MicroRNA convicted of triggering metastasis
CAMBRIDGE, Mass. (Sept. 26, 2007) — The jury is in: microRNAs can
cause tumors to metastasize. These tiny molecules fine-tune protein
production and play a powerful role in biological processes ranging
from development to aging. Now scientists have proved that they can
prompt otherwise sedentary cancer cells to move and invade other tissues.
Labs have been probing the relationship between aberrant microRNA
levels and cancer for several years. They’ve shown that some microRNAs
cause normal cells to divide rapidly and form tumors, but they’ve never
demonstrated that microRNAs subsequently cause cancer cells to metastasize.
“A specific microRNA is able to cause
profound changes in the behavior of cancer cells, which is
striking considering that 10 years ago no one suspected microRNAs
were involved in any biological process,” says Robert Weinberg.” |
Now, working in the lab of Whitehead Member Robert Weinberg,
postdoctoral fellow Li Ma has coaxed cancer cells to break away
from a tumor and colonize distant tissues in mice by simply
increasing the level of one microRNA. Her results appear
online in Nature on September 26.
“Li has shown that a specific microRNA is able to cause
profound changes in the behavior of cancer cells, which is
striking considering that 10 years ago no one suspected microRNAs
were involved in any biological process,” says Weinberg,
who is also an MIT professor of biology.
Ma began with a list of 29 microRNAs expressed at different
levels in tumors versus normal tissue. She examined their
production in two groups of cancer cells—metastatic and
non-metastatic. Metastatic cancer cells (including those taken
directly from patients) contained much higher levels of
one microRNA called microRNA-10b.
Next, Ma forced non-metastatic human breast cancer cells
to produce lots of microRNA-10b by inserting extra copies
of the gene. She injected the altered cancer cells into the
mammary fat pads of mice, which soon developed breast tumors that metastasized.
So what caused this stunning metamorphosis?
MicroRNAs typically disrupt protein production by binding
to the messenger RNAs that copy DNA instructions for proteins
and carry them to “translators.” Ma used a program developed
in the lab of Whitehead Member David Bartel to search for
the target of microRNA-10b. She identified several candidates,
including the messenger RNA for a gene called HoxD10.
Generally involved in development, Hox proteins control
many genes active in an embryo. Some Hox proteins have also
been implicated in cancer. HoxD10, for example, can block
the expression of genes required for cancer cells to
move—essentially applying the brakes to a migration process.
To test whether she had removed the brakes during her experiment,
awakening the dormant migration process, Ma boosted the level of
HoxD10 in the cancer cells with artificially high levels of microRNA-10b.
The cells lost their newly acquired abilities to move and invade.
“I was able to fully reverse microRNA-10b induced migration
and invasion, suggesting that HoxD10 is indeed a functional target,” Ma explains.
“During normal development, this microRNA probably enables cells
to move from one part of the embryo to another,” adds Weinberg.
“Its original function has been co-opted by carcinoma cells.”
This research is funded by the Life Sciences Research Foundation,
the National Institutes of Health and the Ludwig Center for Molecular Oncology at MIT. |
