The goal of this application is to investigate the role of Akt-associated microRNAs in cancer. As master gene regulators, microRNAs impact diverse cellular pathways. Accumulating evidence indicates that microRNAs are often dysregulated in many types of human cancers, and that they may function as oncogenes or tumor suppressors. Of considerable interest, our preliminary studies suggest that microRNA pathways interconnect with the Akt pathway, forming Akt-microRNA regulatory network. For example, suppression of Akt induces miR-145 expression;on the other hand, miR-101 causes activation of Akt, and it promotes estrogen independent growth and tamoxifen resistance. Thus, they belong to a class of Akt-associated microRNAs. We hypothesize that microRNAs and Akt in this network work together to exert their cellular functions. Therefore, a better understanding of this Akt-microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We propose three specific aims in this application.
The first aim will focus on miR-145. We will determine the underlying mechanism of miR-145 regulation, and will determine how miR-145 is downregulated in tumors through the PI3K/Akt pathway.
Aim 2 is to dissect the molecular pathway of microRNA-mediated Akt activation. Specifically, we will determine how miR-101 induces Akt activity and dissect molecular and cellular events of miR-101- mediated Akt activation.
The third aim i s to determine the clinical significance of miR-145 and miR- 101. We will determine whether there is any correlation between miR-145 and clinicopathologic features such as disease stage, metastasis status or other features;we will also determine whether miR-101 is dysregulated in ER positive breast tumors that are intrinsically resistant to tamoxifen. Together, the proposed work will provide a better understanding of Akt-associated microRNAs and the underlying mechanism of gene regulation, leading to tumor initiation, progression and anti-hormone resistance.
MicroRNAs are master gene regulators that are capable of targeting protein-coding genes by translational repression or mRNA degradation. Overwhelming evidence indicates that microRNAs play a causal role in human malignancies. Therefore, a better understanding of how microRNAs regulate cellular pathways, ultimately causing cancer initiation, progression and endocrine resistance will aid in the identification of cancer biomarkers and/or novel therapeutic targets and provide direct benefit to cancer patients.
|Ho, Tsui-Ting; Huang, Jianguo; Zhou, Nanjiang et al. (2016) Regulation of PCGEM1 by p54/nrb in prostate cancer. Sci Rep 6:34529|
|Liu, Hairong; Li, Juan; Koirala, Pratirodh et al. (2016) Long non-coding RNAs as prognostic markers in human breast cancer. Oncotarget 7:20584-96|
|Huang, Jianguo; Zhang, Ali; Ho, Tsui-Ting et al. (2016) Linc-RoR promotes c-Myc expression through hnRNP I and AUF1. Nucleic Acids Res 44:3059-69|
|Singh, R; Gupta, S C; Peng, W-X et al. (2016) Regulation of alternative splicing of Bcl-x by BC200 contributes to breast cancer pathogenesis. Cell Death Dis 7:e2262|
|Gupta, S C; Singh, R; Asters, M et al. (2016) Regulation of breast tumorigenesis through acid sensors. Oncogene 35:4102-11|
|Zhang, Ziqiang; Zhou, Nanjiang; Huang, Jianguo et al. (2016) Regulation of androgen receptor splice variant AR3 by PCGEM1. Oncotarget 7:15481-91|
|Zhang, Ali; Zhao, Jonathan C; Kim, Jung et al. (2015) LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer. Cell Rep 13:209-21|
|Vallabhaneni, Krishna C; Penfornis, Patrice; Dhule, Santosh et al. (2015) Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget 6:4953-67|
|Xing, F; Sharma, S; Liu, Y et al. (2015) miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-Î±. Oncogene 34:4890-900|
|Ho, Tsui-Ting; Zhou, Nanjiang; Huang, Jianguo et al. (2015) Targeting non-coding RNAs with the CRISPR/Cas9 system in human cell lines. Nucleic Acids Res 43:e17|
Showing the most recent 10 out of 25 publications