its ability to bind to P-selectin [9], a protein expressed on thrombin-activated platelets [10,11] and endothelial cells [11,12]. Much remains to be learned about the activity of CD24 in the context of cancer
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