Nuclear receptor TLX and its targeting microRNAs inbrain tumor stem cellsEach year approximately 190,000 people in the United States will be diagnosed with a primary or metastatic brain tumor. Because brain tumors are located at the control center for thought, emotion and movement, their effects on an individual’s physical and cognitive abilities can be devastating. At present, brain tumors are treated primarily by surgery, radiation therapy and chemotherapy, all of which could have long-term side effects. Identifying molecular targets for brain tumors will allow development of novel therapeutic tools for brain tumor treatment. Since stem cells and cancer cells share the ability to self-renew, many pathways that regulate stem cell proliferation may also regulate oncogenesis, therefore could be potential targets of tumor therapies.
We showed previously that orphan nuclear hormone receptor TLX is essential for adult neural stem cell self-renewal. Here we show that TLX is also expressed in glioma cells. Immunostaining of primary glioma tissues revealed that a small population of glioma cells is TLX-positive, coinciding with the concept that brain tumor stem cells represent a small fraction of brain tumor cells that are self-renewable. Moreover, we have isolated CD133- positive glioma stem cells from primary human glioma tissues and demonstrated that TLX is expressed in the CD133-positive glioma stem cells. To investigate the role of TLX in brain tumor progression, we knocked down TLX expression in glioma cells using siRNA technology and transplanted the treated cells into brains of immunodeficient nude mice intracranially. Remarkably, knockdown of TLX expression led to dramatically reduced tumor mass, suggesting that TLX is an important regulator of brain tumor progression. Further determination of TLX role in brain tumor stem cells will be pursued in this proposal. This work has the potential to identify a novel target for brain tumor therapy and led to treatment for brain cancers.
Recently, microRNAs have been identified as novel gene regulators. Tremendous excitements have been stirred in the therapeutic field about using these small RNA molecules as therapies and diagnostic tools. We have identified TLX-targeting microRNAs (miRNAs) by computational approaches and experimental confirmation. These miRNAs repress TLX expression at both protein and messenger RNA levels. We will test the idea that these miRNAs impact brain tumor growth. If so, this may lead to another potential therapy for brain cancers.
Since TLX is a transcription factor, it can regulate tumor cell proliferation through modulating a network of downstream target genes. We propose to identify TLX downstream target genes in brain tumor stem cells using DNA microarray analysis. The role of these genes in brain tumor formation and growth will be investigated. These studies will also provide insights into new molecular targets of brain tumor therapies and yield novel treatment strategies for brain tumor patients.
