Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state

Abstract

Renewal of stem cells differs from cancer cell growth in self-controlled cell division. The mir-302 microRNA (miRNA) family (mir-302s) is expressed most abundantly in slow-growing human embryonic stem (ES) cells, and quickly decreases after cell differentiation and proliferation. Therefore, mir-302s was investigated as one of the key factors essential for maintenance of ES cell renewal and pluripotency in this study. The Pol-II-based intronic miRNA expression system was used to transgenically transfect the mir-302s into several human cancer cell lines. The mir-302 -transfected cells, namely, miRNA-induced pluripotent stem (mirPS) cells, not only expressed many key ES cell markers, such as Oct3/4, SSEA-3, SSEA-4 ,Sox2, and Nanog, but also had a highly demethylated genome similar to a reprogrammed zygotic genome. Microarray analyses further revealed that genomewide gene expression patterns between the mirPS and human ES H1 and H9 cells shared over 86% similarity. Using molecular guidance in vitro, these mirPS cells could differentiate into distinct tissue cell types, such as neuron-, chondrocyte-, fibroblast-, and spermatogonia-like primordial cells. Based on these findings, we conclude that mir-302s not only function to reprogram cancer cells into an ES-like pluripotent state but also to maintain this state under a feeder-free cultural condition, which may offer a great opportunity for therapeutic intervention.

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network

“…28 On the other hand, other reports described the miR-302-367 cluster as a stemness determinant in human embryonic stem cells (ESC) 29 and in inducible pluripotent stem cells (IPS) derived from human skin cancer cells. 30 In this context, the miR-302-367 promoter was transcriptionally regulated by the stemness transcription factors Oct4, Sox2, and Nanog; therefore, its expression in the ESC compartment and during early stages of mouse development was restricted. 20,31 In GiCs, the expression of the miR-302-367 cluster occurs concomitantly with the suppression of Oct4 and Nanog, as well as with the loss of self-renewal.…”

Induced Pluripotency and Oncogenic Transformation Are Related Processes

“…3). Whatever the mechanism, which remains an open question, the fact that ROF were not able to differentiate as efficiently as iPSCs suggest that faithful reprogramming of cancer cells may require a different approach from that used in reprogramming noncancerous somatic cells, a notion supported by the reprogramming of melanoma cells using only miRNAs [58]. To date, a number of cancer cell types have been reprogrammed into iPS-like cells [59], including colorectal, pancreatic, hepatocellular carcinoma, and embryonal carcinoma [60].…”

Overcoming barriers to the clinical utilization of iPSCs: reprogramming efficiency, safety and quality

“…To this end, microRNAs expressed within ES cells that possibly suppress differentiation programs have emerged as possible enhancers of reprogramming. Indeed, several ES-expressed microRNAs, such as miR-291-3p, miR-294, miR-295, and miR-302, are capable of enhancing reprogramming efficiency when overexpressed (Lin et al, 2008;Judson et al, 2009;Melton et al, 2010) (Table 4).…”