Tumor suppressors p53, p63, and p73 inhibit migrating cancer stem cells by increasing the expression of stem cell suppressing miRNAs

Abstract

ZEB1/2 has been shown to suppress the expression of the tumor suppressors E-cadherin, TA-p73, INK4b, CDKN1a, and thereby promotes epithelial to mesenchymal transition, invasion, and metastasis. I have recently shown that p53-dependent miRs, such as miR-192, 215, 145, 203, 200b/c, 183, suppress the expression of ZEB1/2. Another recent study showed that ZEB1/2 suppresses the expression of miR-200b/c, miR-203, & miR-183, which in turn, inhibit the expression of stem cell factors, such as Sox-2, Klf-4, and BMI. ZEB1/2, by inhibiting the expression of stem cell factors suppressing miRs, it up regulates the expression of stem cell factors. By up regulating the stem cell factors and down regulating metastasis suppressors, ZEB1/2 promotes both metastasis and migration of cancer stem cells. p53/p63/p73, by down regulating the expression of ZEB1/2 through its target miRNAs, it could activate the expression of stem cell suppressing miRNAs, such as miR-200b/c, miR-203 & miR-183. Thereby, it could inhibit the expression of stem cell factors, such as Sox-2, Klf-4 and BMI-1(an inhibitor of INK4a/ARF). In addition, p53/p63/p73 appears to inhibit the expression of other EMT inducers, such as Snail1/2 and Twist, expression through its target miRs. Remarkably, bioinformatics analysis of stem cell factors suppressing miRNAs, miR-200, miR-183, miR-141, and miR-203, promoters revealed a number of p53/p63/p73 responsive elements, indicating that they could be direct transcriptional targets of p53/TA-p63/p73. Together, these data suggest that p53/TA-p63/p73, by suppressing the expression of ZEB1/2, Snail1/2, and Twist through its target miRs, it could inhibit migration, metastasis, and proliferation of cancer stem cells. In conclusion, the data presented here provide mechanistic insights into how TA-p63/p73 and p53 function as metastasis suppressors.