Page 190 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster
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176 C H A P T E R 5 Neoplasia
miRNA gene ? miRNA gene ?
Oncogene Tumor
suppressor gene
pre-miRNA pre-miRNA
?
?
Target mRNA ? Target mRNA Abundant
of oncogene Reduced of tumor miRNA
miRNA
suppressor gene
Reduced translational repression Increased translational repression
A Overexpressed oncoprotein B Reduced tumor suppressor protein
Increased proliferation
Reduced apoptosis
Increased invasiveness
Angiogenesis
Figure 5–16 Role of microRNAs (miRNAs) in tumorigenesis. A, Reduced activity of an miRNA that inhibits translation of an oncogene gives rise to
an excess of oncoproteins. B, Overactivity of an miRNA that targets a tumor suppression gene reduces the production of the tumor suppressor
protein. Question marks in A and B are meant to indicate that the mechanisms by which changes in the level or activity of miRNA are not entirely
known.
during the past several years that tumor suppressor genes response to signals that control growth and differentiation.
are sometimes silenced by hypermethylation of promoter As mentioned earlier, epigenetic modifications regulate
sequences, rather than by mutation. As discussed later, gene expression, allowing cells with the same genetic
CDKN2A is a complex locus that encodes two tumor make-up (e.g., a neuron and a keratinocyte) to have com
suppressors, p14/ARF and p16/INK4a, produced from pletely different appearances and functions. In some
two different reading frames; p14/ARF is epigenetically instances, the epigenetic state of a cell dramatically affects
silenced in colon and gastric cancers, while p16/INK4a is its response to otherwise identical signals. For example, the
silenced in a wide variety of cancers. Since this locus pro gene NOTCH1 has an oncogenic role in T cell leukemia,
duces two tumor suppressors that affect the p53 and Rb yet acts as a tumor suppressor in squamous cell carcino
pathways, silencing this locus has the pleasing effect (from mas. As it turns out, activated NOTCH1 turns on pro-
the cancer’s standpoint) of removing two checkpoints with growth genes in the epigenetic context of T cell progenitors
a single alteration. Genome-wide hypomethylation has (e.g., MYC) and tumor suppressor genes (e.g., p21) in the
been shown to cause chromosomal instability and can epigenetic context of keratinocytes.
induce tumors in mice. Thus, epigenetic changes may influ
ence carcinogenesis in many ways. As an added wrinkle, S U M M A RY
deep sequencing of cancer genomes has identified muta Genetic Lesions in Cancer
tions in genes that regulate epigenetic modifications in a
number of cancers. Thus, certain genetic changes in cancers • Tumor cells may acquire mutations through several means,
may be selected for because they lead to alterations of the including point mutations, and nonrandom chromosomal
“epigenome” that favor cancer growth and survival. abnormalities that contribute to malignancy; these include
The epigenetic state of particular cell types—a feature
described as the epigenetic context—also dictates their
