Therapeutic Application of MicroRNAs in Cancer - RNA Interference from Biology to Therapeutics - page 295

polymerase II. The pri-miRNAs are processed in the nucleus by the RNase III
enzyme Drosha into a 60-110-bp fragment called precursor miRNA (pre-miRNA).
Exportin-5 transports the pre-miRNAs into the cytoplasm, and another RNase III
enzyme, Dicer, processes the pre-miRNAs into double-stranded 18-24-bp mature
miRNAs. The double-strand mature miRNA is composed of two complementary
single-stranded molecules, known as the guide strand and the antiguide or passen-
ger strand. The mature miRNA can bind to a complementary sequence, typically in
the 3¢ untranslated region (3¢ UTR), of target mRNAs as part of the RNA-induced
silencing complex (RISC). This base pairing subsequently causes degradation of the
mRNA and/or inhibition of protein translation. miRNAs are predicted to regulate
the expression of ~90% of all human genes. The expression of miRNAs is highly
specific for tissues and developmental stages, and essential miRNA functions have
been observed in several fundamental biological processes, such as development,
organogenesis, and homeostasis.
Recently, dysregulation of miRNA expression was found to contribute to the
initiation and progression of cancer [ 3 ]. The function and expression patterns of
miRNAs have been intensively investigated in various human cancers. The deregu-
lation of miRNA expression has been shown to contribute to cancer development
through various kinds of mechanisms, including deletions, amplifications, or muta-
tions involving miRNA loci, epigenetic silencing, the dysregulation of transcription
factors that regulate specific miRNAs, or by inhibition of miRNA processing [ 4 ] .
miRNA expression profiling is becoming increasingly important as a useful diag-
nostic and prognostic tool, and many studies indicate that miRNAs can act as onco-
genes and/or tumor suppressor genes.

14.1.1 Tumor-Suppressive miRNAs Attenuate Cancer Cell

Malignancy

Among the first and most intensively studied tumor-suppressive miRNAs are let-7
and miR-16. It has been reported that the expression of let-7 is frequently reduced
in lung cancers and that reduced let-7 expression is significantly associated with
shorter patient survival [ 5 ]. In addition, overexpression of let-7 in the lung adeno-
carcinoma cell line, A549, inhibited cellular growth in vitro. The known targets of
let-7 include representative oncogenes such as RAS and HMGA2 [ 6- 8 ] . Expression
of let-7 is lower in lung tumors than in normal lung tissue, while RAS protein is
significantly higher in lung tumors, providing a possible mechanism for let-7 in
cancer. Furthermore, the high-mobility group A2, HMGA2, is oncogenic in a vari-
ety of tumors, including benign mesenchymal tumors and lung cancers. Ectopic
expression of let-7 has shown to reduce HMGA2 expression and cell proliferation
in lung cancer cells.
Emerging evidence suggests that cancer stem cells (CSCs) are responsible for
tumor formation, maintenance, and progression [ 9 ] . These cancer-initiating cells
are rare tumor cells characterized by their strong tumorigenic properties and the