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CANCER STEM CELLS AND
ONCOLOGY RESEARCH
11
th
International Conference on
Journal of Medical Oncology and Therapeutics
|
Volume 3
miR-148A INHIBITS
COLON CANCER STEM
CELL PROPERTIES BY
TARGETING PREGNANE
X- RECEPTOR SIGNALING
Pascussi Jean Marc, Chris Planque
and
Julie
Pannequin
1
CNRS, France
2
INSERM, France
3
University of Monpellier, France
T
herapeutic failure seen in patients with colorectal
cancer (CRC) frequently involves post-treatment tumor
recurrence, due to the enhanced resistance of cancer stem
cells (CSCs). Recently, we reported that the nuclear receptor
Pregnane X- Receptor (PXR, NR1I2) behaves as a key driver
of CSC-mediated tumor recurrence where it drives the
expression of a large network of genes involved in self-
renewal and chemoresistance (Planque C et al. Oncotarget,
2016). In order to determine the molecular mechanisms
that define PXR enrichment in CSCs, we investigated the
role of miR-148a on PXR expression and CSC phenotype.
The miR-148a has been reported to post-transcriptionally
regulate PXR in human liver (Takagi S et al. J Biol Chem,
2008) and has been proposed as a predictive biomarker
in patients with advanced CRC (Takahashi M et al. PLoS
One 2012).The present study demonstrated that miR-148a
is down-regulated in CSC-enriched colonospheres and
ALDHbright cells or after cytotoxic treatments. We also
observed a negative correlation between miR-148a-3P and
PXR and PXR target genes expression in these conditions.
Moreover, transient transfection of miR-148a-3P mimics in
CRC cell lines and in patient-derived CRC cells decreased
PXR and PXR target genes expression (ALDH1A1, ABCG2,
FGF19) and PXR-induced promotion of the CSC phenotype
(proportion of ALDHbright cells, sphere forming potential
and self-renewal following serial spheroid passaging).
Finally, we observed that miR-148a-3P overexpression
impairs chemotherapy-induced enrichment of ALDHbright
cells after Firi treatment. In conclusion, we propose that
the deficiency of miRNA-148a-3P is associated with the
J Med Oncl Ther 2018, Volume 3
preferential expression of PXR in colon CSCs. In addition, our
findings highlight miR-148a as a promising therapeutic agent
that may reduce cancer relapse by selectively sensitizing CSC
to chemotherapy via PXR signaling inhibition.
jean-marc.pascussi@inserm.fr