Therapeutic Application of MicroRNAs in Cancer - RNA Interference from Biology to Therapeutics - page 302

parental cell line [ 40 ]. Likewise, transfection of miR-143 into metastatic human
osteosarcoma cell lines significantly decreased invasiveness but not cell prolifera-
tion in an in vitro study [ 40 ]. In addition, intravenous injection of 50 mg of miR-143
with atelocollagen once in 3 days for 3 weeks to mouse significantly suppressed
lung metastasis of metastatic human osteosarcoma cell lines. Moreover, cells posi-
tive for MMP13, a target of miR-143 in osteosarcoma cells, were found in lung
metastasis-positive cases but not, in at least three cases, in the nonmetastasis group
showing higher miR-143 expression.
Cellular senescence is a barrier to cancer progression. Therefore, senescence
induction is a novel approach to cancer treatment. Xu et al. reported that the expres-
sion of miR-22, which is upregulated in human senescent fibroblasts and epithelial
cells but downregulated in various cancer cell lines, induces growth suppression
and acquisition of a senescent phenotype in human normal and cancer cells through
the suppression of CDK6, SIRT1, and Sp1 genes involved in the senescence pro-
gram [ 42 ]. Significantly, injection of miR-22 complexed with the cationic polymer,
polyethylenimine (PEI), led to reduced lung tumor growth and metastasis suppres-
sion in the mouse model. This suggests that miR-22 plays an important role in
tumor suppression.
An adeno-associated virus (AAV) vector was used for delivery of miR-26a that
exhibits high expression in normal adult liver but low expression in both human and
murine liver tumors. miR-26a directly downregulates cyclins D2 and E2 and induces
a G 1 arrest in human liver cancer cells in vitro [ 43 ]. Systemic administration of miR-
26a in a mouse model of HCC resulted in the inhibition of cancer cell proliferation,
induction of tumor-specific apoptosis, and dramatic protection from disease pro-
gression without toxicity. In addition, overexpression of let-7 that has been pro-
posed to function as a tumor suppressor, and whose expression is commonly
downregulated in nonsmall cell lung cancer, showed significant tumor growth
reduction of nonsmall cell lung tumors in an autochthonous model of NSCLC in
mouse using a lentiviral vector [ 44 ]. In these studies, the authors employed primary
miRNA sequences for miRNA expression by the virus vector. Precise sequences of
primary miRNAs are needed for the correct processing of miRNAs. Knowing the
sequences of primary transcripts enables the therapeutic application of vector-based
delivery systems.
These findings suggest that delivery of miRNAs that are highly expressed in
normal tissues but lost in disease cells may provide a general strategy for miRNA
replacement therapies and that systemic delivery of tumor-suppressive miRNAs
could be used to treat patients with advanced cancers (Fig. 14.1 ).

14.2.3 Exosome Delivery for miRNA Therapeutics

Recently, the group of Lotvall reported the surprising discovery that miRNAs are
contained inside exosomes, which are lipoprotein complexes, including small mem-
brane vesicles of endocytic origin (30-100 nm) [ 45 ]. Exosomes can be formed