Prostate cancer affects a significant number of men every year. The major challenge of prostate cancer management is the development of therapy resistance. Since PCa growth depends on androgen and androgen receptor (AR) functions, androgen deprivation therapy (ADT) and treatment with AR antagonists are the mainstay of advanced PCa. Current therapies although initially effective a group of treatment refractory tumor cells eventually emerges with a more aggressive phenotype which contributes to the progression of incurable metastatic disease. There is a need for development of improved methods to understand the biological basis for acquisition of drug resistance and identify novel targets for therapy. Recently, microRNAs (miRNA) and long non-coding RNAs (lncRNA) as regulatory molecules for modulating function of a diverse array of genes gained significant attention for their potential application as prognostic markers and therapeutic targets. However, the mechanistic role of these regulatory RNAs and their functional interdependence is not fully understood. Our preliminary studies on profiling of RNA transcripts identified a negative correlation in expression between a tumor suppressor miRNA cluster and a novel lncRNA in metastatic prostate cancer cells. A significant loss of expression of this lncRNA was noted upon restored expression of the miRNA cluster in androgen refractory and therapy resistant prostate cancer cells. The objective of the proposed study is to determine the functional relationship between these two classes of non-coding RNAs (ncRNA) and the role of the lncRNA in modulating tumor cell phenotype and sensitivity to ADT. Our hypothesis is that the expression of this LncRNA promotes tumor progression and ADT resistance and its expression is modulated by the miRNA cluster. To test our hypothesis two aims are proposed.
In aim 1, we will study the effect of manipulation of the miRNA cluster on transcription of lncRNA and the stability of the lncRNA transcript using cell culture models. Additionally, we will evaluate the reciprocal expression pattern of these two classes of ncRNAs in a collection of annotated prostate tumor tissues using qRT-PCR. Expression profiles of the miRNA cluster and the lncRNA will be correlated with the disease outcome and risk of biochemical failure.
In aim 2, we will determine the function of the lncRNA in tumor cell growth and behavior, and cellular response to therapeutic agents including ADT and AR antagonists. This approach is innovative because it investigates the function of a novel lncRNA and its interaction with miRNAs, and the implication of this crosstalk in progression of aggressive disease and drug sensitivity of androgen dependent and -independent prostate cancer cells. This study will have a translational impact on management of prostate cancer as the expression levels will be tested in clinical samples and establish the premise of a new drug target.
The proposed studies are of an important and under investigated area of the molecular basis of the development of androgen refractory and therapy resistant prostate cancer. The proposed research has relevance to public health, because it investigates a fundamental mechanism of cancer progression leading to metastasis and drug resistance that are driven by altered RNA and proteins as a result of the selective pressure imposed by the therapeutic agents. This study also investigates the potential of new prognostic markers and therapeutic targets for predicting development of aggressive disease and management of drug resistant prostate cancer.