Ryan Kwong

Introduction: The role of microRNAs (miRs) in cancer is just budding and has only been studied for the past 20 years. MiRs are short, non-coding single stranded RNA sequences that regulate other RNA transcripts and have been implicated in the development of cancer at every stage. MiR-15a and miR-16 are among the best studied in relation to cancer, and dysfunction of these has been strongly correlated to multiple cancers including colorectal, ovarian, esophageal, multiple myeloma, and nasopharyngeal cancers^1-5. These studies also demonstrated that restoring miR-15a/16 function could reduce proliferative and/or metastatic capacity of established model tumor cell lines. In addition, miR-15a/16 has been investigated for its potential to diagnose, guide medical treatment, or enhance existing therapies^2-4. Methods: Investigators used RT-qPCR to quantify miR-15a/16 expression^1-5. SNAIL and vimentin mRNA transcripts served as markers for mesenchymal properties of cancer cells^1-2. In colorectal cancer cells, AP4 3’-UTR luciferase constructs were used to quantify expression in response to miR15a/16-1¹. Researchers used a flag-BMI1 construct and immunoblotted for ATP7B, a known drug efflux transporter, to determine the effect of miR-15a/16 in ovarian cancer². Western blot against CDK4 was used to analyze expression of CDK4 in relation to miR-15a levels in nasopharyngeal carcinoma cells. Subsequently, chromatin immunoprecipitation assay and PCR were used to investigate c-Myc (which is directly related to CDK4 expression) interactions with the miR-15a gene⁵. Results: Introduction of miR-15a/16-1 to colorectal cancer cells negatively regulated AP4 expression which induced a decrease in SNAIL and vimentin mRNA transcripts¹. Similarly, ovarian cancer cells which ectopically expressed these miRs demonstrated a decrease in BMI1, leading to a loss of mesenchymal proteins and gain of epithelial proteins such as E-Cadherin². Furthermore, ovarian cancer cells showed increased cisplatin sensitivity and intracellular concentration due to a downregulation of ATP7B, while increased sensitivity to cisplatin in nasopharyngeal carcinoma was attributed to suppression of CDK4 by miR-15a⁵. Finally, serum and exosomal miR-15a were downregulated in esophageal squamous cell carcinoma and multiple myeloma^3,4. Conclusion: These studies demonstrate the potential of miR-15a/16 in treatment and diagnosis of multiple cancers which leverage an array of natural cellular mechanisms. Once a delivery mechanism is invented for miRs, there is much promise for the use of miR-15a/16 as a monotherapy or adjunct therapy to reduce tumor growth, metastasis, and ultimately, mortality from the disease.

1. Shi L, Jackstadt R, Siemens H, et al. p53-induced miR-15a/16-1 and AP4 form a double-negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. Cancer Res. 2014;74(2):532-42.
2. Dwivedi SKD, Mustafi SB, Mangala LS, et al. Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer. Oncotarget. 2016;7(12):15093-15104.
3. Li J, Li M, Gao F, Ge X. Serum microRNA-15a level acts as a potential diagnostic and prognostic biomarker for human esophageal squamous cell carcinoma. Cancer Biomark. 2017;18(1):11-17.
4. Zhang L, Pan L, Xiang B, et al. Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma. Oncotarget. 2016;7(21):30876-30891.
5. Liu Z, Cheng C, Luo X, et al. CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma. BMC Cancer. 2016;16:238.