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ISABEL LÓPEZ DE SILANES Y MANEL ESTELLER AN. R. ACAD. NAC. FARM.

Cancer

In cancer, most studies have sought to identify mutations in the
coding region and very few naturally occurring mutations in
noncoding areas have been described to date. Genetic alterations
in 3’UTR sequences can modify the binding properties of trans-acting
factors and lead to deregulation in protein production. The examples
below illustrate the importance of the genetic alterations in AREs in
promoting malignancy and its usefulness in determining cancer
therapy. The first example described was for the oncogene c-fos and
its viral counterpart v-fos. The coding region of both c-fos and v-fos is
identical differing only in a missing 67-bp (that contains a ARE) in the
v-fos 3’UTR. Consequently, v-fos mRNA is more stable than
c-fos mRNA and this may account in part for its higher oncogenic
potential (11). Other naturally alteration in AREs have been described
such as the disruption of the 3’UTR during the integration of Human
papillomavirus type 16 (HPV-16), 3’UTR rearrangement of Cyclin D1
and translocation and deletion of ARE in the proto-oncogene c-myc,
all of them linked to malignant transformation. 3’UTR polymorphism
also affect mRNA stability as it has been found for the thymidylate
synthase (TYMS) gene. The polymorphism in the 3’UTR consists of the
deletion (D)/insertion (I) of a 6-bp stretch (TTAAAG). The D allele
showed decreased message stability compared to the I allele due to
increased binding to the decay-promoting protein AUF1 (12). In
agreement with this finding, colorectal tumors from D-allele carriers
have decreased intratumoral TYMS mRNA levels (13) suggesting that
the 3’UTR polymorphism can have an impact on the efficiency of
TYMS-targeted chemotherapy treatment. Another relevant example is
a novel single-nucleotide polymorphism (SNP) in the human
dihydrofolate reductase (DHFR) gene that influences mRNA
expression levels as well.

Other commonly found alteration in cancer is the frequently
elevated levels of RNA-binding proteins as it has been documented
for the mRNA-stabilizing protein HuR, and the destabilizing AUF1
and TTP in a wide variety of malignancies (6, 14-16). Depending on
the type of tumor, AUBPs with similar functions (e.g., AUF1 and
TTP) can have oncogenic or tumor suppressor activities (15, 16).
These studies suggest that AUBP play a central role in cancer by

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