Abstract
PurposeChemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumor’s acquired drug resistance, the related action mechanism is still not explored specifically.MethodsTo elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.ResultsSmall RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-sensitive cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine–cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin’s inhibition of the cell cycle of sensitive cells.ConclusionSensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.
Highlights
Esophageal cancer is the eighth most common tumor in the world
Sensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle
The exosomes secreted by tumor cells mediate information transfer between tumor cells, which can make sensitive cells obtain drug resistance. [6,13] Wei et al found that by treating the tamoxifen-sensitive breast cancer cell line MCF-7 with the exosome secreted by chemotherapy-resistant cell line MCF-7TamR, it can acquire drug resistance, because the miR-221/222 in the exosome secreted by the drug-resistant cell line inhibited the expression of the estrogen receptor α target gene (ERα). [14,15,16] miR-222 can make the chemotherapy-resistant breast cancer cells regain their sensitivity to adriamycin
Summary
Esophageal cancer is the eighth most common tumor in the world. Esophageal cancer patients in China account for more than half of the total number of esophageal cancer patients in the world, and here the mortalities of both male and female patients are the highest. [1,2] The occurrence of esophageal cancer is affected by multiple factors, including genetics, living environment, bad habits (such as smoking and drinking) and others. [1] It is not easy to detect esophageal cancer at an early stage, and esophageal cancer in the middle and advanced stages is generally treated with chemotherapy and radiation. As a broad-spectrum antitumor drug, cisplatin mainly causes DNA damage in tumor cells, and is a common chemotherapeutic drug used to treat esophageal cancer. [3,4] drug resistance generated by esophageal cancer cells is a decisive factor that affects the chemotherapeutic effects. The exosomes secreted by tumor cells mediate information transfer between tumor cells (drug-resistant cells and sensitive cells), which can make sensitive cells obtain drug resistance. [6,13] Wei et al found that by treating the tamoxifen-sensitive breast cancer cell line MCF-7 with the exosome secreted by chemotherapy-resistant cell line MCF-7TamR, it can acquire drug resistance, because the miR-221/222 in the exosome secreted by the drug-resistant cell line inhibited the expression of the estrogen receptor α target gene (ERα). By combining high-throughput sequencing technology with later cytobiological verification, we found that this phenomenon may be related to the cell cycle
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
