MAGE-A3 is a prognostic biomarker for poor clinical outcome in cutaneous squamous cell carcinoma with perineural invasion via modulation of cell proliferation.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Antigens, Neoplasm/*metabolism ; Biomarkers, Tumor/*metabolism ; Carcinoma, Squamous Cell/*metabolism ; Carcinoma, Squamous Cell/*pathology ; Neoplasm Proteins/*metabolism ; Peripheral Nerves/*pathology ; Skin Neoplasms/*metabolism ; Skin Neoplasms/*pathology; Animals ; Antibodies/pharmacology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Collagen/genetics ; Collagen/metabolism ; Cyclins/metabolism ; Humans ; Matrix Metalloproteinases/genetics ; Matrix Metalloproteinases/metabolism ; Mice ; Neoplasm Invasiveness ; Neoplasm Staging ; Prognosis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Treatment Outcome ; Up-Regulation/drug effects
    • Abstract:
      Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. Perineural invasion is associated with aggressive disease and a greater likelihood of poor outcomes. In this study, 3 of 9 patients with cutaneous squamous cell carcinoma and perineural invasion exhibited poor clinical outcomes. Tumors from these patients expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. In addition to perineural invasion, the tumors exhibited poor differentiation and deep invasion and were subsequently classified as Brigham and Women's Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59, 36.83±19.41 vs. 11.59±5.83, 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody exhibited a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p = 0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblots revealed overexpression of MAGE-A3 and cyclin E, A, and B protein in tumors at 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3) compared with parental cells. These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion compared with normal skin tissue (1132.56±882.7 vs. 107.62±183.62, 1118.15±1109.49 vs. 9.5±5, 2603.87±2385.26 vs. 5.29±3, 957.95±627.14 vs. 400.42±967.66, 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of cutaneous squamous cell carcinoma patients.
      Competing Interests: Jean-Philippe Therrien and James Lee were employees and shareholders of GlaxoSmithKline while these studies were being performed. This does not alter our adherence to Plos One policies on sharing data and materials.
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    • Grant Information:
      TL1 TR001447 United States TR NCATS NIH HHS; UL1 TR001445 United States TR NCATS NIH HHS; T32 AR064184 United States AR NIAMS NIH HHS
    • Accession Number:
      0 (Antibodies)
      0 (Antigens, Neoplasm)
      0 (Biomarkers, Tumor)
      0 (Cyclins)
      0 (MAGEA3 protein, human)
      0 (Neoplasm Proteins)
      0 (RNA, Messenger)
      9007-34-5 (Collagen)
      EC 3.4.24.- (Matrix Metalloproteinases)
    • Publication Date:
      Date Created: 20201123 Date Completed: 20201223 Latest Revision: 20221028
    • Publication Date:
      20240105
    • Accession Number:
      PMC7682861
    • Accession Number:
      10.1371/journal.pone.0241551
    • Accession Number:
      33227008