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■ Treating Prostate/Ovarian Cancer
The Connection Between Ovarian
Cancer and MicroRNA
Although ovarian cancer is the fifth-leading cause of death from cancer in women, scientists don’t have a
good handle on how it forms.
Compiled by the
National Cancer Institute,
National Institutes of Health
Anew study suggests that a microRNA—a
molecule made by cells to turn genes on
and off—may help kick-start a type of ovarian
cancer called high-grade serous ovarian cancer.
Cells with high levels of the microRNA, called
miR-181a, were pushed to become ovarian cancer
by turning off two important genes, scientists
who led the study found. These and other findings
from the National Cancer Institute-funded
study were published June 26 in Nature
Communications.
“One of the defining features of ovarian tumors
is a large degree of genomic instability,”
said the study’s lead investigator, Analisa DiFeo,
Ph.D., of the University of Michigan. That means
chromosomes are destroyed, copied or stitched
together with other chromosomes, she explained.
Dr. DiFeo’s team has been hunting for a substance
made by early-stage ovarian cancer cells
that might help catch the disease earlier. But to
find a biomarker, they first needed a better understanding
of how the disease starts.
The current thinking is that ovarian cancer
starts in fallopian tube cells that have a few gene
mutations. Those abnormal cells eventually turn
into a precursor of cancer, or precancer. Years later,
the precancer becomes full-blown ovarian cancer.
But scientists don’t know what drives the transition
from mutated fallopian tube cells to precancer
to ovarian cancer. There is some evidence
that genome instability drives the transition, Dr.
DiFeo explained. She and her team wondered
whether a microRNA might be the cause of genome
instability.
MicroRNAs turn genes down by grabbing onto
messenger RNA—the middleman between genes
and proteins—and stopping protein production.
In so doing, microRNAs help fine-tune the activity
of genes. In fact, a single microRNA can regulate
a thousand different genes.
Several microRNAs have been linked to the development,
growth and spread of different types
of cancer.
For instance, in 2014, Dr. DiFeo’s team found
that women with ovarian cancer whose tumors
had low levels of miR-181a lived more than four
years longer without their cancer coming back
than women whose tumors had high levels of
the microRNA.
In the new study, the team saw that, across
10,000 patients with 38 different types of cancer,
those with tumors that had low levels of miR-
181a lived several years longer.
Given their earlier work with miR-181a, the researchers
decided to start there. First, they took
human fallopian tube cells with certain mutations
(those that are found in cells that turn into
ovarian cancer) and engineered them to have
high levels of miR-181a.
These cells grew on top of one another, formed
tumor-like structures and had genome instability—all
typical hallmarks of ovarian cancer.
Cells carrying a nonworking microRNA didn’t
form tumors in mice. But cells with excess miR-
181a formed tumors that acted like human
ovarian cancer. The tumors spread to the mice’s
intestines, for example.
It’s rare to “transform a normal cell to a cancer
cell with just expression of one microRNA. Typically,
you need multiple [genetic changes] for
transformation,” Dr. DiFeo explained. That goes
to show that microRNAs are “small but mighty,”
she added.
So how does a little piece of RNA turn cells to
the dark side? The answer turned out to be miR-
181a’s effects on protein production.
The levels of more than 400 proteins differed
between cells with the nonworking microRNA
and cells with excess miR-181a, the researchers
found. One protein in particular, called RB1,
caught their attention because it controls cell division
and protects cells from genome instability.
Low levels of RB1 are thought to help ovarian
and other cancers grow.
Additional experiments confirmed that excess
miR-181a lowered levels of RB1 in the
fallopian tube cells. As a result, the cells had
unstable genomes, grew out of control and
formed tumors.
But another question remained: How do cells
with excess miR-181a survive with such unstable
genomes? Cells normally self-destruct if their
DNA is damaged beyond repair.
The answer, the researchers learned, is miR-
181a’s effect on another protein, known as
STING. STING’s job is to push the self-destruct
button if it finds broken DNA floating around.
But because excess miR-181a lowered levels of
STING in fallopian tube cells, the cells avoided
that fate.
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