Abstract
Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker. Exosomes are microvesicles released by body cells for intercellular communication. Circular RNAs (circRNAs) are non-coding RNAs with covalently closed loops and enriched in exosomes. Crosstalk between circRNAs in exosomes and chemo-resistance in CRC remains unknown. This research aims to identify exosomal circRNAs associated with FOLFOX-resistance in CRC. FOLFOX-resistant HCT116 CRC cells (HCT116-R) were generated from parental HCT116 cells (HCT116-P) using periodic drug induction. Exosomes were characterized using transmission electron microscopy (TEM), Zetasizer and Western blot. Our exosomes were translucent cup-shaped structures under TEM with differential expression of TSG101, CD9, and CD63. We performed circRNAs microarray using exosomal RNAs from HCT116-R and HCT116-P cells. We validated our microarray data using serum samples. We performed drug sensitivity assay and cell cycle analysis to characterize selected circRNA after siRNA-knockdown. Using fold change >2 and p < 0.05, we identified 105 significantly upregulated and 34 downregulated circRNAs in HCT116-R exosomes. Knockdown of circ_0000338 improved the chemo-resistance of CRC cells. We have proposed that circ_0000338 may have dual regulatory roles in chemo-resistant CRC. Exosomal circ_0000338 could be a potential biomarker for further validation in CRC.
Highlights
Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker
To date, nothing has been reported on the analysis of circRNA expression in exosomes derived from chemoresistant CRC cells
Zeta potential of exosomes refers to the electric potential difference between the stationary layer of ions bound to the vesicles and solution[30]
Summary
Chemo-resistance is associated with poor prognosis in colorectal cancer (CRC), with the absence of early biomarker. This research aims to identify exosomal circRNAs associated with FOLFOX-resistance in CRC. Knockdown of circ_0000338 improved the chemo-resistance of CRC cells. We have reported on the profile of circRNA in drug-resistant HCT116 cells with clinical validation of candidate circRNAs in 25 FFPE (formalin-fixed paraffin-embedded) tissue samples from CRC patients[15]. To date, nothing has been reported on the analysis of circRNA expression in exosomes derived from chemoresistant CRC cells. This study aims to generate the expression profile of circRNAs in exosomes derived from FOLFOX-resistant CRC cells. Expressed exosomal circRNAs may serve as potential biomarker or target for early diagnosis of chemoresistance among CRC patients
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