MicroRNA mimics as potential differentiation agents for treating neuroblastoma

Neuroblastoma,

the

most

common

extracranial

solid

tumor

of

childhood,

arises

from

neural

crest

cell

precursors

that

fail

to

differentiate.

Inducing

cell

differentiation

is

an

important

therapeutic

strategy

for

neuroblastoma.

We

developed

a

direct

functional

high-­‐content

screen

to

identify

differentiation-­‐

inducing

microRNAs,

in

order

to

develop

microRNA-­‐based

differentiation

therapy

for

neuroblastoma.

We

discovered

novel

microRNAs,

and

more

strikingly,

three

microRNA

seed

families

that

induce

neuroblastoma

cell

differentiation.

In

addition,

we

showed

that

microRNA

seed

families

were

overrepresented

in

the

identified

group

of

fourteen

differentiation-­‐inducing

microRNAs,

suggesting

that

microRNA

seed

families

are

functionally

more

important

in

neuroblastoma

differentiation

than

microRNAs

with

unique

sequences.

We

further

investigated

the

differentiation-­‐inducing

function

of

the

microRNA-­‐506-­‐3p/microRNA-­‐124-­‐3p

seed

family,

which

was

the

most

potent

inducer

of

differentiation.

We

showed

that

the

differentiation-­‐inducing

function

of

microRNA-­‐506-­‐3p/microRNA-­‐

124-­‐3p

is

mediated,

at

least

partially,

by

down-­‐regulating

expression

of

their

targets

CDK4

and

STAT3.

We

further

showed

that

expression

of

miR-­‐506-­‐3p,

but

not

miR-­‐124-­‐3p,

is

dramatically

up regulated

in

differentiated

neuroblastoma

cells,

suggesting

the

important

role

of

endogenous

miR-­‐506-­‐3p

in neuroblastoma.