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MiRNA-200 induces apoptosis but uses a different pathway possibly the CD95/
Fas pathway. Zaman et al. (2010) found that transfection of miRNA-145 into PC-3
prostate carcinoma cells caused increased apoptosis. The miRNAs-17-92 are said to
promote the development of myc-induced murine B cell lymphoma, by obliteration
of mRNAs coding for proteins promoting apoptosis. The bcl-2 family genes which
regulate apoptosis have been described as targets of certain miRNAs. The tumour-
suppressor PTEN/Akt pathway has also been cited as an miRNA target. Suppression
of PTEN and inhibition of apoptosis is one of the mechanisms (Bar and Dikstein,
2010; Zhang et al., 2010a, 2012a).
The regulation of anti-apoptosis gene bcl-2 might also be involved in some
instances (Si et al., 2007). Cell proliferation might be influenced by other pathways
that include altering the function of cell cycle regulatory proteins. MiRNAs have been
reported to function as tumour suppressors by targeting c-myc, the cell cycle regula-
tor cyclin A1 and the homeobox protein Six1. Six1 is targeted by miRNA-185 (Imam
et al., 2010). Davis et al. (2009) reported upregulated expression of miRNA-221 with
downregulation of p27kip1 in the induction of proliferation by PDGF. It is evident
from recent work that miRNAs might function by regulating cyclin-dependent kinases
(cdks). Zheng et al. (2011) found that miRNA-21 promotes proliferation and invasion
by subduing p12 (CDK2-AP1). The latter suppresses cell proliferation by inhibiting
cdk2 and G1/S transition. They have shown that miRNA-21 targets p12 (CDK2-AP1)
by interaction with specific motifs of its 3′-UTR. MiRNAs might function via the
cdc42 (cell division control) protein signalling, a Rho-type-like GTPase that is regu-
lated by G1-cdk. Cdc42 is overexpressed in many tumours and activating mutations
have been shown to lead to cell transformation, tumorigenesis and invasion (Stengel
and Zheng, 2011). MiRNAs might use the cdc42 route to facilitate transduction of sig-
nals from RTKs, G-protein-coupled receptors (GPCRs) and integrins. Cdc42 activates
downstream pathways regulated by PAKs (p21-activated protein kinases), namely
MAPK/PAK3-ERK (extracellular signal-regulated kinase) promoting cell prolifera-
tion and also PAK1-JNK (c-Jun N-terminal kinase) pathways that influence apoptosis.
With its ability to modulate cytoskeletal organisation cdc42 possibly could also modu-
late invasive behaviour. It is interesting therefore to note that MiRNA-137 is down-
regulated in gastric carcinoma cells in association with upregulating of cdc42. When
levels are restored miRNA-137 appears to target cdc42 and inactivates it leading to G1
arrest and apoptosis (Chen et al., 2011b).
It would be of much interest to note that activation of p53, a tumour suppressor and
key regulator of cell cycle progression, was shown some while ago to upregulate the
expression of some, notably of miRNA-34a and downregulate the expression of other
miRNAs. Indications are that this miRNA might induce apoptosis and arrest cell cycle
progression in G1. Also of interest is that p53 appeared to bind to a site proximal to the
first non-coding exon of the miRNA (Tarasov et al., 2007). Transfection into the colo-
rectal cancer HCT-116 cells and experimental upregulation of expression of miRNA-
211 halved the expression of CHD5 (chromodomain helicase DNA-binding protein
5), a postulated tumour suppressor, and resulted in enhanced cell proliferation. Forced
expression of miRNA-21 enhanced Bcl-2 and Bcl-xL by around 30% and reduced Bad
gene expression by approximately 20% (Cai et al., 2012).
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