Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma.

Abstract

Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.

• Authors: Masaru Miyazaki, Mikiko Aoki, Yasuko Okado, Kaori Koga, Makoto Hamasaki, Takashi Nakagawa, Toshifumi Sakata, Kazuki Nabeshima
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 8 Pg. 3045-3056 (Aug 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32473077 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• BSG protein, human
• Biomarkers, Tumor
• GPI-Linked Proteins
• RNA, Small Interfering
• Basigin
• 5'-Nucleotidase
• NT5E protein, human
• MMP2 protein, human
• Matrix Metalloproteinase 2

Topics

• 5'-Nucleotidase (genetics, metabolism)
• Adult
• Aged
• Aged, 80 and over
• Basigin (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• Biopsy
• Cancer-Associated Fibroblasts (pathology)
• Carcinoma, Squamous Cell (genetics, mortality, pathology)
• Cell Line, Tumor
• Coculture Techniques
• Disease-Free Survival
• Ear Canal (pathology)
• Ear Neoplasms (genetics, mortality, pathology)
• Female
• Follow-Up Studies
• GPI-Linked Proteins (genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Kaplan-Meier Estimate
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Middle Aged
• Neoplasm Grading
• Neoplasm Invasiveness (pathology)
• Prognosis
• RNA, Small Interfering (metabolism)
• Retrospective Studies
• Tumor Microenvironment