Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells

Abstract

Accumulating evidence suggests a role for microRNAs in human carcinogenesis as novel types of tumor suppressors or oncogenes. However, their precise biological role remains largely elusive. In the present study, we aimed to identify microRNA species involved in the regulation of cell proliferation. Using quantitative RT-PCR analysis, we demonstrated that miR-34a was highly up-regulated in a human colon cancer cell line, HCT 116, treated with a DNAdamaging agent, adriamycin. Transient introduction of miR-34a into two human colon cancer cell lines, HCT 116 and RKO, caused complete suppression of cell proliferation and induced senescencelike phenotypes. Moreover, miR-34a also suppressed in vivo growth of HCT 116 and RKO cells in tumors in mice when complexed and administered with atelocollagen for drug delivery. Gene-expression microarray and immunoblot analyses revealed down-regulation of the E2F pathway by miR-34a introduction. Up-regulation of the p53 pathway was also observed. Furthermore, 9 of 25 human colon cancers (36%) showed decreased expression of miR-34a compared with counterpart normal tissues. Our results provide evidence that miR-34a functions as a potent suppressor of cell proliferation through modulation of the E2F signaling pathway. Abrogation of miR-34a function could contribute to aberrant cell proliferation, leading to colon cancer development.microRNA ͉ p53 ͉ adriamycin ͉ atelocollagen

miR-449a targets HDAC-1 and induces growth arrest in prostate cancer

“…Activation of miR-34a by p53 normally promotes cell-cycle arrest through the modulation of E2F protein expression (He et al, 2007;Raver-Shapira et al, 2007;Tarasov et al, 2007). Further, it was shown that introduction of miR-34a into cancer cells suppressed their growth in vivo, thereby demonstrating the potency of this tumor-suppressive miRNA (Tazawa et al, 2007).…”

Systemic Delivery of a miR34a Mimic as a Potential Therapeutic for Liver Cancer

“…3) and reduced levels of the tumor-suppressor miRNA have been observed in a variety of cancer types, including liver cancer (4,5). When introduced into cancer cells, miR34a induces cell-cycle arrest (6), senescence (7), and apoptosis (7). The miRNA also inhibits cancer stem cell development (8)(9)(10).…”

MicroRNA‐214 is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells

“…Moreover, previous studies have demonstrated that a number of miRNAs are also involved in tumor pathogenesis and the development of different types of human cancers, including cervical (17), ovarian (8,18), lung (19), breast (9), colon (10), and prostate cancers (12).…”

“…Recent studies have shown that miRNAs are aberrantly expressed in different cell types and at different developmental stages, suggesting that miRNAs play important roles in cell growth (8)(9)(10)(11)(12), differentiation (13,14), metabolism (15), and programmed cell death (16). Moreover, previous studies have demonstrated that a number of miRNAs are also involved in tumor pathogenesis and the development of different types of human cancers, including cervical (17), ovarian (8,18), lung (19), breast (9), colon (10), and prostate cancers (12).…”