Colorectal cancer (CRC) is a common hereditary tumor that is often fatal Its pathogenesis involves multiple genes, including circular RNAs (circRNAs) Notably, circRNAs constitute a new class of noncoding RNAs (ncRNAs) with a covalently closed loop structure and have been characterized as stable, conserved molecules that are abundantly expressed in tissue/development-specific patterns in eukaryotes Based on accumulating evidence, circRNAs are aberrantly expressed in CRC tissues, cells, exosomes, and blood from patients with CRC Moreover, numerous circRNAs have been identified as either oncogenes or tumor suppressors that mediate tumorigenesis, metastasis and chemoradiation resistance in CRC Although the regulatory mechanisms of circRNA biogenesis and functions remain fairly elusive, interesting results have been obtained in studies investigating CRC In particular, the expression of circRNAs in CRC is comprehensively modulated by multiple factors, such as splicing factors, transcription factors, specific enzymes and cis-acting elements More importantly, circRNAs exert pivotal effects on CRC through various mechanisms, including acting as miRNA sponges or decoys, interacting with RNA binding proteins, and even translating functional peptides Finally, circRNAs may serve as promising diagnostic and prognostic biomarkers and potential therapeutic targets in the clinical practice of CRC In this review, we discuss the dysregulation, functions and clinical significance of circRNAs in CRC and further discuss the molecular mechanisms by which circRNAs exert their functions and how their expression is regulated Based on this review, we hope to reveal the functions of circRNAs in the initiation and progression of cancer and highlight the future perspectives on strategies targeting circRNAs in cancer research

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Comprehensive landscape and future perspectives of circular RNAs in colorectal cancer

Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).

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The emerging role of ferroptosis in intestinal disease.

Distant metastasis is the main cause of death for cancer patients. Recently, the newly discovered programmed cell death includes necroptosis, pyroptosis, and ferroptosis, which possesses an important role in the process of tumor metastasis. At the same time, it is widely reported that non-coding RNA precisely regulates programmed death and tumor metastasis. In the present review, we summarize the function and role of necroptosis, pyrolysis, and ferroptosis involving in cancer metastasis, as well as the regulatory factors, including non-coding RNAs, of necroptosis, pyroptosis, and ferroptosis in the process of tumor metastasis.

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Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis.

Background Ferroptosis is an iron-dependent and oxidative cell death form Recent studies suggested that circular RNAs (circRNAs) regulated ferroptosis in tumour cells Circ_0007142 was identified as a carcinogenic molecule in colorectal cancer (CRC), but its function on ferroptosis in CRC remains unknown Methods Circ_0007142, microRNA-874-3p (miR-874-3p) and glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) levels were assayed using the quantitative real-time polymerase chain reaction (qRT-PCR) Cell survival and proliferation were measured by Cell Counting Kit-8 (CCK-8) assay Protein detection was performed by Western blot Cell apoptosis was analysed by flow cytometry Ferroptosis was assessed by iron accumulation and oxidative stress Target binding was evaluated by dual-luciferase reporter assay In vivo research was conducted by tumour xenograft in mice Results Circ_0007142 was overexpressed in CRC After expression inhibition of circ_0007142, proliferation was reduced, while apoptosis and ferroptosis were facilitated in CRC cells Mechanically, circ_0007142 was found as a miR-874-3p sponge and miR-874-3p inhibitor eliminated the regulation of si-circ_0007142 in CRC cells MiR-874-3p targeted GDPD5 and upregulation of GDPD5 reversed the miR-874-3p-triggered tumour inhibition and ferroptosis promotion in CRC cells Moreover, GDPD5 was regulated by the circ_0007142/miR-874-3p axis Circ_0007142 also affected CRC tumorigenesis in vivo through the regulation of miR-874-3p and GDPD5 Conclusion All these findings proved that circ_0007142/miR-874-3p/GDPD5 axis regulated tumorigenesis and ferroptosis of CRC cells Circ_0007142 might be an available marker for ferroptosis in CRC therapy

Circ_0007142 downregulates miR-874-3p-mediated GDPD5 on colorectal cancer cells.

Ferroptosis is a novel form of programmed cell death, and it is characterized by iron-dependent oxidative damage, lipid peroxidation and reactive oxygen species accumulation. Notable studies have revealed that ferroptosis plays vital roles in tumor occurrence and that abundant ferroptosis in cells can inhibit tumor progression. Recently, some noncoding RNAs (ncRNAs), particularly microRNAs, long noncoding RNAs, and circular RNAs, have been shown to be involved in biological processes of ferroptosis, thus affecting cancer growth. However, the definite regulatory mechanism of this phenomenon is still unclear. To clarify this issue, increasing studies have focused on the regulatory roles of ncRNAs in the initiation and development of ferroptosis and the role of ferroptosis in progression of various cancers, such as lung, liver, and breast cancers. In this review, we systematically summarized the relationship between ferroptosis-associated ncRNAs and cancer progression. Moreover, additional evidence is needed to identify the role of ferroptosis-related ncRNAs in cancer progression. This review will help us to understand the roles of ncRNAs in ferroptosis and cancer progression and may provide new ideas for exploring novel diagnostic and therapeutic biomarkers for cancer in the future.

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Ferroptosis in Cancer Progression: Role of Noncoding RNAs

Circular ATP binding cassette subfamily B member 10 (circABCB10) has been identified to have oncological functions in several tumors However, the roles of circABCB10 in rectal cancer remain unknown The expression of circABCB10, microRNA (miR)-326 and C-C motif chemokine ligand 5 (CCL5), and apoptosis related-protein was detected using quantitative real-time polymerase chain reaction or western blot, respectively Cell survival or apoptosis was measured using cell counting kit-8 assay or flow cytometry The accumulations of intracellular lipid reactive oxygen species (ROS) and Fe2+ were analyzed using C11-BODIP dye or iron kit assay, respectively In vivo experiments were conducted using the murine xenograft model The interaction between miR-326 and circABCB10 or CCL5 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay CircABCB10 and CCL5 were upregulated but miR-326 was downregulated in rectal cancer The knockdown of circABCB10 promoted rectal cancer cell ferroptosis and apoptosis in vitro as well as inhibited tumor growth in vivo miR-326 was a target of circABCB10, and the miR-326 inhibition could partially attenuate circABCB10 deletion-induced cell ferroptosis and apoptosis miR-326 directly interacted with CCL5, and the miR-326 inhibition suppressed cell ferroptosis and apoptosis by targeting CCL5 Besides, we observed that miR-326 was negatively regulated by circABCB10, while CCL5 was positively regulated by it, and circABCB10 served as a sponge of miR-326 to regulate the CCL5 expression in rectal cancer cells CircABCB10 silence promoted rectal cancer cell ferroptosis and apoptosis by regulating the miR-326/CCL5 axis, suggesting a potential therapeutic target for rectal cancer therapy

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T Wang

Papers

CircABCB10 silencing inhibits the cell ferroptosis and apoptosis by regulating the miR-326/CCL5 axis in rectal cancer