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Peiró et al. J Cancer Metastasis Treat 2019;5:49 I http://dx.doi.org/10.20517/2394-4722.2018.109 Page 7 of 11

Extracellular matrix metalloproteinase inducer (EMMPRIN) glycoprotein, also known as cluster of
differentiation 147 (CD147), is a densely glycosylated type I transmembrane glycoprotein, highly expressed
in tumors . This glycoprotein is known to induce a number of malignancy characteristics in breast cancer
[47]
cells, such as invasiveness, angiogenesis, anchorage independent growth and chemioresistance. SUM102 and
BT474 cells were treated with human recombinant EMMPRIN, in which the levels of STAT3 and HIF-1α were
observed to be increased. To investigate the role of HIF-1α, the cells were infected with lentivirus carrying
HIF-1α shRNA . HIF-1α was observed to increase the percentage of CD24 surface markers (stem-like cells)
[47]
and decreased the percentage of CD44 via STAT3. In addition, miR-106a/b targeted STAT3 and HIF-1α,
and mammary neoplasms treated with miR-106a/b had decreased STAT3 and HIF-1α, and consequently
a significant attenuation of stem-like characteristics . Also working with miRNA, Pakravan et al.
[48]
[47]
evaluated whether the transfer of exosomes from mesenchymal stem cells (MSCs) containing miR-100 - a
tumor suppressor - could have an effect on angiogenesis in breast cancer cells. The miR-100 present in MSCs
exosomes was found to inhibit the expression of HIF-1α and mTOR in MDA-MB-231 and MCF-7 cells, which
consequently inhibited VEGF expression, contributing to the control of angiogenesis .
[48]

To understand the functioning of pathways of acquisition of malignancy characteristics, notorious in
breast cancer, Kuo et al. treated several breast cancer cell lines with pharmacological doses of dimethyl-
[49]
2-ketoglutarate (DKG). DKG induced HIF-1α in 6 cell lines, rapidly but transiently, and DKG treatment was
shown to create a “pseudohypoxic” state in normoxia. An increase in succinate and fumarate rates was then
seen, along with a decline in SDH and FH levels. This imbalance of metabolites may then impair PHD2
activity, stabilizing HIF-1α and reprogramming the surface of breast cancer cells . The phenotype was
[49]
maintained for up to 3 cell passages, and an increase of Carbonic anhydrase 9 (CAIX) (which is one of the
genes downstream of the HIF-1α signaling pathway) was seen in DKG-treated breast cancer cells. Taking
into account that CAIX is seen in high-grade cancers, this result suggests mitochondrial dysregulation may
induce tumorigenicity . Considering that, Tosatto et al. evaluated mitochondrial calcium uniporter
[49]
[50]
(MCU) in the progression of breast cancer cells. The MCU is a selective channel that absorbs Ca2+ ions in
the mitochondria, which is correlated with infiltration in lymph nodes and tumor size. Silencing of the MCU
drastically decreased mitochondrial ROS levels and down-regulated HIF-1α. When treated with Paraquat (a
substance that generates superoxide production), there was an increase in the transcription of HIF-1α, which
led the researchers to relate HIF-1α to an effector of MCU depletion .
[50]
A novel class of an antigenic strategy known as the decoy approach was used by Zhu et al. , who showed
[51]
that cells treated with a HIF-1α decoy had the transcriptional activity of HIF-1α inhibited and entered
apoptosis.

HIF-1α INHIBITION BY NATURAL COMPOUNDS
Still considering the inhibition of HIF-1α as antineoplastic therapy, we have listed here the most recent
works dealing with natural compounds, be they extracted from animal plants or microbes.

Manassantin A (MA), a compound isolated from the organism Saururus cernuus, which was identified
as a potent inhibitor of HIF-1α was used in an attempt to inhibit the function of HIF-1α in breast cancer
cells . Several MA derivatives were synthesized in the search for one presenting low toxicity and a good
[9]
inhibitory effect on HIF-1α. LXY6090 was developed which initially inhibited HIF-1α activity well. The
compound was used in T47D, MCF-7 and MX-1 lines, and a decrease in the protein levels of HIF-1α in the
cells was observed in a dose-dependent manner. LXY6090 also inhibited the accumulation of HIF-1α mRNA
by promoting proteasome degradation in a VHL-dependent way. In addition to these effects, LXY6090 was
also observed to inhibit the hypoxia-induced protein expression of HIF-1α target genes such as VEGF and
IGF-2, demonstrating a great potential as the target of further research for the treatment of breast cancer
associated with an up-expression of HIF-1α.