Downregulation of SHCBP1 Promotes Ferroptosis in Oral Squamous Cell Carcinoma by Suppressing GDF15-Mediated SLC7A11

Background: Oral squamous cell carcinoma (OSCC) is a malignant tumor that poses a serious threat to patient's health and life. Despite extensive advances in the treatment of OSCC, the 5-year survival rate of OSCC remains dissatisfactory. SHC SH2 domain-binding protein 1 (SHCBP1) is involved in the development, metastasis and carcinogenesis of various types of cancers, but its specific role in OSCC is not well understood. This study aims to explore the role of SHCBP1 in OSCC. Methods: Gain-of-function and loss-of-function assays were conducted on the SCC-9 and CAL-27 cells to investigate the role of SHCBP1 in ferroptosis. This was achieved by overexpressing and downregulating the level of SHCBP1. Additionally, both cell lines were treated with erastin, ferrostatin-1, ZVAD-FMK and necrosulfonamide to further explore the role of SHCBP1 in ferroptosis. The direct role of growth differentiation factor 15 (GDF15) was also confirmed by overexpressing it in both cell lines. The expression of SHCBP1 was examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and Western blot. The effects of SHCBP1 on various cellular processes such as growth, invasion, mobility, epithelial-mesenchymal transition (EMT), and ferroptosis were investigated in SCC-9 and CAL-27 cells. This was done using cell counting kit-8 (CCK-8), colony formation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, Transwell (R) assays, and examination of the ferroptosis level. Additionally, a xenografted mouse model was constructed to conduct in vivo assays. Results: The expression of SHCBP1 was significantly increased in both OSCC tissues and cell lines (p < 0.01). Interfering with SHCBP1 suppressed the growth of OSCC (p < 0.05). Additionally, silencing SHCBP1 inhibited invasion, migration, and EMT, while enhancing ferroptosis in SCC-9 and CAL-27 cells, vice versa (p < 0.05). Besides, downregulation of SHCBP1 attenuated the expression of solute carrier family 7 member 11 (SLC7A11) and GDF15 (p < 0.05), which was reversed with the overexpression of GDF15 (p < 0.05). Moreover, the upregulation of GDF15 also reversed the effects of shSHCBP1 on proliferation, migration, invasion and ferroptosis in CAL-27 and SCC-9 cells (p < 0.05). Conclusions: Downregulation of SHCBP1 inhibits the progression and development of OSCC through GDF15 and enhances ferroptosis by repressing GDF15-mediated SLC7A11 in OSCC.

Automated summary

Downregulation of SHCBP1 inhibits the progression and development of OSCC by repressing GDF15-mediated SLC7A11, and enhances ferroptosis.