Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

Abstract

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cyclearrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27 KIP1 . Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2-p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cellcycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.

microRNA-200b and microRNA-200c promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs

“…35 The pathways constraining the proliferative response in normal cells are perturbed in most cancers. Previous studies have showed that RECK plays an important role in regulating SKP2 and p27 Kip1 expression, 12 which is important to control mammalian cell proliferation.…”

“…11 Recent research has shown that RECK can suppress cell proliferation and induce cellular senescence when acutely expressed in cancer cells and that at least some of these effects can be attributed to the downregulation of SKP2 (S-phase kinaseassociated protein 2) and consequent upregulation of p27 Kip1 (also known as cyclin-dependent kinase inhibitor 1B, CDKN1B). 12 In the present study, we predicted that RECK was a target of miR-200b and miR-200c (miR-200b/c). After measuring the expression levels of miR-200b/c and RECK in human colorectal cancer and normal adjacent tissue samples, we detected an inverse correlation between miR-200b/c and RECK protein levels in human colorectal cancer tissues and cell lines.…”

Silencing of Reversion-Inducing Cysteine-Rich Protein with Kazal Motifs Stimulates Hyperplastic Phenotypes through Activation of Epidermal Growth Factor Receptor and Hypoxia-Inducible Factor-2α

“…Yoshida et al found that the inhibition of cancer cell proliferation is mediated by S-phase kinase-associated protein 2 (SKP2) targeting p27 kip1 [34], which suggests that different molecules might be involved in the suppression of cell growth by RECK in a cell-specific manner. Thus, the downregulation of RECK and the stabilization of HIF-2α by hypoxia may contribute to the development of the hyperplastic phenotype in premalignant cells by increasing the expressions of genes involved in cell cycle progression.…”

Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity

“…Construction of the control adenoviral vector (Ad-LacZ) and the vector expressing human RECK (Ad-RECK) have been described [43, 44]. Replication-defective viruses were produced from these recombinant cosmids following the protocols of Miyake et al [45].…”