The Application of MicroRNAs in Cancer Diagnostics - RNA Interference from Biology to Therapeutics - page 279

required for differentiation [ 236, 237 ]. A central theory of carcinogenesis is the
dedifferentiation of cancer cells into a phenotype resembling stem cells, possibly
through mechanisms involving the PRCs (reviewed in [ 238, 239 ] ). The close asso-
ciation of deregulated lincRNAs with PRCs, therefore, suggests a pivotal role for
such lincRNAs in cancer.
Hox antisense intergenic RNA (HOTAIR) is one of the most publicized exam-
ples of a cancer-associated lincRNA capable of interacting with PRC2. HOTAIR
resides in the HOXC gene locus and is frequently overexpressed in breast cancer,
colorectal cancer, and hepatocellular carcinoma [ 240- 242 ] . Overexpression of
HOTAIR in breast cancer-derived cell lines modulates the pattern of PRC2 occu-
pancy into resembling that of embryonic fibroblasts, and many of the genes targeted
by HOTAIR/PRC2 are associated with breast cancer. Furthermore, HOTAIR trans-
fected cells have a greater invasive potential in matrix invasion assays in vitro as
well as when injected into mice [ 240 ]. These observations likely explain the finding
of high HOTAIR expression in breast cancer, colorectal cancer, and hepatocellular
carcinoma as a significant predictor of metastasis and death [ 240- 242 ] . Thus, poten-
tially, HOTAIR may be useful as a future biomarker for aggressive cancer types.
Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is also known to be
overexpressed in prostate cancer [ 243 ]. PCAT-1 (like HOTAIR) interacts with PRC2
in order to regulate expression of downstream genes. However, PCAT-1 itself is also
regulated by PRC2. Accordingly, expression of PCAT-1 and the PRC2 subunit
EZH2 are almost mutually exclusive [ 243 ]. The implications of this relationship for
cancer development are still unresolved, but it appears that PCAT-1 is upregulated
in a subset of metastatic and high-grade tumors, which express low levels of EZH2.
Overexpression of PCAT-1 in prostate cancer cell lines results in higher levels of
proliferation, providing a likely explanation for the advantage of overexpression
of PCAT-1 in cancer cells. In summary, HOTAIR and PCAT-1 are two examples of
novel lincRNAs which may be used as diagnostic and/or prognostic markers for
different cancer types. Many more are likely to be discovered in the near future.
Long ncRNAs, including lincRNAs, are also emerging as possible enhancers of
gene transcription (reviewed in [ 234 ]). The mechanism(s) employed by activating
lncRNAs are unclear, but they seem capable of activating neighboring genes as
well as genes located several kilobases and more away [ 244 ] . Transcribed ultracon-
served regions (T-UCRs) constitute a likely subgroup of novel activating lncRNAs.
The corresponding UCRs are defined as genomic regions more than 200 base
pairs long that are 100% identical in mouse, rat, and human genomes [ 245 ] . UCRs
are strongly depleted in genomic regions containing germline copy number varia-
tions [ 246, 247 ] . The extreme evolutionary conservation and the apparent selec-
tion against alterations in copy number of these sequences suggest that they
perform essential cellular functions.
Based on the criteria listed above, there are 481 UCRs in the human genome
(excluding rRNA genes), most of which are transcribed [ 248 ] . UCRs are found
within protein coding genes as well as in introns and in intergenic regions [ 245 ] .