Understanding the molecular mechanisms in the control of xenobiotic disposition is critical for rational drug development and therapy. Although some mechanisms are known, much remains undefined. MicroRNAs (miRNAs) are a large group of recently identified, short, noncoding RNAs that govern target gene expression in cells. The PI's laboratory has demonstrated that several miRNAs (e.g., miR-27b, -328 and -519c) control posttranscriptional regulation of cytochrome P450 enzymes (e.g., CYP3A4) and ABC transporters (e.g., ABCG2), and consequently affect drug disposition. Furthermore, there is increasing evidence that some miRNAs are differentially expressed in human tumor and non-tumor tissues. Indeed, several aberrantly expressed miRNAs (e.g., miR-34a) have been identified as master regulators of cancer cellular processes. Very recently, the PI's group has revealed that a previously uncharacterized miRNA miR-1291 modulates intracellular doxorubicin accumulation and chemosensitivity via direct targeting of ABCC1. In addition, miR-1291 is significantly downregulated in human pancreatic ductal adenocarcinoma (PDAC) as well as pancreatic and breast cancer cell lines. Restoration of miR-1291 function inhibits tumorigenesis in vivo, which is associated with an induction of cell cycle arrest in vitro. Therefore, studies ar proposed to test the hypothesis that miR-1291 controls multiple cellular processes through the regulation of target genes, and miR-1291 may be utilized to treat cancers or improve the efficacy of anticancer drugs (e.g., doxorubicin).
Aim 1 is to delineate the mechanistic functions of miR-1291 in the regulation of drug disposition and endobiotics homeostasis.
Aim 2 is to define the roles and molecular mechanisms of miR-1291 in the control of cancer cell proliferation, invasion, and tumor progression processes.
Aim 3 is to establish the effectiveness and safety profiles of miR-1291 therapeutics in clinically relevant animal models. The feasibility of the proposed research is supported by exciting preliminary findings obtained from patient samples as well as animal and human cell line models. Results are anticipated to establish the mechanistic roles of miR-1291 in the regulation of drug disposition and cell differentiation processes, and lay the basic foundation for the development of miR-1291-based therapy.

Public Health Relevance

The proposed studies are aimed at establishing the mechanistic roles of a previously uncharacterized microRNA miR-1291 in the control of drug disposition and cell differentiation processes, and assessing miR- 1291-based cancer therapeutics. Results shall improve the molecular understanding of drug disposition and tumor progression, and provide insights into the development of new cancer treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA175315-02
Application #
8848050
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Mietz, Judy
Project Start
2014-05-12
Project End
2019-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Zhang, Qian-Yu; Ho, Pui Yan; Tu, Mei-Juan et al. (2018) Lipidation of polyethylenimine-based polyplex increases serum stability of bioengineered RNAi agents and offers more consistent tumoral gene knockdown in vivo. Int J Pharm 547:537-544
Ho, Pui Yan; Duan, Zhijian; Batra, Neelu et al. (2018) Bioengineered Noncoding RNAs Selectively Change Cellular miRNome Profiles for Cancer Therapy. J Pharmacol Exp Ther 365:494-506
Li, Peng-Cheng; Tu, Mei-Juan; Ho, Pui Yan et al. (2018) Bioengineered NRF2-siRNA Is Effective to Interfere with NRF2 Pathways and Improve Chemosensitivity of Human Cancer Cells. Drug Metab Dispos 46:2-10
Jian, Chao; Tu, Mei-Juan; Ho, Pui Yan et al. (2017) Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models. Oncotarget 8:30742-30755
Yu, Ai-Ming; Ingelman-Sundberg, Magnus; Cherrington, Nathan J et al. (2017) Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 7:241-248
Jilek, Joseph L; Tian, Ye; Yu, Ai-Ming (2017) Effects of MicroRNA-34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice. Drug Metab Dispos 45:512-522
Yu, Ai-Ming; Tian, Ye; Tu, Mei-Juan et al. (2016) MicroRNA Pharmacoepigenetics: Posttranscriptional Regulation Mechanisms behind Variable Drug Disposition and Strategy to Develop More Effective Therapy. Drug Metab Dispos 44:308-19
Tu, Mei-Juan; Pan, Yu-Zhuo; Qiu, Jing-Xin et al. (2016) MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis. Oncotarget 7:45547-45561
Ho, Pui Yan; Yu, Ai-Ming (2016) Bioengineering of noncoding RNAs for research agents and therapeutics. Wiley Interdiscip Rev RNA 7:186-97
Zhao, Yong; Tu, Mei-Juan; Wang, Wei-Peng et al. (2016) Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest. Sci Rep 6:26611

Showing the most recent 10 out of 16 publications