Journal
JOURNAL OF DENTAL RESEARCH
Volume 101, Issue 7, Pages 848-858Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/00220345211073072
Keywords
gasdermin E; pyroptosis; oral squamous cell carcinoma; immunity; chemoresistance; cancer stem cell
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Funding
- National Natural Science Foundation of China [82072996, 81874131]
- National Key Research and Development Program [2017YFSF090107]
- Hubei Province Natural Science Funds for Distinguished Young Scholar [2017CFA062]
- Innovative Research Team of High-Level Local Universities in Shanghai [ZLCX2018 0500]
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Gasdermin E (GSDME) is highly expressed in oral squamous cell carcinoma (OSCC) and is associated with better prognosis. Chemotherapy drugs can induce GSDME-mediated pyroptosis, and the loss of GSDME function attenuates the anti-tumor effect of cisplatin.
Gasdermin E (GSDME), as the major executive protein of pyroptosis, has been considered to be linked to antitumor immunity in recent years. However, the role of GSDME in oral squamous cell carcinoma (OSCC) remains to be elucidated. Here, by using a human OSCC tissue microarray, human OSCC tissue, and Tgfbr1/Pten conditional knockout mice, we found that GSDME was strongly expressed in OSCC and that GSDME expression in primary tumors was higher than that in metastatic lymph nodes. In addition, GSDME expression in OSCC was positively related to better prognosis. Moreover, GSDME-mediated pyroptosis occurred upon stimulation with chemotherapy drugs, and functional knockdown of GSDME attenuated the cisplatin-induced antitumor effect. Consistent with these results, bioinformatic analysis indicated that GSDME expression was positively correlated with the sensitivity of a number of antitumor drugs approved by the US Food and Drug Administration. Inhibition of GSDME expression by small interfering RNA in SCC7 cells significantly increased the expression of the cancer stem cell markers, CD44 and ALDH1. Furthermore, multiplexed immunohistochemistry and flow cytometry indicated that the expression of GSDME positively correlated with tumor-infiltrating CD8(+) T cells, granzyme B, and M1 phenotype macrophages. Collectively, these findings demonstrated that GSDME is a potential positive prognostic factor of OSCC, and GSDME-mediated pyroptosis induced by chemotherapy plays a role in antitumor response.
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