Vol:.(1234567890)
Apoptosis (2018) 23:388–395
https://doi.org/10.1007/s10495-018-1461-z
1 3
Treating metastatic prostate cancer with microRNA-145
Alexandre Iscaife
1
· Sabrina Thalita Reis
1
· Denis Reis Morais
1
· Nayara Izabel Viana
1
· Iran Amorim da Silva
1
·
Ruan Pimenta
1
· Andre Bordini
1
· Nelson Dip
1
· Miguel Srougi
1
· Katia Ramos Moreira Leite
1
Published online: 1 June 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Prostate cancer (PCa) is an incurable disease at the metastatic stage. Although there are different options for treatment, the
results are limited. MicroRNAs (miRNAs) are a group of small, noncoding, regulatory RNAs with important roles in regulat-
ing gene expression. miR-145 is reported to be a key tumor suppressor miRNA (tsmiR) that controls important oncogenes,
such as MYC and RAS. In this study, in vitro studies were performed to show the control of MYC and RAS by miR-145.
Flow cytometry was used to analyze cell proliferation and apoptosis. The efficacy of miR-145 in treating metastatic PCa
was tested in nude mice using a model of bone metastasis promoted by intraventricular injection of PC-3MLuc-C6 cells.
Tumor growth was evaluated by an in vivo bioluminescence system. After the full establishment of metastases on day 21, six
animals were treated with three intravenous doses of miR-145 (on days 21, 24 and 27), and six were injected with scramble
miRNA as controls. Compared to the controls, tumor growth was significantly reduced in animals receiving miR-145, most
importantly on day 7 after the third and last dose of miRNA. After discontinuing the treatment, tumor growth resumed,
becoming similar to the group of non-treated animals. A decrease in MYC and RAS expression was observed in all cell
lines after treatment with miR-145, although statistical significance was achieved only in experiments with LNCaP and PC3
cell lines, with a decrease in 56% (p = 0.012) and 31% (p = 0.013) of RAS expression, respectively. Our results suggest that
miR-145 is a potential molecule to be tested for treatment of metastatic, castration-resistant PCa.
Keywords Prostate cancer · Metastasis · Therapy · MicroRNA · Molecular biology
Introduction
Nearly 14% of men are diagnosed with prostate cancer
(PCa) during their lifetime, and 3% will die of the disease.
Although the 5-year overall survival of PCa is approximately
100%, the rate drops to 28% if PCa progresses to the meta-
static stage [1].
The treatment for metastatic PCa is based on blocking
androgen signaling, and this approach is typically effective
for an average of 3 years. After that time, several mecha-
nisms promote tumor growth, although serum testosterone
levels remain low. Although new drugs have shown good
results, such as Bicalutamide [2] and Enzalutamide [3], this
phase of PCa, referred to as castration-resistant disease, still
presents great challenges to oncologists and urologists, so
the development of new and effective treatments is urgent.
MicroRNAs (miRNAs) are a group of small noncoding
regulatory RNAs, ~ 22 nucleotides in length, that play a
fundamental role in the regulation of gene expression [4].
They are involved in the regulation of multiple cellular pro-
cesses, including proliferation, differentiation, cellular stress
responses and apoptosis. miRNAs can act as tumor suppres-
sor genes (tsmiRs) or oncogenes (oncomiRs), depending on
their targets, and changes in the biogenesis and expression
of miRNAs are associated with tumor development and the
progression of several types of neoplasia, including prostate
[5, 6].
There are reports evaluating the use of miRNAs for the
treatment of tumors exploring different miRNAs and tech-
nologies for drug delivery; some are already in clinical or
preclinical phases of development [7].
For PCa, there are few studies reporting reduction in
tumor growth, sensitization of tumors to cytotoxic drugs or
* Alexandre Iscaife
iscaifeboni@yahoo.com.br
1
Laboratorio de Investigação Medica da Disciplina de
Urologia – LIM 55, Faculdade de Medicina FMUSP,
Universidade de Sao Paulo, Av. Dr Arnaldo, 455, Sala 2145,
São Paulo, SP, Brazil
@Phil_Robichaud
@deepthiw
@JoseServera