Tumor-derived extracellular vesicles confer 5-fluorouracil resistance in esophageal cancer via long noncoding RNA AC116025.2 delivery

  • Mol Carcinog. 2022 Oct 14. doi: 10.1002/mc.23469.
Shuyao Zhang  1 ,  Shaojie Liu  2 ,  Jingqing Ren  2 ,  Hanshuo Zhang  2 ,  Song Chen  3 ,  Yun Chen  1 ,  Shengqi Zhang  4  5 ,  Wang Chen  1 ,  Chengcheng Xu  1 ,  Shilong Zhong  6 ,  Sulin Liu  7 ,  Chaoxian Lin  8
Affiliations
  • 1. Department of Pharmacy, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China.
  • 2. Department of Gastrointestinal Surgery, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China.
  • 3. Department of Medical Imaging, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Jinan University, Guangzhou, China.
  • 4. Dafeng Hospital of Chaoyang District in Shantou City, Shantou, China.
  • 5. Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China.
  • 6. Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 7. The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
  • 8. Shantou Chaonan Minsheng Hospital, Shantou, China.
PMID: 36239547 DOI: 10.1002/mc.23469
Abstract

5-Fluorouracil (5-FU) resistance is one of the main causes for treatment failure in esophageal Cancer (EC). Here, we intended to elucidate the mechanism of tumor-derived extracellular vesicles (TEVs)-encapsulated long noncoding RNAs (lncRNAs) AC116025.2 in 5-FU resistance in EC. EVs were isolated from the serum samples of EC patients and HEEC, TE-1, and TE-1/5-FU cells, followed by RT-qPCR detection of AC116025.2 expression in EVs. The relationship among AC116025.2, MicroRNA (miR)-4496, and SEMA5A was evaluated. Next, EC cells were cocultured with EVs, followed by lentivirus transduction and plasmid transfection for studying the role of TEVs-AC116025.2 in EC cells in relation to miR-4496 and SEMA5A. Tumor formation in nude mice was applied for in vivo confirmation. Elevated AC116025.2 expression was seen in the EVs from the serum of 5-FU insensitive patients and from 5-FU-resistant EC cells. Mechanistically, AC116025.2 bound to miR-4496 that inversely targeted SEMA5A in EC cells. EVs-oe-AC116025.2 augmented EC cell viability, colony formation, and 5-FU resistance, but diminished their Apoptosis through miR-4496-mediated SEMA5A. Furthermore, EVs-oe-AC116025.2 augmented tumor formation and 5-FU resistance of EC cells in vivo. Conclusively, our data offered evidence of the promoting mechanism of TEVs in the 5-FU resistance of EC by delivering AC116025.2.

Keywords
5-fluorouracil resistance; SEMA5A; esophageal cancer; long noncoding RNA AC116025.2; microRNA-4496; tumor cell-derived extracellular vesicles.
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