NEW YORK (GenomeWeb) – The National Institutes of Health this month earmarked more than $1.4 million in funding to support five research projects investigating microRNAs in cancer progression and treatment response.
The first grant was awarded to Scripps Research Institute scientist Peiqing Sun to build off work previously conducted in his lab showing that one cancer-associated miRNA — miR-30 — disrupts a key tumor-suppressing mechanism, known as Ras-induced senescence, by targeting the transcriptional co-activator CHD7 and an RNA-binding protein called TNRC6A.
With the NIH funding, Sun and his colleagues aim to test the hypothesis that CHD7 acts as a transcriptional coactivator to induce the transcription of a key senescence effector, and that by suppressing CHD7, miR-30 inhibits the expression of this effector. They also plan to see whether miR-30 suppression of TNRC6A results in global miRNA downregulation, leading to disruption of Ras-induced senescence.
Lastly, Sun and his team analyze the effect of miR-30 on senescence induction and cancer development in vivo using miR-30 transgenic mice and a mouse cancer model. Further, expression levels of miR-30, CHD7, and TNRC6A will be determined in human tumor samples in order to establish that miR-30 contributes to human cancer development by directly targeting CHD7 and TNRC6A.
Sun expects the work to provide mechanistic insights into the functioning of miR-30 in oncogene-induced senescence and, hopefully, yield new avenues for cancer therapy.
The grant began on May 1 and runs for five years. It is worth $393,213 in its first year.
Also receiving NIH funding is Fox Chase Cancer Center's Zeng-Jie Yang, who is studying the role of miRNAs in the tumor field effect — a presence of abnormal tissue outside of a neoplastic area that is predisposed to tumor formation.
To conduct the research, Yang will take advantage of a Ptc heterozygous mouse model of medulloblastoma. According to his grant's abstract, both pre-neoplastic cells and end-stage tumor cells have been reported to lack Ptc expression, but the mechanisms underlying the silencing of the Ptc gene are still not known.
Yang and his team hope to confirm recent studies by other groups showing the miRNAs repress Ptc in these mice, specifically identifying which miRNAs are responsible for the downregulation. If successful, the work will be the first to demonstrate that miRNA dysregulation is essential tumor initiation in pre-neoplastic cells.
The two-year grant began on May 1 and is worth $194,119 in the first year.
The third grant went to University of California, Los Angeles investigator Albert Lai to follow up on his lab's identification of miR-148a as a tumor suppressor in DNA methylation studies.
Data generated by Lai's lab suggests that a hypermethylation profile known as glioma-CpG island methylator phenotype (G-CIMP), which is associated with a cancer-linked mutation in isocitrate dehydrogenase, is critical in the development of gliomas by silencing tumor suppressors and potentially genes involved in differentiation. As such, the scientists speculate that this hypermethylation may also suppress tumor-suppressor miRNAs in these tumors.
"We used unbiased methylation profiling to identify hypermethylated miRNA genes in the context of G-CIMP, and among these candidates, miRNA-148a appears not only to have tumor suppressive properties but also to directly regulate DNMT1, a key gene involved in DNA methylation maintenance," Lai wrote in his grant's abstract.
To twar the hypothesis that derepression of the miRNA may be an effective treatment strategy for gliomas, Lai and his team will use the NIH funding to study the molecular links between isocitrate dehydrogenase mutation and miR-148a downregulation. They also aim to identify downstream targets of miR-148a that may contribute to tumor suppression, and to test the effects of the miRNA's restoration in glioma cells.
The grant began on May 1 and runs for five years. It is worth $319,550 in the first year.
The NIH also awarded a grant to Emory University's Ya Wang to investigate the role of miR-21 in tumor response to radiation treatment.
Previously, Wang and her colleagues showed that the miRNA is involved in cell radioresistance by promoting DNA double-strand repair, which suggests that its downregulation could sensitize cancer cells to such treatment.
In order to effectively do so, however, "we need to know the whole picture of miR-21 signaling in irradiated tumor cells in vitro and in vivo," she wrote in the grant's abstract.
As such, Ya aims to use the NIH award to study whether ATR activation, which results from ionizing radiation, stimulates miR-21 expression, and the links between the miRNA and key components in oncogenic pathways. The scientists will also study the effects of miR-21 in the tumor microenvironment in mice lacking or overexpressing the miRNA, both before radiation treatment and after.
Findings of the work may provide guidance on how to block miR-21 in order to improve the effects of radiation cancer therapy.
The grant began on May 15 and runs until April 30, 2019. It is worth $323,700 in the first year.
The last grant was awarded to Lizhong Wang of the University of Alabama at Birmingham to support his investigation into whether miRNAs can serve as biomarkers of tumor progression and treatment response.
In previous work, miR-200c/141 and miR-155 levels in plasma were shown to be highly upregulated in animal models during lung and breast tumor progression and metastasis — findings that were validated in a small population of breast cancer patients.
To build off of these findings, Wang and his colleagues aim to use RT-PCR to validate the miRNAs as biomarkers for the early detection of tumor progression and prediction of therapeutic response in a larger breast cancer patient population. Outcomes will be compared with existing biomarkers.
Using mouse models, the scientists also hope to identify the cellular sources of the circulating miRNAs.
The grant began on May 1 and runs until April 30, 2016. It is worth $191,835 in the first year.