How miRNAs can help researchers better understand ovarian cancer

ILLU_0920_OvarianCancer_Metastasis

Ovarian cancer is the seventh most commonly diagnosed cancer in women worldwide and the leading cause of death among all malignancies of the female reproductive system (1, 2). Dysregulation of microRNA (miRNA) has been found to play a fundamental role in the onset, progression and dissemination of various cancers, including ovarian cancer. miRNAs have been shown to lower the susceptibility of ovarian cancer cells to drugs (3), increasing their ability to survive after detaching from the extracellular matrix (ECM) (4) – a key step in metastasis, and disrupting key signaling pathways promoting the oncogenic potential of cells (5).

In a recent study, Dr Eoh and colleagues found that levels of miRNA-630 were higher in ovarian cancer cell lines resistant to the drug paclitaxel, compared to cell lines that were susceptible to paclitaxel (3). Using specific miRCURY LNA miRNA Inhibitors, Dr Eoh and colleagues showed that inhibiting miR-630 in paclitaxel-resistant cell lines decreased cell proliferation and increased susceptibility to paclitaxel. Similar results were obtained in a pilot experiment using patient-derived xenograft models (3). Levels of the protein APAF-1, a key molecule in the intrinsic or mitochondrial pathway of apoptosis and predicted to be a potential target of miR-630, was inversely related to levels of miRNA-630. These findings suggest that miR-630 might be a potential therapeutic target for chemotherapy-resistant ovarian cancer.

MicroRNAs, such as miR141, may play a key role in ovarian cancer metastasis by increasing the resistance of tumor cells to anoikis, apoptosis in response to inappropriate cell/ECM interactions (4). While assaying for miRNAs upregulated in advanced ovarian cancer cell lines, using miRCURY LNA miRNA PCR Assays, Dr Mak and team identified miR141 as a potential role player. It turns out, increased expression of miR141 in ovarian cancer cell lines promotes cell proliferation, tumor growth, resistance to specific cell death signals and metastases (4). The zinc finger protein AP-2rep (KLF12), which is a direct target of miR141, is increased in ovarian cancer cells and subsequently increases their susceptibility to anoikis (4).

Other research has shown that epigenetic processes, such as methylation-mediated silencing of miR-193a-3p, can disrupt signaling pathways implicated in ovarian and other cancers (3). In a 2018 study by Dr Chen and team (5), levels of miR-193a-3p were lower in high-grade ovarian cancer cells compared to low-grade cells. Examining expression using miRCURY LNA miRNA Detection probes, Dr Chen showed that miR-193a-3p levels were inversely related to levels of human growth factor receptor-bound protein-7 (GRB7), the aberrant upregulation of which is implicated in several different types of cancer (6).

The exact role of miRNAs in ovarian cancer remains to be fully elucidated. With the help of new techniques and tools, such as Locked Nucleic Acid (LNA) technology, researchers will be able to better understand miRNA expression profiles in tissues and biological fluids, thereby paving the way to earlier detection and surveillance of ovarian cancer.

 

References

  1. 1. Coburn, S.B. et al. (2017). International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer 140(11), 2451-2460. Link
  2. 2. Torre, L.A. et al. (2015). Global cancer statistics, 2012. CA: A Cancer Journal for Clinicians 65, 87–108. Link
  3. 3. Eoh, K.J. et al. (2018). MicroRNA-630 inhibitor sensitizes chemoresistant ovarian cancer to chemotherapy by enhancing apoptosis. Biochemical and Biophysical Research Communications 497, 2:513-520. Link
  4. 4. Mak, C.S.L. et al. (2017) MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis. Molecular Cancer 16, 11–38. Link
  5. 5. Chen, K. et al. (2018) Methylation-associated silencing of miR-193a-3p promotes ovarian cancer aggressiveness by targeting GRB7 and MAPK/ERK pathways. Theranostics 8(2), 423-436. Link
  6. 6. Pero, S.C. et al. (2003) Grb7-based molecular therapeutics in cancer. Expert Rev Mol. Med. 10;5(14), 1-11 Link

Click HERE to learn more about Locked Nucleic Acid (LNA) technologies for miRNA research.

Adityarup Chakravorty

Adityarup Chakravorty received his Ph.D. in cellular and molecular biology from the University of Wisconsin-Madison, where he studied aspects of latent infection by Epstein-Barr Virus. He is a science writer passionate about communicating to a wide audience about novel and exciting topics in across science fields. He has written science communication on various topics including the volcanic origins of iron ore and how microbes power their metabolic reactions to grow and survive.

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