Abstract
BackgroundThe main cause of death in colorectal cancer patients is metastasis. Accumulating evidences suggest that circRNA plays pivotal roles in cancer initiation and development. However, the underlying molecular mechanisms of circRNAs that orchestrate cancer metastasis remain vague and need further clarification.MethodsTwo paired CRC and adjacent normal tissues were used to screen the upregulated circRNAs by circRNA-seq; then, cell invasion assay was applied to confirm the functional invasion-related circRNAs. According to the above methods, circHERC4 (hsa_circ_0007113) was selected for further research. Next, we investigated the clinical significance of circHERC4 in a large cohort of patients with CRC. The oncogenic activity of circHERC4 was investigated in both CRC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying circHERC4 as a malignant driver.ResultsWe demonstrated that circHERC4 was aberrantly elevated in CRC tissues (P < 0.001), and was positively associated with lymph node metastasis and advanced tumor grade (P < 0.01). Notably, the expression of circHERC4 was associated with worse survival in patients with CRC. Silencing of circHERC4 significantly inhibited the proliferation and migration of two highly aggressive CRC cell lines and reduced liver and lung metastasis in vivo. Mechanistically, we revealed that circHERC4 inactivated the tumor suppressor, miR-556-5p, leading to the activation of CTBP2/E-cadherin pathway which promotes tumor metastasis in CRC.ConclusionsCircHERC4 exerts critical roles in promoting tumor aggressiveness through miR-556-5p/CTBP2/E-cadherin pathway and is a prognostic biomarker of the disease, suggesting that circHERC4 may serve as an exploitable therapeutic target for patients with CRC.
Highlights
The main cause of death in colorectal cancer patients is metastasis
To select metastasis-relative circRNAs, Short interfering RNA (siRNA) of these selected circRNAs were transfected into Colorectal cancer (CRC) cells and a transwell invasion assay was applied to screen out the functional circRNAs
We found the expression of circHERC4 was significantly upregulated in CRC cells, among which the circHERC4 expression was relatively high in DLD-1 and HCT116 cells and relatively low in SW480 cells compared with HCoEpic cells (Fig. 3a)
Summary
The main cause of death in colorectal cancer patients is metastasis. Accumulating evidences suggest that circRNA plays pivotal roles in cancer initiation and development. The underlying molecular mechanisms of circRNAs that orchestrate cancer metastasis remain vague and need further clarification. Discovering molecular drivers of CRC progression is helpful to improve clinical management through better prognostic predictions and potentially more effective targeted treatments. With the development of deep RNA sequencing technology [7], large amounts of circRNAs have been discovered, revealing that circRNAs could be coded from exons or introns and have multiple regulatory characters in different biological processes and various diseases [8,9,10]. The functions and underlying mechanisms of certain dysregulated circRNAs in CRC remain largely unknown and the specific characteristics of circRNAs provide a novel potential biomarker and therapeutic target during tumorigenesis and progressions of cancer [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
