Logan Rivera

Background: Colorectal cancer is a prevalent neoplasm affecting the rectum and colon, accounting for approximately 10% of cancer diagnoses and being the third leading cause of cancer-related deaths globally. The disease presents with symptoms such as abdominal pain, weight loss, and blood in the stool. Diagnosis involves imaging techniques such as X-ray, biopsy, and colonoscopies. Treatment for colorectal cancer is limited and typically involves chemotherapy and immunotherapy.¹ One promising avenue of research involves the study of exosomes, membrane-bound vesicles located extracellularly that carry a variety of biomolecules and play a crucial role in cell-cell communication.^2,3 Circular RNA (circRNA) is a key player in the regulation of colorectal cancer, being formed by a backsplicing event during transcription. Dysregulated circRNA in colorectal cancer cells modulates metabolism by a variety of mechanisms, making it a promising target for new treatment options.^4-8

Objective: Dysregulated circRNAs associated with colorectal cancer play a modulatory role in tumor progression.

Search Methods:  The databases PubMed and Web of Science were searched within the timeframe of 2013 to 2017 using keywords such as “circRNA,” “colorectal cancer,” and “exosomes.”

Results:  Circular RNAs are known to sponge miRNAs, preventing them from decreasing their target expression. To elucidate the mechanism by which circFNDC3B modulates colorectal cancer (CRC), researchers first screened for miRNAs differentially expressed in CRC cells and identified miR-937-5p as a candidate. Using a FISH hybridization assay, the interaction between circFNDC3B and miR-937-5p was confirmed, and it was found that miR-937-5p negatively regulates TIMP3, a gene involved in cancer progression and metastasis. Furthermore, circFNDC3B was found to be positively associated with TIMP3 levels, likely through miR-937-5p as an intermediate step. The results indicate that decreased levels of circFNDC3B are expected to increase miR-937-5p, resulting in a corresponding drop in TIMP3 levels. Using a biological database, potential interactions between TIMP3 and other proteins were identified, and VEGFA was predicted to interact with TIMP3. VEGFA plays a crucial role in regulating angiogenesis, a process essential for cancer growth and metastasis.⁸

Conclusions:  Colorectal cancer is a common cancer with limited treatment options. However, circRNAs have emerged as potential diagnostic tools and therapeutic targets for the disease. Dysregulated circRNAs in serum could be used for early and accurate diagnosis, personalized treatment plans, and the development of novel therapeutics. The mechanism of CircFNDC3B, a circRNA, has shown the potential to modulate colorectal cancer by sequestering mi-937-5p, which negatively regulates the expression of TIMP3, negatively affecting VEGFA responsible for promoting angiogenesis. However, there are limitations to the use of circRNAs, including the inability to treat upregulated circRNAs with additional exosomal circRNA, and the lack of infrastructure for producing exosomal circRNA at scale. Research is needed to identify dysregulated circRNAs and to develop effective treatments. Regardless, circRNAs offer promising avenues for diagnostic and therapeutic development in colorectal cancer, which could improve patient outcomes.^2,8

Works Cited:

1. Ranasinghe R, Mathai M, Zulli A. A synopsis of modern – day colorectal cancer: Where we stand. Biochim Biophys Acta Rev Cancer. Mar 2022;1877(2):188699. doi:10.1016/j.bbcan.2022.188699
2. Wei F, Li Y. The emerging roles of exosome-derived noncoding RNAs in the tumor immune microenvironment and their future applications. Biomed Pharmacother. Dec 2022;156:113863. doi:10.1016/j.biopha.2022.113863
3. Ghafouri-Fard S, Taheri M, Hussen BM, Vafaeimanesh J, Abak A, Vafaee R. Function of circular RNAs in the pathogenesis of colorectal cancer. Biomed Pharmacother. Aug 2021;140:111721. doi:10.1016/j.biopha.2021.111721
4. Chen R-X, Chen X, Xia L-P, et al. N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nature Communications. 2019/10/16 2019;10(1):4695. doi:10.1038/s41467-019-12651-2
5. Pan Z, Cai J, Lin J, et al. A novel protein encoded by circFNDC3B inhibits tumor progression and EMT through regulating Snail in colon cancer. Molecular Cancer. 2020/04/02 2020;19(1):71. doi:10.1186/s12943-020-01179-5
6. Yang Y, Luo D, Shao Y, et al. circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer. Cancer Communications. 2023;43(1):100-122. doi:https://doi.org/10.1002/cac2.12380
7. Zeng W, Zhu J-F, Guo J, et al. m6A-modified circFNDC3B inhibits colorectal cancer stemness and metastasis via RNF41-dependent ASB6 degradation. Cell Death & Disease. 2022/11/29 2022;13(11):1008. doi:10.1038/s41419-022-05451-y
8. Zeng W, Liu Y, Li WT, Li Y, Zhu JF. CircFNDC3B sequestrates miR-937-5p to derepress TIMP3 and inhibit colorectal cancer progression. Mol Oncol. Nov 2020;14(11):2960-2984. doi:10.1002/1878-0261.12796