A lectin-based glycomic approach identifies FUT8 as a driver of radioresistance in oesophageal squamous cell carcinoma.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Dordrecht : Springer
    • Subject Terms:
      Esophageal Neoplasms/*metabolism ; Esophageal Squamous Cell Carcinoma/*metabolism ; Fucosyltransferases/*metabolism ; Radiation Tolerance/*physiology; Animals ; Basigin/metabolism ; Cells, Cultured ; Glycomics/methods ; Glycosylation ; Heterografts ; Humans ; Lectins ; Mice ; Mice, Nude
    • Abstract:
      Purpose: Radio-resistance is recognized as a main factor in the failure of radiotherapy in oesophageal squamous cell carcinoma (ESCC). Aberrant cell surface glycosylation has been reported to correlate with radio-resistance in different kinds of tumours. However, glycomic alterations and the corresponding enzymes associated with ESCC radio-resistance have not yet been defined.
      Methods: Two radioresistant cell lines, EC109R and TE-1R, were established from parental ESCC cell lines EC109 and TE-1 by fractionated irradiation. A lectin microarray was used to screen for altered glycan patterns. RNA-sequencing (RNA-seq) was employed to identify differentially expressed glycosyltransferases. Cell Counting Kit-8, colony formation and flow cytometry assays were used to measure cell viability and radiosensitivity. Expression of glycosyltransferase in ESCC tissues was assessed by immunohistochemistry. In vivo radiosensitivity was analysed using a nude mouse xenograft model. Downstream effectors of the enzyme were verified using a lectin-based pull-down assay combined with mass spectrometry.
      Results: We found that EC109R and TE-1R cells were more resistant to irradiation than the parental EC109 and TE-1 cells. Using lectin microarrays combined with RNA sequencing, we found that α1, 6-fucosyltransferase (FUT8) was overexpressed in the radioresistant ESCC cell lines. Both gain- and loss-of-function studies confirmed that FUT8 regulates the sensitivity of ESCC cells to irradiation. Importantly, we found that high FUT8 expression was positively linked to radio-resistance and a poor prognosis in ESCC patients who received radiation therapy. Moreover, FUT8 inhibition suppressed the growth and formation of xenograft tumours in nude mice after irradiation. Using a lectin-based pull-down assay and mass spectrometry, we found that CD147 could be glycosylated by FUT8. As expected, inhibition of CD147 partly reversed FUT8-induced radio-resistance in ESCC cells.
      Conclusions: Our results indicate that FUT8 functions as a driver of radio-resistance in ESCC by targeting CD147. Therefore, FUT8 may serve as a marker for predicting the response to radiation therapy in patients with ESCC.
    • Grant Information:
      81502666 National Natural Science Foundation of China; 81902494 National Natural Science Foundation of China
    • Contributed Indexing:
      Keywords: CD147; FUT8; Glycomic; Oesophageal squamous cell carcinoma; Radioresistance
    • Accession Number:
      0 (BSG protein, human)
      0 (Lectins)
      136894-56-9 (Basigin)
      EC 2.4.1.- (Fucosyltransferases)
      EC 2.4.1.68 (Glycoprotein 6-alpha-L-fucosyltransferase)
    • Publication Date:
      Date Created: 20200601 Date Completed: 20210602 Latest Revision: 20210602
    • Publication Date:
      20240829
    • Accession Number:
      10.1007/s13402-020-00517-5
    • Accession Number:
      32474852