Researchers based out of the United States identified a new microRNA as a key regulator of stemness and metastasis in prostate cancer cells.
In the United States, the second leading cause of cancer related deaths in men is prostate cancer. While new research and therapies are advancing, a large percentage of patients with this disease continue to progress to the advanced stages.
For years, researchers have used biological indicators such as the prostate-specific antigen (PSA) to aid in early detection and diagnosis of prostate cancer. This enzyme is derived from prostate tissue, which is released by normal and tumor cells, and plays a role in semen liquefaction. While serum PSA quantities often correlate with prostate volume, the researchers in this study say that the PSA is not the most optimal prognostic indicator of prostate cancer. PSA serum levels are not only elevated in prostate cancer, but also in patients with benign prostatic hyperplasia. This has resulted in more patients being incorrectly diagnosed with prostate cancer.
Researchers, based out of California’s Veterans Affairs Medical Center in San Francisco, the University of California, and Georgia’s Augusta University, conducted a study in hopes of solving this problem by identifying a new potential prognostic indicator of prostate cancer: “MicroRNA-4287 is a novel tumor suppressor microRNA controlling epithelial-to mesenchymal transition in prostate cancer.” This paper was chosen as the cover paper for Oncotarget’s Volume 11, Issue #51.
“In the present study, we analyzed the role of miR-4287 in prostate cancer using clinical tissues and cell lines. We observed that miR-4287 is significantly downregulated in patient-derived tumor tissues.”
Previous Studies
MicroRNAs (miRNAs) have begun to emerge over the years as important molecular mediators of human biology. miRNAs have also become useful biomarkers that are capable of aiding researchers in potential early diagnosis and differentiating between a low-, intermediate-, and high-risk prostate cancer prognosis. Previous research conducted by authors in this study has revealed a particular cluster of miRNAs within the 8p region of chromosome 21 that have tumor suppressing properties and are downregulated in prostate cancer patients. This overall downregulation contributes to metastasis and disease progression.
“miRNA-383, -3622a, -3622b and -4288 are significantly downregulated in prostate cancer patients and these miRNAs function as tumor suppressors and play [an] important role in preventing cancer cell growth, proliferation and metastasis.”
Found in advanced prostate cancer, researchers have also uncovered the unusual deletion of miRNAs in region 8p of chromosome 21. The team uncovered a better understanding of prostate cancer progression after learning that, with the progression of this disease, miRNAs in this region are not only downregulated, but lost.
“This region, in addition to harboring a tumor suppressor gene NKX3-1, [13] contains a series of miRNAs that are eventually lost upon disease progression as a result of chromosomal deletion.”
In this study, the researchers chose to analyze a new miRNA in the 8p region of chromosome 21. To their knowledge, miRNA-4287 has never previously been studied in the context of prostate cancer progression.
The Study
Supported by the National Cancer Institute at the National Institutes of Health, prostate carcinoma tissue samples and cell lines were collected for this study from the American Type Culture Collection, San Francisco Veterans Affairs Medical Center, and Augusta University. The researchers used the Qiagen miRNeasy FFPE and mini kit to extract RNA from samples. The analyses they carried out included flow-symmetry, quantitative real-time polymerase chain reaction, miRNA transfections, in vitro migration and invasion assays, cellular viability assays, fluorescence-activated cell-sorting cell cycle analysis, fluorescein isothiocyanate-phalloidin staining, PSA serum level testing, and western blotting.
“To understand the biological function of miR-4287 in cancer cells, we further interrogated cellular targets for miRNA-4287 using TargetScan [20].”
Results
“Although we did not observe any significant correlation between loss of miR-4287 expression with the increasing tumor stage and pathological grade in prostate cancer, we noticed that increasing serum PSA levels correlated negatively with miR-4287 expression.”
In their flow-symmetry analysis, researchers found that miRNA-4287 over-expression caused an increase in G2/M phase in prostate cancer cell lines. They also found that PSA serum levels correlated inversely with miRNA-4287 levels. Previous studies have shown that androgen receptors control the transcriptional landscape of prostate cancer cells. Therefore, researchers suggest that PSA may be regulatorily controlled by the androgen receptor, or vice versa.
“The inverse relationship between PSA and miR-4287 indicates a possible regulatory control of miR-4287 via androgen receptor pathway or vice versa.”
The team also found that miRNA-4287 targets mediators of the epithelial-to-mesenchymal transition (EMT) pathway by directly repressing SLUG, and indirectly repressing stem cell marker CD44 mRNA. It has been reported that the cell-adhesion molecule CD44 mRNA plays critical roles in cancer stemness and prostate cancer metastasis. Researchers suggest this means that miR-4287 has a tumor suppressing role in the progression of prostate cancer.
“Importantly, we demonstrate for the first time, that miR-4287 is a key negative regulator of prostate cancer stemness marker CD44 and EMT mediator SLUG.”
Conclusion
“In conclusion, in the present study we define a tumor-suppressor role of a novel miRNA-4287 in prostate cancer via its regulation of prostate cancer EMT and stemness.”
These miRNAs, now including miRNA-4287, play consequential roles in prostate cancer, and their loss in advanced stages is critical to disease progression. The researchers hope their findings will aid in the development of new therapeutic interventions to reinstate the expression of tumor suppressor microRNAs to better treat aggressive prostate cancer.
Click here to read the full scientific paper, published in Oncotarget.
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