Taylor Flaherty

Background: Ovarian cancer is the most fatal gynecologic cancer with a 47% five-year survival rate and a majority of tumors diagnosed in late-stages.^1,2 While biomarkers such as CA125 aid in the diagnosis of ovarian cancer, early detection is limited.³ The poor prognosis for many patients is likely due to the lack of early diagnoses, resistance to chemotherapy, and a limited knowledge of therapeutic biomarkers that contribute to the tumor microenvironment.^1,3 The emerging field of circular RNAs has become increasingly important in multiple cancer-related functions.^4,5 Circular RNAs are generated through back splicing and commonly act as tumor suppressors by miRNA sponging. Sponging consists of response elements on circRNAs binding to miRNAs and sequestering them from target genes.^5,6 Circular RNA ITCH has been shown to be dysregulated in ovarian cancer and may prove a promising biomarker in ovarian cancer.^5,6

Objectives: Investigate the role of circRNA ITCH as a tumor suppressor in ovarian cancer, including its circulating levels and sponging mechanisms in cancerous and non-cancerous cells.

Search Methods: A PubMed search yielding results from 2017 to 2023 was conducted using key terms “circular RNA”, “ovarian cancer”, “circRNA ITCH”, “circular RNA sponging”.

Results: CircRNA ITCH levels in tissues from patients with epithelial ovarian cancer were found to be significantly decreased when compared to non-cancerous tissues.^7-10 Additionally, clinicopathological correlations showed a negative correlation between circRNA ITCH levels and tumor size as well as FIGO stage in ovarian cancer tissues.⁹ Ovarian cancer cell lines (SKOV3, A2780, OVCAR3) were transfected with circRNA ITCH plasmids that resulted in increased apoptosis as well as decreased proliferation and invasion compared to control cell lines.^7,9,11 To further investigate circRNA ITCH pathways in ovarian cancer, the sponging of miR-145 to upregulate RASA1 was investigated.⁷ MiR-145 levels were shown to be decreased in circRNA ITCH overexpressed ovarian cancer cells and inversely correlated.⁷ RASA1 was identified as a direct target of miR-145 and results demonstrated that its levels were increased in ovarian cancer cells with overexpressed circRNA ITCH or miR-145 inhibitor.⁷ Similar experiments were performed to investigate the sponging of circRNA ITCH on miR-106a to upregulate CDH1.⁸ Ovarian cancer cells overexpressing circRNA ITCH showed decreased miR-106a levels and increased CDH1 protein levels.⁸ The sponging of miR-145/RASA1 and miR-106a/CDH1 via circRNA ITCH was confirmed both in vitro and in vivo.^7,8

Conclusions: These studies demonstrated that circRNA ITCH normally functions as a tumor suppressor, but is dysregulated in ovarian cancer.^7-10 Sponging of microRNAs (miR-145, miR-106a) via circRNA ITCH was shown to upregulate target genes (RASA1, CDH1).^7,8 RASA1 is known to be involved in the inhibition of cell proliferation and migration in various cancers, while CDH1 has been implicated in the epithelial-mesenchymal transition in ovarian cancer.^7,8 These results indicate circRNA ITCH as a potential biomarker in the diagnosis of ovarian cancer. Additionally, understanding the functions of circRNA ITCH downstream targets (RASA1 and CDH1) may support development of RNA targeted therapies for patients.

Works Cited:

1. Penny SM. Ovarian Cancer: An Overview. Radiol Technol. Jul 2020;91(6):561-575.
2. Torre LA, Trabert B, DeSantis CE, et al. Ovarian cancer statistics, 2018. CA Cancer J Clin. Jul 2018;68(4):284-296. doi:10.3322/caac.21456
3. Bonifácio VDB. Ovarian Cancer Biomarkers: Moving Forward in Early Detection. Adv Exp Med Biol. 2020;1219:355-363. doi:10.1007/978-3-030-34025-4_18
4. Cheng D, Wang J, Dong Z, Li X. Cancer-related circular RNA: diverse biological functions. Cancer Cell Int. Jan 6 2021;21(1):11. doi:10.1186/s12935-020-01703-z
5. Najafi S. The emerging roles and potential applications of circular RNAs in ovarian cancer: a comprehensive review. J Cancer Res Clin Oncol. Sep 2 2022;doi:10.1007/s00432-022-04328-z
6. Qiu Y, Chen Y, Agbede O, Eshaghi E, Peng C. Circular RNAs in Epithelial Ovarian Cancer: From Biomarkers to Therapeutic Targets. Cancers (Basel). Nov 21 2022;14(22)doi:10.3390/cancers14225711
7. Hu J, Wang L, Chen J, et al. The circular RNA circ-ITCH suppresses ovarian carcinoma progression through targeting miR-145/RASA1 signaling. Biochem Biophys Res Commun. Oct 20 2018;505(1):222-228. doi:10.1016/j.bbrc.2018.09.060
8. Lin C, Xu X, Yang Q, Liang L, Qiao S. Circular RNA ITCH suppresses proliferation, invasion, and glycolysis of ovarian cancer cells by up-regulating CDH1 via sponging miR-106a. Cancer Cell International. 2020/07/23 2020;20(1):336. doi:10.1186/s12935-020-01420-7
9. Luo L, Gao Y, Sun X. Circ-ITCH correlates with small tumor size, decreased FIGO stage and prolonged overall survival, and it inhibits cells proliferation while promotes cells apoptosis in epithelial ovarian cancer. Cancer Biomark. 2018;23(4):505-513. doi:10.3233/cbm-181609
10. Yan H, Xiang H, Sun B, Feng F, Chen P. Circular RNA-ITCH Inhibits the Proliferation of Ovarian Carcinoma by Downregulating lncRNA HULC. Reprod Sci. Jan 2020;27(1):375-379. doi:10.1007/s43032-019-00049-w
11. Li Y, Ge YZ, Xu L, Jia R. Circular RNA ITCH: A novel tumor suppressor in multiple cancers. Life Sci. Aug 1 2020;254:117176. doi:10.1016/j.lfs.2019.117176