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Principal Investigator: YONG ZHU
Organization: YALE UNIVERSITY
Fiscal Year: 2020
Award: $218,588
Funding agency: National Cancer Institute
Abstract
The goal of the proposed study is to demonstrate the viability of a novel Piwi-interacting RNA (piRNA)-based
therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). piRNAs are an abundant class of small
(26-31 nt) non-coding RNAs with approximately 23,000 known human members and play a pivotal role in the
maintenance of genomic stability in germ cells via epigenetic silencing of transposable elements (TE). Recent
evidence from our group and others has suggested that piRNAs can also induce DNA methylation at non-TE
protein-coding genes, including cancer-related genes in somatic cells. However, the role of piRNAs in human
cancers has not been fully studied and no previous publication has explored the use of piRNA as a therapeutic
tool. Our previous analyses have detected marked differences in expression of several piRNAs between normal
liver tissue and HCC tissue as well as anti-cancer effects of an exogenously modulating expression of one of
these identified piRNAs. In the proposed study, we seek to expand upon these important findings by further
examining the potential anticancer impact in vivo for the candidate piR-37213. Specifically, we will first examine
the anti-tumor effect of piR-37213 on HCC cells in vivo using an orthotopic mouse xenograft model (Specific Aim
1), which allows us to test whether the observed anti-proliferative effects in vitro can be replicated in live animals.
We will also examine molecular mechanisms accounting for the anti-tumor effect of piR-37213 (Specific Aim 2).
In this Aim, we will first perform a genome-wide expression profiling study to reveal the gene regulation network
and global impact of piR-37213, and confirm these findings with relevant in vitro assays if applicable. Next, we
will perform a RNA pull-down assay to explore potential piRNA binding sequences. This study represents the
key first step in the development of an innovative, piRNA-based therapeutic strategy that may be utilized as a
personalized treatment approach via the restoration of normal piRNA expression on an individual basis.
Knowledge obtained from this study will advance our understanding of a novel mechanism underlying HCC
biology, expand knowledge of the role and function of piRNA in tumorigenesis, and provide new avenues of
research that can be exploited to facilitate the development of novel therapeutic strategies.
Terms: <Accounting><Advanced Cancer><Advanced Malignant Neoplasm><Affect><Anchorage-Independent Growth><Animals><Assay><Athymic Mice><Athymic Nude Mouse><Bioassay><Biologic Assays><Biological Assay><Biology><Body Tissues><Cancer Treatment><Cancers><Carcinoma Cell><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cellular Proliferation><Clinical><Code><Coding System><DNA Methylation><DNA Transposable Elements><Development><Encapsulated><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exploratory/Developmental Grant><Expression Profiling><Functional RNA><Gametes><Gene Action Regulation><Gene Expression Regulation><Gene Inactivation><Gene Regulation><Gene Regulation Process><Gene Silencing><Gene Transcription><Genes><Genetic Transcription><Genome Stability><Genomic Stability><Germ Cells><Germ Lines><Germ-Line Cells><Goals><HCC cell><HCC cell line><Hep3B><Hep3B cell line><Hepatic Cancer><Hepatocarcinogenesis><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Heritability><Human><Implant><In Vitro><Individual><Knowledge><Liver><Liver Carcinogenesis><Liver Cells Carcinoma><Maintenance><Malignant Cell><Malignant Epithelial Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant neoplasm of liver><Maps><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modern Man><Modification><Molecular><Molecular Analysis><Murine><Mus><Nature><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Normal Cell><Nude Mice><Oncogenesis><Patients><Play><Primary carcinoma of the liver cells><Proteins><Publications><Publishing><R21 Mechanism><R21 Program><RNA><RNA Binding><RNA Expression><RNA Gene Products><RNA bound><Reproductive Cells><Research><Ribonucleic Acid><Role><Safety><Scientific Publication><Sex Cell><Short interfering RNA><Small Interfering RNA><Somatic Cell><Technology><Testing><Therapeutic><Tissues><Transcription><Transposable Elements><Treatment Efficacy><Untranslated RNA><Work><Xenograft Model><anti-cancer><anti-cancer research><anti-cancer therapy><anti-tumor effect><anticancer><anticancer research><anticancer therapy><antitumor effect><base><cancer cell><cancer research><cancer therapy><carcinogenesis in the liver><clinical practice><developmental><exploratory developmental study><gene locus><genetic locus><genome integrity><genome scale><genome-wide><genomewide><genomic integrity><genomic locus><hepatic body system><hepatic carcinogenesis><hepatic organ system><hepatocellular carcinogenesis><hepatocellular carcinoma cell line><human disease><improved><in vitro Assay><in vivo><initial cell><innovate><innovation><innovative><intervention efficacy><lipid nanoparticle><liver cancer><liver cancer pathogenesis><liver carcinoma><liver tumorigenesis><malignancy><malignant liver tumor><member><miRNA><miRNAs><migration><neoplasm/cancer><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><noncoding><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pre-clinical><preclinical><response><restoration><sexual cell><siRNA><social role><therapeutic efficacy><therapeutically effective><therapy efficacy><tool><transcriptional silencing><translational study><treatment strategy><tumor><tumorigenesis>