miR-33a-5p in small extracellular vesicles as non-invasive biomarker for oxaliplatin sensitivity in human colorectal cancer cells

Abstract

microRNAs (miRNAs) contained in small extracellular vesicles (sEVs) are candidates for non-invasive biomarkers. Oxaliplatin (L-OHP) has been approved for advanced colorectal cancer (CRC) chemotherapy. However, the response to L-OHP differs among CRC patients. In addition, CRC cells often acquire the resistance to L-OHP. This study aimed at the prediction of L-OHP sensitivity by measuring extracellular miRNAs levels. Firstly, we compared intracellular miRNAs expressions in L-OHP-sensitive CRC cells (SW620 and HCT116 cells) with those in acquired and intrinsic L-OHP-resistant cells. In microarray and real-time RT-PCR analyses, the intracellular miR-33a-5p, miR-210–3p, and miR-224–5p expressions were lower in acquired and intrinsic L-OHP-resistant CRC cells than sensitive cells. Furthermore, in SW620 cells, L-OHP sensitivity was decreased by miR-33a-5p inhibitor. On the other hand, miR-210–3p or miR-224–5p inhibitor did not affect L-OHP sensitivity in SW620 cells. Secondly, the amount of miR-33a-5p, miR-210–3p, and miR-224–5p in sEVs was compared. The amount of miR-33a-5p and miR-210–3p in sEVs secreted from acquired and intrinsic L-OHP-resistant cells tended to be small. miR-224–5p was not detected in sEVs secreted from three types of CRC cells examined. To the best of our knowledge, this is the first study demonstrating that miR-33a-5p and/or miR-210–3p in sEVs would be candidates for biomarkers of L-OHP sensitivity. In particular, miR-33a-5p is a promising candidate because it would be directly involved in L-OHP sensitivity.

The Role of Exosomal Non-Coding RNAs in Colorectal Cancer Drug Resistance

“…More specifically, ex-miR-200c and ex-miR-141 were suggested as potential biomarkers for mesenchymal-epithelial transition of oxaliplatin-resistant CRC cells [74] while the exosomal expression level of let-7b was associated with the cells' invasion activity [75]. Last, but not least, another work by the same authors reported that the downregulation of miR-33a-5p and miR-210-3p is correlated with oxaliplatin resistance; a possible explanation implicates the inhibition of several genes related with DNA damage repair mechanisms [76].…”

Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer

“…Exosomal miRNAs may act as chemoresistance regulators and anticipate poor results in CRC patients. Shota Tanaka et al found that acquired and intrinsic L-OHP-resistant CRC cells had lower expression of miR-33a-5p and/or miR-210-3p than sensitive cells, suggesting that miR-33a-5p would be a candidate biomarker of L-OHP sensitivity [ 135 ]. In another study, exosomal miR-208b was related to a decrease in oxaliplatin-based chemosensitivity in CRC, as it promotes Treg proliferation by targeting PDCD4 [ 136 ].…”

Connection between Radiation-Regulating Functions of Natural Products and miRNAs Targeting Radiomodulation and Exosome Biogenesis

“…As mentioned above, most radiation-modulating natural-product-regulated miRNAs (Table 3) are associated with exosome biogenesis and miRDB results for exosome biogenesismodulating targets. However, other miRNAs , such as miR-3960 [143], miR-6085 [144], miR-18a-5p [145], miR-22-3p [146], miR-126-3p [147], miR-137-3p [148], miR-122-5p [149], miR-23a-3p [150], miR-155-5p [151], miR-33a-5p [152], miR-574-3p [153], miR-132-3p [154], miR-211-5p [155], miR-375-3p [156], miR-181c-3p [157], miR-146a-5p [158], miR-542-3p [159], miR-877-3p [160], miR-192-5p [161], miR-451a [162], miR-215-5p [163], miR-99b-3p [164], miR-549a-5p [165], and miR-1247-5p [166], have only been reported in terms of exosome biogenesis-modulating effects, without available miRDB results for exosome biogenesis-modulating targets.…”

“…miR-33a-5p was underexpressed in oxaliplatin-resistant colon cancer cells compared to sensitive control cells. Exosomal miR-33a-5p was present at only a low level in resistant colon cancer cells [152]. Placenta-derived exosomal miR-574-3p was underexpressed after chemerin, enhancing proliferation and angiogenesis for gestational diabetes mellitus [153].…”