Biomedical Engineering Reference
In-Depth Information
5.2.2 Gain of miRNA Function and Cancer
Various cancers have increased expression of specific miRNAs, such as the miR-
17-92 cluster in B-cell lymphomas and miR-155 in lymphomas. The miR-17-92
cluster includes seven miRNAs and is present on the 13q31.3 locus, a locus
frequently amplified in B-cell lymphomas. The expression of this cluster is
known to be under the control of c-myc. The increased expression of this cluster
of miRNAs has been shown to be important for B-cell lymphomagenesis and
lung cancer tumorigenesis (Hayashita et al., 2005; He et al., 2005). Tumor growth
was further augmented because the miR-17-92 cluster also suppresses the func-
tion of the anti-angiogenic factors Tsp1 and CTGF (Dews et al., 2006). Indivi-
dual members of this cluster, such as miR-20a, have been shown to be oncogenic
in prostate cancers, as they act as anti-apoptotic factors. It was shown that mir-
17-5p and miR-20a regulate expression of E2F1-3 (Sylvestre et al., 2007). There is
a marked increase in the expression of miR-155 in lymphomas, and transgenic
models overexpressing miR-155 in B cells have shown B-cell polyclonal prolif-
eration followed by B-cell malignancies (Costinean et al., 2006). These observa-
tions established miR-155 as an oncogenic factor. In addition to its role in B-cell
lymphomas, miR-155 has been shown to be important in lung, breast, and
pancreatic cancers (Gironella et al., 2007; Iorio et al., 2005; Yanaihara et al.,
2006). One of the possible targets of miR-155 in B-cell lymphoma is Pu.1, a
transcription factor important for early B-cell commitment and development
(Vigorito et al., 2007). In pancreatic cancers, miR-155 is known to target the
stress-induced cell cycle arrest and pro-apoptotic factor TP53INP1, and their
expression levels were inversely related (Gironella et al., 2007).
5.2.3 Gain or Loss of miRNA Function and Cancer
There are groups of mRNAs that can be important in cancer pathogenesis when
their expression levels are low (tumor suppressor) or high (oncogenic), depending
on their cellular context. This group of miRNAs includes miR-221/222, miR-
125b, miR-17-5p, and miR-21. miR-221/222 are located on the X chromosome
and have been shown to be up-regulated in many types of cancer, including
thyroid cancer, glioblastomas, non-small cell lung cancer, and prostate cancer
(Galardi et al., 2007; Garofalo et al., 2008; le Sage et al., 2007; Visone et al.,
2007b). The oncogenic functions of miR-221/222 are mediated through down-
regulation of p27
Kip1
. These miRNAs function as tumor suppressors in the
context of erythroleukemia, where they target mRNA of the proto-oncogene
KIT (Felli et al., 2005). The oncogenic function of miR-125b in prostate cancer,
where it is shown to facilitate androgen-independent growth, is through targeting
of Bak1 (a Bcl2 family member of pro-apoptotic factors) (Shi et al., 2007). In
some cases of breast, thyroid, and prostate cancers, miR-125b functions as a
tumor suppressor (Ozen et al., 2008; Visone et al., 2007a; Volinia et al., 2006). In
breast cancers, it is known to suppress the expression of HER2 and HER3 (Scott
et al., 2007). One member of the miR-17-92 cluster, miR-17-5p, is shown to
