Regulation of cancer metastatic program by P53/miRNA-34 Axis dependent CD44 expression

Abstract

CD44 is a transmembrane glycoprotein involved in cell-cell and cell-matrix adhesion and in cell migration. This protein participates in a wide variety of cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. Recent study reveals that CD44 plays an important role in regulation of cancer stem cells. P53 tumor suppressor is the key player at the center of a complex molecular network regulating diverse cancer related pathways. MiRNA are short non-coding RNAs, on average only 22 nucleotides long, which interact with complementary or near-complementary matched sites in the untranslated regions (UTRs) of mRNA targets. It is a vital and evolutionarily ancient component of genetic regulation and can have tumor suppressor or oncogenic activity. The previous studies on miRNA-34 family induced by p53 activation had focus on the function of cell cycle arrest, apoptosis. But the relationship of the p53/miRNA-34 tumor suppressor network and cancer stem cells remains unclear.In this study, we showed miR-34 family''s direct target sites on CD44 by the bioinformatic prediction, which lie in 3'' UTR and 5'' UTR. We also examined the Regulation of CD44 by p53-miR34 tumor suppressor network and the role of CD44 in cancer migration and invasion. The results are as follows:1. The miRNA-34 family has target sites on 3’ UTR and 5’ UTR of CD44 simultaneously.2. CD44 is highly expressed in A549 cells and MDA-MB 231 cells.3. Loss of p53 function and p53 degradation potentiate CD44 protein expression and 3’ UTR and 5’ UTR’s activity. 4. CD44 is a direct target of miRNA-34.5. MiRNA-34 inhibits CD44-mediated cancer cell migration and invasion.The results of the study provide insight into the mechanisms by which p53/miR-34 axis restrains CD44, and suggest the therapeutic strategy in cancer stem cells.