MICRORNA-MEDIATED REGULATION OF LUNG CANCER

miRNAs are a recently identified class of non–protein encoding
small RNAs present in the genomes of plants and animals.
Ranging in size from 20 to 25 nucleotides, miRNAs are small
RNA molecules that are capable of regulating gene expression
by either direct cleavage of a targeted mRNA or inhibiting
translation by interacting with the 3’ untranslated region
(UTR) of a target mRNA. They are considered to play an
important role in the pathogenesis of cancer—as either oncogenes
or TSGs—because of abnormal expression found in several
types of cancer, including lung cancer. 113–121 Additionally,
more than 50% of miRNAs are located in cancer-associated
genomic regions or fragile sites. 122,123
As observed for analyses on mRNA, protein and methylation
patterns in lung cancer, miRNA microarrays have
enabled the identification of many lung cancer-associated miRNAs.
120,121,124–132 One of the most widely studied miRNAs in
lung cancer is the lethal-7 ( let-7 ) miRNA family. Functioning
as a tumor suppressor, it has been shown to regulate NRAS,
KRAS , and HMGA2 133,134 via binding to the let-7 binding
sites in their respective 3’ UTRs. 133,135 It is frequently underexpressed
in lung tumors, particularly NSCLC, compared with
normal lung, and decreased expression has also been associated
with poor prognosis. 120,125 Induction of let-7 miRNA expression
has been found to inhibit growth in vitro 120,134,136,137
and reduce tumor development in a murine model of lung
cancer. 137,138 In addition to let- 7, other miRNAs with suggested
tumor-suppressing effects in lung cancer include miR-126 , miR-
29a/b/c , miR-1 , 125–128 and recently, miR-128b was reported to
be a direct regulator of EGFR with frequent LOH occurring in
NSCLC cell lines. 129 Oncogenic miRNAs found to be overexpressed
in lung cancer include the miR-17-92 cluster of seven
miRNAs (with suggested targets that include PTEN and RB),
miR-205 , miR-21 , and miR-155 . 121,130
LUNG CANCER STEM CELLS AND
HEDGEHOG, NOTCH, AND WNT SIGNALING
The Hedgehog (HH), Wnt, and Notch signaling pathways are
important in normal lung development—specifically, progenitor
cell development and pulmonary organogenesis—however, they
are now also being studied in regard to their role in tumor development
(Fig. 5.2). These signaling pathways are thought to be
involved in the regulation on stem/progenitor cell self-renewal
and maintenance, and although this process is normally a tightly
regulated process, genes that comprise these pathways are often
mutated in human cancers, 139–141 leading to abnormal activation
of downstream effectors. In relation to cancer treatment, cancer
stem cells are of great importance because they are thought to be
resistant to cytotoxic therapies. If correct, this presents a need for
effective therapies against these self-renewal signaling pathways.
In the HH pathway, increased signaling results in activation
of the GLI oncogenes (GLI1, GLI2, and GLI3) that
can regulate gene transcription. 142–144 The HH signaling
pathway was originally shown to have persistent activation in
SCLC with high expression of SHH, PTCH, and GLI1, 145
but an important role in NSCLC was also recently demonstrated.
146 The Notch signaling pathway is important in cell
fate determination and can also promote and maintain survival
in many human cancers. 147–150 A recent study in mammary
stem cells suggests that the cytokine IL-6 may function as a
regulator of self-renewal in normal and tumor mammary stem
cells through the Notch pathway through upregulation of the
Notch-3 receptor, 151 which is expressed in approximately 40%
of resected lung cancers. 152 The multifunctional cytokine IL-6
is involved in activation of JAK family of tyrosine kinases, 153
which in turn activate multiple pathways through signaling
molecules such as STAT3, MAPK, and PI3K. 154 In lung
adenocarcinomas, activated mutant EGFR has also been shown
to induce levels of IL-6 leading to activation of STAT3. 155 The
Wnt pathway has critical roles in organogenesis, cancer initiation
and progression, and maintenance of stem cell pluripotency.
In NSCLC, studies have found dysregulation of Wnt
pathway members such as Wnt1, Wnt2, and Wnt7a, as well
as upregulation of Wnt pathway agonists (Dvl proteins, LEF1,
and Ruvb11) and underexpression or silencing of antagonists
(WIF-1, sFRP1, CTNNBIP1, and WISP2).