The main goal of this project is to develop prognostic biomarkers based on long non-coding RNA analysis that can predict risk assessment of kidney cancer. The major problem or critical barrier in the field is that there are no biomarkers or methods to predict clinical outcome of kidney cancer. To address this problem, we will investigate whether long non-coding RNAs (lncRNAs) can be used as genetic biomarkers to predict which localized indolent kidney cancers are likely to progression and metastasize. Original Hypotheses: The proposed hypotheses are radically different and innovative. The first hypothesis is that the differential expression of oncogenic lncRNAs HOTAIR and MALAT1 and their binding miRNAs in different stages and grades of kidney cancer may serve as prognostic biomarkers. The second hypothesis is that suppression of oncogenic MALAT1 and HOTAIR by siRNAs or activation of their binding miRNAs will inhibit kidney cancer growth and progression using both in vitro and in vivo models. The third hypothesis is that the molecular mechanisms of oncogenic long non-coding RNAs HOTAIR and MALAT1 action is through binding to polycomb repressive complex 2, [PRC2 (EZH2 / SUZ12 / EED)] that in turn modulates histone modification complexes, activates epithelial-mesenchymal transition pathway genes (snail, slug, twist, vimentin, ZEB1 and ZEB2) and induces kidney cancer progression. To address these hypotheses, we have proposed the following specific aims.
Specific Aim # 1. Investigate whether MALAT1, HOTAIR and their regulatory miRNAs are genetic biomarkers to help in the clinical assessment of kidney cancer.
Specific Aim # 2. Investigate the functional significance of non-coding RNAs in suppression of kidney cancer growth and progression using both in vitro and in vivo models.
Specific Aim # 3. Investigate the molecular mechanisms of action of MALAT1 and HOTAIR in kidney cancer growth and progression. Impact: This project has high impact because it will investigate the role of non-coding RNAs as genetic biomarkers for risk assessment of kidney cancer. We will investigate the functional significance of non-coding RNAs in kidney cancer using both in vitro and in vivo models. We will also investigate the molecular mechanisms of action of non-coding RNAs through binding to PCR2 that in turn modulates histone modification complexes, activates EMT genes and induces kidney cancer progression. The proposed concepts, methods and technology will advance the field of non-coding RNAs as genetic biomarkers and potential therapeutic targets for the management of kidney cancer.

Public Health Relevance

The main goal of this project is to develop prognostic biomarkers based on long non-coding RNA analysis that can predict risk assessment of kidney cancer. The major problem is that there are no biomarkers or methods to predict clinical outcome of kidney cancer and to address this problem, we will investigate whether long non- coding RNAs MALAT1 and HOTAIR and their regulatory miRNAs can be used as genetic biomarkers to predict which localized indolent kidney cancers are likely to progression and metastasize.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA199694-02
Application #
9270533
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Snyderwine, Elizabeth G
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$350,674
Indirect Cost
$121,924
Name
Northern California Institute Research & Education
Department
Type
Research Institutes
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Imai-Sumida, Mitsuho; Chiyomaru, Takeshi; Majid, Shahana et al. (2017) Silibinin suppresses bladder cancer through down-regulation of actin cytoskeleton and PI3K/Akt signaling pathways. Oncotarget 8:92032-92042