NEW YORK (GenomeWeb) – The National Institutes of Health this month awarded more than $1 million in grant funding to support four research projects examining the effect of microRNAs on cancer and their potential for treating the disease.
The first grant was awarded to University of Massachusetts Medical School Assistant Professor Wen Xue to fund his studies into the potential of miR-34a as a treatment for lung cancer, with the goal of establishing technologies that can be used to study the therapeutic potential of other miRNAs, as well.
Dysregulation of this miRNA has long been associated with a number of different cancers ranging from lung cancer to liver cancer. And one company — Mirna Therapeutics — has advanced a miR-34a mimic to Phase I testing for solid tumors.
With the NIH funding and in his recently established lab at UMMS, Xue aims to develop a novel conditional miRNA expression system, a nanoparticle delivery system, and an miRNA target identification platform to enable studies of miR-34a in autochthonous mouse models and genetically defined human cancer cells.
With these tools, he hopes to identify the mechanisms by which miR-34a inhibits lung tumor progression and uncover the miRNA's target genes that are relevant to cancer, setting the stage for similar work with other cancer-related miRNAs.
Xue's three-year grant began on Sept. 1 and is worth $249,000 in its first year.
Also receiving NIH funding this month is Albert Einstein College of Medicine Assistant Professor Keisuke Ito, whose research on myelodysplastic syndrome (MDS) — a hematological condition characterized by poor red blood cell production and that frequently progresses to leukemia — has led him to investigate the role of miRNAs in the disease.
Last year, Ito and colleagues at Harvard University published data showing that one specific miRNA, miR-22, is upregulated in both MDS and leukemia, and that this aberrant expression correlates with poor patient survival. They further demonstrated that the miRNA directly targets the tumor suppressor TET2, promoting hematopoietic stem cell self-renewal and transformation.
To build upon these findings, Ito plans to use his grant funding to first study how TET2 contributes to the oncogenic function of miR-22 using transgenic mice that conditionally express the miRNA in the hematopoietic compartment in order to establish the gene as a therapeutic target, according to his grant's abstract.
Ito then plans to test the therapeutic potential of miR-22 inhibition in animal models of MDS and examine the genes regulated by the miR-22/TET2 pathway to further understand the consequences of TET2 repression in hematopoiesis. "We will focus our analysis on the genetic manipulation of these genes, both in vivo and in vitro, in murine hematopoietic stem cells from transgenic mice, to observe the subsequent effects on MDS pathogenesis induced by [the] microRNA," he noted.
Ito's grant began on Sept. 1 and runs until June 30, 2018. It is worth $250,000 in the first year.
The NIH also awarded a grant this month to another Albert Einstein College of Medicine researcher, Amit Verma, who is similarly studying the effect of miRNAs in MDS. His research, however, has led him to miR-21, which he and collaborators reported to be a mediator of hematopoietic suppression in the disease.
According to a 2013 paper, SMAD7, a negative regulator of transforming growth factor-beta (TGF-beta) receptor-I kinase, is "markedly reduced" in MDS and leads to "ineffective hematopoiesis by overactivation of TGF-beta signaling." Additional investigation revealed that miR-21 binds to the 3'UTR of SMAD7 and reduces its expression in hematopoietic cells, and that silencing the miRNA boosted hematocrit and led to an increase in SMAD7 expression in vivo.
In light of these data, Verma is using his NIH funding to further investigate miR-21 in MDS.
"We have shown that [the transcription factor] STAT3 is selectively overexpressed in MDS stem cells and has been shown to regulate miR-21 expression in other models," he wrote in his grant's abstract. "We will determine the role of STAT3 expression/activation in upregulation of miR-21 and stimulation of TGF-beta signaling in MDS using a combination of biochemical and functional approaches."
Next, he and his team will try to determine the role miR-21 overexpression has in ineffective hematopoiesis in MDS and identify its downstream effectors. Given that anemia is a hallmark of MDS, an in vitro model of human erythropoiesis will be used to examine the miRNA's overexpression on red cell differentiation and proliferation.
And because miR-21 has a number of other targets in addition to SMAD7, Verma will also look into the effects of the miRNA on red cell dysplasia by targeting the GTPase exchange factor DOCK4, which has critical roles in red cell membrane formation, the abstract states.
Lastly, Verma plans to study the therapeutic potential of miR-21 inhibitors for MDS in vitro and in animal models of bone marrow failure.
His grant began on Sept. 1 and runs through May 2018. It is worth $374,972 in the first year.
The last grant was awarded to Georgia Regents University Professor Shuang Huang, who is studying the role of miR-375 in breast cancer progression and metastasis.
Earlier this year, Huang and his lab reported that the miRNA was elevated in epithelial-like breast cancer cells and that ectopic expression of miR-375 suppressed epithelial-to-mesenchymal transition in mesenchymal-like breast cancer cells. Further, the transcription factor short stature homeobox 2 (SHOX2), which is expressed at high levels in mesenchymal-like breast cancer cells but at low levels in epithelial-like ones was identified as a target of the miRNA.
His lab has also found that the transcription factor's forced expression was also found to reverse miR-375-mediated EMT suppression, as well as the existence of a double-negative feedback loop in which the miRNA suppresses endogenous SHOX2 expression by directly targeting its 3' UTR and SHOX2 represses miR-375 transcription through the action of lysine (K)-Specific demethylase 5B (KDM5B).
In light of these discoveries and the fact that SHOX2 is known to promote TGF-beta receptor I transcription, Huang and his team aim to use the NIH funding to further explore the involvement of miR-375/SHOX2 in breast cancer cell EMT. Their findings are expected to uncover new therapeutic targets for breast cancer.
The five-year grant project began on Sept. 2 and is worth $313,671 in its first year.