Posted July 31, 2014
Shao-Yao Ying Ph.D., University of Southern California, Los Angeles, California
Stem cells are a special class of cell lines, capable of differentiating into any other cell type. Dr. Shao-Yao Ying previously showed that a family of microRNAs (miRNAs) called mir-302 could reprogram human skin cells to become stem cells. This was a particularly novel discovery since miRNAs were once thought of as cellular "junk" since they are not used to make proteins like other RNAs. With funding from a fiscal year 2009 PCRP Idea Development Award (PC093594), Dr. Ying proposed to apply this finding to prostate cancer, and investigate whether mir-302 could reprogram prostate cancer cells back to normal prostate cells, essentially eliminating the tumor. If so, this would identify a novel therapeutic strategy - especially for advanced disease states such as castration-resistant prostate cancer.
To test his idea, Dr. Ying established human derived prostate tumor tissues in mice using an androgen-independent prostate cancer cell line (PC3), simulating castration-resistant prostate cancer. The prostate tumors were allowed to grow to a large size and were then injected with DNA vectors expressing mir-302. Dr. Ying found that the size of the tumors in the mir-302 treatment group was dramatically reduced relative to untreated mice. Further studies showed that the inhibition of prostate tumor growth by mir-302 was due to decreased cell proliferation and enhanced cell death (apoptosis). While Dr. Ying has not been able to determine yet whether the changes in the mir-302-expressing prostate tumor cells were the result of being reprogrammed to normal prostate cells, this does not diminish the significance of his findings and their implication for future therapeutic development. Since recent discoveries indicate that miRNAs are relatively stable in the blood and tissue fluid, Dr. Ying believes that "it is highly likely that mir-302s can be directly delivered into the cells as drugs for treating or preventing advanced prostate cancer in the future."
miR-302 prevents tumor growth through two different pathways. It silences several key regulators in the cell cycle, such as CDK2 and cyclin D/cyclin D2, resulting in significant changes in the cell cycle. miR-302 also silences BMI-1, which results in expression of p16Ink4a and p14/p19Arf. Both events cause reduced cell proliferation, and consequently prevention of tumor growth.
Lin SL, Chang DC, Chang-Lin S, Lin CH, Wu DT, Chen DT, Ying SY. (2008) Mir-302 reprograms human skin cancer cells into pluripotent ES-cell-like state. RNA. 14:2115-2124. PMID:18755840.
Lin SL, Chang DC, Ying SY, Leu D, Wu DT. (2010) MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. Cancer Res. 70:9473-9482 PMID: 21062975.
Public and Technical Abstracts: In Vivo Reprogramming of Prostate Cancer Cells to Normal Prostatic Cells (IDA)