Systemic Delivery of Synthetic MicroRNA-16 Inhibits the Growth of Metastatic Prostate Tumors via Downregulation of Multiple Cell-cycle Genes

Abstract

Recent reports have linked the expression of specific microRNAs (miRNAs) with tumorigenesis and metastasis. Here, we show that microRNA (miR)-16, which is expressed at lower levels in prostate cancer cells, affects the proliferation of human prostate cancer cell lines both in vitro and in vivo. Transient transfection with synthetic miR-16 significantly reduced cell proliferation of 22Rv1, Du145, PPC-1, and PC-3M-luc cells. A prostate cancer xenograft model revealed that atelocollagen could efficiently deliver synthetic miR-16 to tumor cells on bone tissues in mice when injected into tail veins. In the therapeutic bone metastasis model, injection of miR-16 with atelocollagen via tail vein significantly inhibited the growth of prostate tumors in bone. Cell model studies indicate that miR-16 likely suppresses prostate tumor growth by regulating the expression of genes such as CDK1 and CDK2 associated with cell-cycle control and cellular proliferation. There is a trend toward lower miR-16 expression in human prostate tumors versus normal prostate tissues. Thus, this study indicates the therapeutic potential of miRNA in an animal model of cancer metastasis with systemic miRNA injection and suggest that systemic delivery of miR-16 could be used to treat patients with advanced prostate cancer.

MicroRNAs as regulators of bone homeostasis and bone metastasis

“…In addition, miR-16 was shown to inhibit bone metastasis in a mouse prostate cancer xenograft model. 68 MiR-146a was shown to target ROCK1 in androgen-independent PC3 cells; overexpression of miR-146a led to reduced proliferation and invasion, and impaired adhesion to a monolayer of human bone marrow endothelial cells. 69 Finally, multiple studies have shown inhibitory effects from miR-145 on prostate cancer bone metastasis.…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…LNA directed against miR-21 reduced tumor growth in vivo [110] , which suggests a therapeutic role for anti-miR-21 in treating cancers. In addition, miR-16, which is frequently deleted and/ or down-regulated in human cancers, significantly inhibits prostate tumor growth in vivo when delivered by atelocollagen via tail vein injection [111] . These results indicate that the delivery of miR-16 could be used to treat patients with advanced prostate cancer.…”

MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice

“…Fifty micrograms of double-strand mature mmu-miR-29a (miR-29a) or nonspecific oligonucleotide (negative control for miR-29a: NC miRNA) (Bonac, Fukuoka, Japan) was mixed with 200 µl of atelocollagen (Atelo gene; KOKEN, Tokyo, Japan) and injected via the tail vein every 3 days. 36 MiRNA was administrated two times in mice treated for 1 week and four times in mice treated for 2 weeks. Thus, mice for each fibrotic model were now spread over eight groups: observed without any treatment (1 week observation/2 weeks observation), administrated only atelocollagen, a vehicle for nucleotides (1 week vehicle/2 weeks vehicle), administrated NC miRNA (1 week NC miRNA/2 weeks NC miRNA), or administrated miR-29a (1 week miR-29a/2 weeks miR29a) (Figure 2a).…”