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Author: Rainbow
Summary: To date, many specific circular RNAs have been identified in a variety of tumors, which regulate the occurrence and progression of tumors.
On November 16, Liu Fanlong and Zhang Honghe from Zhejiang University School of Medicine jointly published an online article entitled "Specific intracellular retention of circSKA3 promotes colorectal cancer metastasis by attenuating ubiquitination and" in the journal Cell Death & Disease degradation of SLUG", studies have shown that colorectal cancer cells may retain circSKA3 in the cytoplasm through specific cell motifs, thereby inhibiting exosome secretion, while intracellular circSKA3 can block the ubiquitinated degradation of SLUG and promote the metastasis of colorectal cancer. Specific ASOs targeting the key cyclization elements and functional motifs of circSKA3 may be promising drugs for the treatment of colorectal cancer.
https://www.nature.com/articles/s41419-023-06279-w
Background:
01
Recently, circular RNA (circRNA) has been recognized as an important epigenetic regulator involved in various tumor biological processes, such as cell proliferation, apoptosis, autophagy, angiogenesis, energy metabolism, immune surveillance, migration, and invasion. Typically, circular RNAs are produced by reverse splicing after upstream gene transcription. Circular RNAs play a biological role by adsorbing miRNAs, binding functional RNA-binding proteins (RBPs), forming pseudogenes after reverse transcription, regulating gene transcription or RNA splicing in the nucleus, and even encoding polypeptides.
To date, a number of specific circular RNAs have been identified in a variety of tumors that regulate tumorigenesis and progression. For example, in hepatocellular carcinoma (HCC), circVAMP3 accelerates the formation of stress granules and inhibits the translation of the proto-oncogene c-myc, while circANAPC7 inhibits pancreatic cancer progression through the PHLPP2-AKT-TGF-β signaling pathway.
Analysis of circular RNA sequencing data revealed that some circular RNAs were downregulated in tumor tissue samples but upregulated in serum samples. The researchers further studied and found that tumor cells can actively excrete the tumor-inhibiting circular RNA circRHOBTB3 through exosomes to maintain the fitness of cancer cells. This mechanism results in lower levels of circRHOBTB3 in tumor tissues and higher levels in serum in colorectal cancer (CRC) patients. However, it is unclear why some other circular RNAs are upregulated in tumor tissue samples but downregulated in serum samples.
CircSKA3 (hsa_circ_0000467) is formed by exon 4 cyclization of the spindle and centromere-associated protein 3 (SKA3) genes, and its expression is increased in colorectal cancer tissues but decreased in serum samples. The SKA3 maternal gene is located on human chromosome 13q and regulates cell mitosis, proliferation, apoptosis, and eukaryotic development by forming a heterodimer with SKA1 or SKA2 and participating in the formation of spindles and centromeres. Previous studies have found that abnormally high expression of SKA3 is closely related to the occurrence and progression of hepatocellular carcinoma, laryngeal squamous cell carcinoma and breast cancer. In addition, several studies have reported aberrant expression of circSKA3 in breast cancer and medulloblastoma. However, the clinical significance and biological role of circSKA3 in colorectal cancer have not been reported.
circSKA3 promotes colorectal cancer
Migration, invasion, and metastasis of cells
02
To elucidate the biological role of circSKA3 in colorectal cancer, the researchers examined circSKA3 expression in CRC cell lines. The results showed higher levels of circSKA3 in CRC cell lines (HCT116, SW620, SW480, and HCT8) compared to other cell types, including NCM460, Helf, and Caf. The researchers used two siRNAs targeting the BSJ locus of circSKA3 to silence circSKA3 in HCT116 and SW620 cells, and found that these siRNAs significantly silenced circSKA3 but did not affect the host gene SKA3. Silencing of circSKA3 also significantly inhibited the migration and invasion of HCT116 and SW620 cells.
The researchers used shRNAs to construct cell lines that stably silence circSKA3 and confirmed that these shRNAs specifically silenced circSKA3 at the mRNA level and at the protein level without affecting the host gene SKA3. Silencing of circSKA3 by shRNA also significantly inhibited migration and invasion, but only slightly inhibited cell proliferation. To further confirm the oncogenic role of circSKA3 in colorectal cancer, the researchers used CRISPR-RfxCas13d/BSJ-gRNA to target the circSKA3 BSJ site in HCT116 and SW620 cells for circSKA3 silencing. When circSKA3 was specifically silenced in HCT116 and SW620 cells, migration and invasion were significantly inhibited, but cell proliferation was not significantly changed.
In addition, the researchers constructed a circSKA3 overexpression vector and used it to transfect HCT8 and SW480 cell lines. Overexpression of circSKA3 did not alter the expression of the host gene SKA3 at the mRNA level or at the protein level. In addition, the overexpression of circSKA3 significantly promoted migration and invasion, but did not alter the proliferative potential of colorectal cancer cells. When the researchers re-expressed circSKA3 in shRNA-mediated circSKA3-silenced HCT116 cells, the migration and invasion potential was restored. These data suggest that circSKA3 can promote the migration and invasion of colorectal cancer cells in vitro.
Findings:
03
In summary, studies have shown that colorectal cancer cells may retain circSKA3 in the cytoplasm through specific cell motifs, thereby inhibiting exosome secretion, while intracellular circSKA3 can block the ubiquitination degradation of SLUG and promote the metastasis of colorectal cancer. Specific ASOs targeting the key cyclization elements and functional motifs of circSKA3 may be promising drugs for the treatment of colorectal cancer.
Resources:
https://www.nature.com/articles/s41419-023-06279-w
Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please visit a regular hospital.
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