<p>Elevated Levels of circRUNX1 in Colorectal Cancer Promote Cell Growth and Metastasis via miR-145-5p/IGF1 Signalling</p>

Abstract

Background: Emerging evidence suggests that circular RNAs (circRNAs) are vital regulators in a range of cancers. "miRNA sponge" is the most reported role played by circRNAs in many tumors. The insulin-like growth factor (IGF) 1 pathway plays a key role in the development and progression of many cancers, including colorectal cancer (CRC). The aim of the study is to establish the potential clinical value and driving molecular mechanisms of circRNAs in CRC. Materials and Methods: Real-time quantitative RT-PCR (qRT-PCR) was performed to measure the circRUNX1 expression in 52 tissue samples from CRC patients. We verified the tumor promotor role of circRUNX1 in cell-based in vitro and in vivo assays. Human growth factor array was used to identify circRUNX1-regulated signaling pathways. We then used a double luciferase reporter assay and RNA fluorescence in situ hybridization to identify the downstream miR-145-5p of circRUNX1. Furthermore, we performed Western blotting and biological function assays to demonstrate if the circRUNX1/miR-145-5p/IGF1 axis is responsible for the proliferation of CRC cells and promotes CRC development. Results: By performing qRT-PCR from CRC tissues and paired adjacent normal mucosa tissues, we identified that circRUNX1 expression was significantly upregulated in CRC tissues and positively related with lymph node metastasis, distant metastasis and advanced tumor-node-metastasis tumor stage in patients. Functionally, circRUNX1 knockdown inhibited cell proliferation and migration and promoted apoptosis, whereas its overexpression exerted opposite effects. In vivo, circRUNX1 promoted tumor growth and metastasis. Mechanically, circRUNX1 shared miRNA response elements with IGF1. circRUNX1 competitively bound to miR-145-5p and prevented miR-145-5p from decreasing the expression of IGF1, which facilitated tumor growth. Conclusion: Our studies verified that circRUNX1 functions as a tumor promotor in CRC cells by targeting the miR-145-5p/IGF1 signaling pathway and may have potential use as a prognostic indicator and therapeutic target in CRC patients.

Circular RNAs: Emerging Regulators of the Major Signaling Pathways Involved in Cancer Progression

“…It is important to mention that there are circRNAs—for instance, circ_0002577 and circ-RUNX1—which increase the expression levels of IGF1R and IGF1 , respectively, leading to enhanced PI3K/AKT signaling activity, elevated cancer cell proliferation rate, and EMT [ 110 , 123 ]. However, due to the crosstalk between PI3K/AKT and MAPK signaling, the hypothesis of a synergistic function cannot be excluded.…”

Novel Regulators of the IGF System in Cancer

“…A circRNA derived from backsplicing of the IGF1R itself, named circIGF1R, is detectable in hepatocellular carcinoma clinical specimens and promotes cell proliferation by activating the PI3K/Akt pathway [ 103 ]. Among other major components of the IGF axis, IGF1 is upregulated by the action of circRUNX1 on miR-145-5p or circ_0014130 on miR-142-5p, in colorectal [ 104 ] or nonsmall cell lung cancer [ 105 ], respectively, with substantial effects on cell proliferation, cell cycle progression, cell migration and inhibition of apoptosis. Recently published data support the impact of circRNA/IGF2 interaction in modulating cancer cell metabolism [ 106 ].…”

CircRUNX1 functions as an oncogene in colorectal cancer by regulating circRUNX1/miR‐485‐5p/SLC38A1 axis

“…Circ_0136666 aggravated CRC cell growth and motility by decreasing miR‐136 and increasing SH2B1 35 . More importantly, Chen et al uncovered that circRUNX1 level was enhanced in CRC tissues and triggered CRC cell colony formation, proliferation and motility and hampered apoptosis through miR‐145‐5p/IGF1 axis 36 . These findings indicated that circRUNX1 played a vital regulatory role in CRC by circRNA/miRNA/mRNA axis.…”