Carine Rizk

Introduction. Colorectal cancer (CRC) is the third most common cause of cancer deaths in the United States in 2020¹. Among patients diagnosed with CRC, 20% have a metastatic growth and 40% have a recurrence after initial local treatment, making the prognosis poor, with a 5-year survival rate of less than 20%¹. For diagnosis, colonoscopy is used to identify the primary cancer. However, it is an invasive diagnostic method and has low adherence rates². Fecal occult blood tests are used, but they show low sensitivity for detecting pre-neoplastic lesions and high rates of false positives⁴.  Thus, there is a need to identify and validate sensitive and specific CRC early-stage biomarkers that predict the course of the disease. Exosomes contain abundant miRNA, which are endogenous, non-coding, 18-25 nucleotides long, single-stranded RNA released into the bloodstream, involved in cell proliferation, cell-to-cell communication, energetics and chemoresistance⁵. As such, studies are starting to look at exosomal miRNA as biomarkers for early diagnosis, prognosis and therapeutic response prediction. Methods. Studies performed miRNA-seq in human colon cancer cells to find biomarkers from the electron transport chain, hypoxic conditions and chemoresistant states^10,11,15. Exosomes were isolated and the expression levels of candidate miRNA were measured by RT-PCR^10,11. Migration and invasion assays were used to look at miRNA metastatic potential¹¹. mRNA targets were found by prediction programs and validated by dual luciferase reporter assays¹¹. Bioinformatic tools, KEGG and GO functional analyses, were used to determine the interconnected roles of the selected miRNA¹⁵. Results. UQCRB, a protein found in the electron transport chain complex III, has been shown to be highly expressed in colorectal cancer¹¹. miR-4435 was upregulated in exosomes of mutated UQCRB-expressing cells and human colon cancer cells, and targets TIMP3, a tumor suppressor. Additionally, exosomal miR-361-3p was found to overactive the NF-kB pathway, a key regulator of CRC proliferation¹⁰. A study identified a panel of 6 miRNA correlated with tumor location and stage in oxaliplatin-based chemotherapy and elucidated the functional importance of RNA polymerase II¹⁵. Conclusions. Studies identified potential promising miRNA for early diagnosis, prognosis and therapeutic response prediction of CRC. Big data is paving the future of CRC biomarker identification, especially miRNA-mRNA network analyses that provide significant insight into key pathophysiological mechanisms¹². However, it remains important to validate previously identified differentially expressed exosomal miRNAs as CRC biomarkers¹⁴.

1. Biller LH, Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A JAMA. 2021;325(7):669-685. doi:10.1001/jama.2021.0106
2. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, CA Cancer J Clin. 2020;70(3):145-164. doi:10.3322/caac.21601
3. Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17(2):111-130. doi:10.1038/s41575-019-0230-y
4. Rapado-González Ó, Álvarez-Castro A, López-López R, Iglesias-Canle J, Suárez-Cunqueiro MM, Muinelo-Romay L. Circulating microRNAs as Promising Biomarkers in Colorectal Cancer. Cancers. 2019;11(7):E898. doi:10.3390/cancers11070898
5. Marcuello M, Vymetalkova V, Neves RPL, et al. Circulating biomarkers for early detection and clinical management of colorectal cancer. Mol Aspects Med. 2019;69:107-122. doi:10.1016/j.mam.2019.06.002
6. Identification and Validation of MicroRNA Profiles in Fecal Samples for Detection of Colorectal Cancer – PubMed. Accessed February 7, 2022. https://pubmed.ncbi.nlm.nih.gov/31622624/
7. Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, Cerrada E, Rodriguez Yoldi Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer. Int J Mol Sci. 2017;18(1):197. doi:10.3390/ijms18010197
8. Recio-Boiles A, Cagir B. Colon Cancer. In: StatPearls. StatPearls Publishing; 2022. Accessed February 7, 2022
9. Mannavola F, Salerno T, Passarelli A, Tucci M, Internò V, Silvestris Revisiting the Role of Exosomes in Colorectal Cancer: Where Are We Now?. Front Oncol. 2019;9:521. Published 2019 Jun 19. doi:10.3389/fonc.2019.00521
10. Li J, Yang P, Chen F, et al. Hypoxic colorectal cancer‐derived extracellular vesicles deliver microRNA‐361‐3p to facilitate cell proliferation by targeting TRAF3 via the noncanonical NF‐κB pathways. Clin Transl Med. 2021;11(3):e349. doi:10.1002/ctm2.349
11. Hong JW, Kim JM, Kim JE, et al. MiR-4435 is an UQCRB-related circulating miRNA in human colorectal cancer. Sci Rep. 2020;10(1):2833. doi:10.1038/s41598-020-59610-2
12. Ma J, Wang P, Huang L, Qiao J, Li J. Bioinformatic analysis reveals an exosomal miRNA-mRNA network in colorectal cancer. BMC Med Genomics. 2021;14(1):60. Published 2021 Feb 27. doi:10.1186/s12920-021-00905-2
13. Han J, Sun W, Liu R, et al. Plasma Exosomal miRNA Expression Profile as Oxaliplatin-Based Chemoresistant Biomarkers in Colorectal Adenocarcinoma. Front Oncol. 2020;10:1495. doi:10.3389/fonc.2020.01495
14. Wang J, Yan F, Zhao Q, et al. Circulating exosomal miR-125a-3p as a novel biomarker for early-stage colon cancer. Sci Rep. 2017;7(1):4150. Published 2017 Jun doi:10.1038/s41598-017-04386-1
15. Ren D, Lin B, Zhang X, Peng Y, Ye Z, Ma Y, et al. Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling Oncotarget. (2017) 8:49807–23. doi: 10.18632/oncotarget.17971
16. Martin RD, Hébert TE, Tanny Therapeutic Targeting of the General RNA Polymerase II Transcription Machinery. Int J Mol Sci. 2020;21(9):3354. Published 2020 May 9. doi:10.3390/ijms21093354