Molecular Pharmacology and Biological Chemistry
James Lee

Targeting MicroRNA-21 for Therapy Against Prostate Cancer Progression and Metastasis

  • Faculty Advisor

    Ming Zhang

Published On

May 2012

Originally Published

NURJ 2011-12

Introduction

With its ability to affect every organ and tissue through various mechanisms, cancer is one of the most complex diseases that we face. Prostate cancer is the most prevalent cancer in men; one in six men will be diagnosed with prostate cancer during his lifetime, and one in thirty-six men will die of the disease.1,2 The role of microRNA-21 (mir-21) in prostate cancer has not been clearly defined yet, and the goal of this experiment is to investigate how mir-21 affects prostate cancer progression and metastasis (invasion of other organs). Understanding its role might be a key in designing a new therapeutic approach to prostate cancer.

Background

MicroRNAs (miRNA) regulate gene expression by degrading messenger RNA (mRNA) that encode for proteins.[3][4] A single miRNA molecule can interact with as many as hundreds of target mRNAs and can therefore orchestrate many different pathways at once to elicit a broader cellular response.[3][4] A few of these modulators are deregulated in cancer, making miRNA a potential target for therapy.[3]

Cancer results from multiple perturbations of different genes and proteins.[3] Within this context, miRNAs serve as pivotal centers, capable of concurrently regulating networks of related processes in cancer progression and metastasis (figure 1).[3][5] Considering this unique ability of miRNA, miRNA-mediated cancer therapy will be more comprehensive than therapy targeting individual genes or proteins.[3] Also, miRNA’s specificity for mRNA sequences make miRNA treatment more effective than current chemotherapy that affects normal cells.[3]

Figure 1

Mir-21 is one of the miRNAs deregulated in cancer.[5] Its over-expression is correlated with tumor growth, but its mechanism is not yet understood.5 Understanding mir-21’s role in prostate cancer can help develop a therapeutic approach targeting mir-21-mediated pathways.

Previous research suggests that transforming growth factor beta (TGF-β) and Ras, two proteins involved in cancer, activate mir-21.[4][5] In prostate cancer, Ras activation and aberrant TGF- β activity play significant roles in tumor progression, suggesting a relationship between these proteins and mir-21.[5][6] Also, maspin, a key tumor suppressor, is believed to be downregulated by mir-21, contributing to tumor proliferation and invasion.[2][7][8][9][10][11] Therefore I hypothesize that TGF- β and Ras induce mir-21 expression in prostate cancer. This in turn silences maspin, subsequently leading to prostate cancer progression and metastasis.

Method

First, the relationship between mir-21 and maspin will be investigated. Prostate cancer cells will be treated with anti-mir-21 that inhibits mir-21. Anti-mir-21-treated cells with low mir-21 will be compared with untreated cells with high mir-21 for maspin expression. Then, to investigate the effect of mir-21 on tumor characteristics, assays that investigate cell proliferation, migration, and invasion will be conducted with cells expressing high vs. low mir-21 levels. Subsequently, to further examine the mechanism of mir-21, prostate cancer cells will be integrated with TGF-β construct that can regulate TGF-β expression. Mir-21 levels will then be measured in cells with high vs. low TGF-β. The above experiments will be repeated with Ras construct. If the results confirm the hypothesis, TGF-β, Ras, mir-21, and maspin levels will be analyzed in prostate cancer patient samples of various disease types to confirm the relationships seen in vitro results.

Significance

This study can demonstrate the role of mir-21 in prostate cancer, which is not yet clear. Better understanding of how mir-21 regulates processes related to prostate cancer can be of tremendous implication considering its high prevalence and mortality, and the unique characteristics of miRNAs make mir-21 an important potential target for novel therapy for cancer.

ABOUT THE AUTHOR

James Lee

BIBLIOGRAPHY

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8. Shi, H. Y.; Zhang, W.; Liang, R.; Abraham, S.; Kittrell, F. S.; Medina, D.; Zhang, M., Blocking tumor growth, invasion, and metastasis by maspin in a syngeneic breast cancer model. Cancer Res 2001, 61 (18), 6945-51.

9. Latha, K.; Zhang, W.; Cella, N.; Shi, H. Y.; Zhang, M., Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition. Mol Cell Biol 2005, 25 (5), 1737-48.

10 .Shao, L. J.; Shi, H. Y.; Ayala, G.; Rowley, D.; Zhang, M., Haploinsufficiency of the maspin tumor suppressor gene leads to hyperplastic lesions in prostate. Cancer Res 2008, 68 (13), 5143-51.

11. Abraham, S.; Zhang, W.; Greenberg, N.; Zhang, M., Maspin functions as tumor suppressor by increasing cell adhesion to extracellular matrix in prostate tumor cells. J Urol 2003, 169 (3), 1157-61.

12. Garzon, R., Marcucci, G. & Croce, C.M. Targeting microRNAs in cancer: rationale, strategies and challenges. Nature reviews. Drug discovery 9, 775-89 (2010).