Competing Endogenous RNA: A Mechanism for Cancer to Regulate Gene Expression

Overview

Competing endogenous RNA (ceRNA) is a post-transcriptional regulatory mechanism that is an emerging focal point in the field of molecular biology. As our knowledge on ceRNA grows, we also uncover tumorigenic exploitations of this mechanism. In this write-up, I’ll explain ceRNA and its role in cancer.

Understanding ceRNA

ceRNA is a recently discovered phenomenon by which the expression of one RNA influences the expression of another by competitively reacting with limited amounts of micro RNA’s  (miRNA)[1].

miRNA’s are small (~20 nucleotides in length) RNA’s that bind to messenger RNA’s (those destined to encode for proteins) and result in their degradation or limited translation[2]. The miRNA is incorporated into a larger protein complex- RISC- with the ability to cleave mRNA that has a region corresponding to the incorporated miRNA[3]. These corresponding regions are refered to as miRNA recognition elements (MRE).

Multiple mRNA’s may have the same MRE’s, thus creating a competitive environment between mRNA’s over which one will bind to the miRNA and get destroyed. This is the process underlying ceRNA. Essentially, there is a limited number of miRNA’s and a limited number of mRNA’s in the cytoplasm. So, if a miRNA is used in the degradation of one mRNA, called mRNA-A, then it cannot be used in the degradation of another mRNA, say mRNA-B. It should follow then, that if mRNA-A is upregulated at the transcriptional level, then mRNA-B will be upregulated at the translational level due to the miRNA being consumed by mRNA-A not being able to degrade mRNA-B. In this example, mRNA-A and mRNA-B would be ceRNA’s as they compete for degradation amidst a limited amount of miRNA’s.

ceRNA in Cancer

As with many normal cellular mechanisms, cancerous cells have been found to take advantage of ceRNA to increase expression of potentially tumorigenic pathways such as angiogenesis or endothelial-mesenchymal transitioning[4,5]. Hypothetically, a tumor cell could develop a mutation in a gene corresponding to a VEGF- a signal protein in angiogenesis- ceRNA. the VEGF ceRNA would then compete with the VEGF mRNA for miRNA’s, resulting in less degradation of VEGF mRNA and more VEGF proteins and more angiogenesis

ceRNAInfo

In this hypothetical example, the cancer cell is able to indirectly upregulate angiogensis by increasing expression of a ceRNA. Note also that cancer can regulate gene expression through ceRNA in the opposite manner as well. That is, reducing the expression of tumor suppressor ceRNA so that more miRNA’s are present to limit the tumor suppressor’s expression. It is important to note that miRNA’s can be both tumorigenic and tumor suppressive[6].

The role of ceRNA in cancer has garnered a lot of attention in recent years as sequencing and computational power has increased to be able to identify such interactions.

Some actual ceRNA interactions in cancer include:

  1. PTEN and CNOTL6, VAPA, and ZEB2[7]
  2. BRAF and BRAFP1[8]
  3. KRAS and KRAS1P[9]

miRNA’s in Cancer Therapy

Just as cancer exploits ceRNA to control gene expression so can medicine. A relatively new class of medicine called antimiR’s. AntimiR’s act similar to ceRNA’s in cells in that they “sponge” miRNA’s that may be lead to tumorigenesis by binding to and resulting in the degradation of tumor suppressor mRNA’s. One such example of an antimir is anti-mir-21. Its target, mir21, is a micro RNA that targets a number of tumor suppressors, such as PTEN (mentioned above)[10] and, consequently, is commonly found in a variety of cancer types[11]. Intuitively, antimir21 works by sponging up mir21 in cells, preventing them from binding to  tumor suppressors which allows them to do their job.

Outro

The role of ceRNA in cancer is just emerging, and more studies are identifying networks. With each discovery of a ceRNA network, a potential therapeutic target is also identified. Understanding how cancer can take advantage of cellular pathways leads to more precision and a better prognosis for personalized treatment of cancer.

References

  1. Kartha RV, Subramanian S. Competing endogenous RNAs (ceRNAs): new entrants to the intricacies of gene regulation. Frontiers in Genetics. 2014;5:8. doi:10.3389/fgene.2014.00008.
  2. Eulalio , et al. Getting to the root of miRNA-mediated gene silencing. Cell. 2008;Jan 11;132(1):9-14. DOI:10.1016/j.cell.2007.12.024.
  3. Pratt AJ, et al. The RNA-induced silencing complex: A versatile gene-silencing machine. J of Bio Chem. 2009;284 (27):17897-17901. doi:10.1074/jbc.R900012200.
  4. Gao S, et al. IGF1 3’UTR functions as a ceRNA in promoting angiogenesis by sponging miR-29 family in osteocarcinoma. J mol histo. 2016 Apr;47(2):135-43. doi: 10.1007/s10735-016-9659-2.
  5. Chang H, Liu Y, Xue M, et al. Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition. Nucleic Acids Research. 2016;44(6):2514-2527. doi:10.1093/nar/gkw126.
  6. Baohong Z, et al. microRNAs as oncogenes and tumor suppressors. Dev Bio. 2007 Feb; 302:1 1-12. doi: doi.org/10.1016/j.ydbio.2006.08.028.
  7. Tay Y, et al. Coding-independent regulation of the tumor suppressor PREN by competing endogenous mRNAs. Cell 2011;147 (2): 344-357. doi: 10.1016/j.cell.2011.09.029.
  8. Florian K, et al. The BRAF pseudogene functions as a competitive endogenous RNA andinduces lymphoma in vivo. Cell 2015; 161 (2): 319-331. doi:10.1016/j.cell.2015.02.043.
  9. Poliseno L, et al. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2012; 465 (7301): 1033-1038. doi: 10.1038/nature09144.
  10. Meng F, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007; 133 (2): 647-58. doi:10.1053/j.gastro.2007.05.022.
  11. Feng Y-H, Tsao C-J. Emerging role of microRNA-21 in cancer. Biomedical Reports. 2016;5(4):395-402. doi:10.3892/br.2016.747.

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