Abstract
Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor in various types of cancer. However, it promotes colon cancer progression. The aim of this study is to clarify the underlying mechanism by which PROX1 regulates tumorigenicity of colon cancer. Association of PROX1 and clinicopathological features was studied by immunohistochemical staining. Pri-miR-9-2 and miR-9 were detected by quantitative real-time PCR. Assays of cell invasion, adhesion, and matrix metalloproteinase activity were used to study PROX1-mediated epithelial-mesenchymal transition (EMT). PROX1 was overexpressed in 43% (59/136) of colon cancer tissues and its expression was correlated with E-cadherin downregulation (P = 0.00005), advanced tumor staging (P = 0.005), and lymph node metastasis (P = 0.000009). Enforced expression of PROX1 in DLD-1 cells caused downregulation of E-cadherin and integrins and attenuated cell adhesion. These cells showed increase of matrix metalloproteinase activity and invasive ability. Conversely, knockdown of PROX1 in SW620 cells restored E-cadherin protein expression and reduced invasiveness. Unexpectedly, repression of E-cadherin by PROX1 was not mediated by transcriptional inhibition. We found that PROX1 bound to miR-9-2 promoter and triggered its expression to suppress E-cadherin 3'UTR reporter activity and protein expression. Anti-miR-9 restored E-cadherin in SW620 cells, whereas precursor miR-9 inhibited E-cadherin in PROX1-knockdown cells. The miR-9 level was higher in tumor tissues with high PROX1/low E-cadherin than that of tumor tissues with low PROX1/high E-cadherin. Our results provide mechanistic insights by which PROX1 promotes EMT and colon cancer progression. Targeting of PROX1-mediated oncogenic activity may be helpful for the treatment of colon cancer.
Highlights
Prospero homeobox 1 (PROX1) is an evolutionally conserved transcription factor that controls the fate and differentiation of neuron precursor cells, lymphatic endothelial cells, retinal progenitor cells, and hepatocytes [1,2,3,4]
PROX1 was overexpressed in 43% (59/136) of colon cancer tissues and its expression was correlated with E-cadherin downregulation (P 1⁄4 0.00005), advanced tumor staging (P 1⁄4 0.005), and lymph node metastasis (P 1⁄4 0.000009)
We found that PROX1 bound to miR-9-2 promoter and triggered its expression to suppress E-cadherin 30UTR reporter activity and protein expression
Summary
PROX1 is an evolutionally conserved transcription factor that controls the fate and differentiation of neuron precursor cells, lymphatic endothelial cells, retinal progenitor cells, and hepatocytes [1,2,3,4]. The Drosophia counterpart of PROX1, Prospero, has been shown to function as a brain. Authors' Affiliations: 1Institute of Biomedical Sciences, National Sun YatSen University; 2Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine; 3Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung; and 4National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
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