Abstract
BackgroundSolute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11’s expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC.MethodsWe included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps.ResultsNRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features.ConclusionOur study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.
Highlights
Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear
We analyzed the correlation between the clinicopathological characteristics, including the expression of SLC7A11 and nuclear factor erythroid-2 (NRF2) and the efficacy of CRT, and the results demonstrated that higher expression levels of SLC7A11 and NRF2 were related to a poor therapy response in patients with ESCC who received CRT
In summary, the results of this study demonstrated that SLC7A11 plays an important role in the radiosensitivity of ESCC cells by interacting with NRF2, and that expression of SLC7A11 is related to the radiosensitivity and long-term prognosis of ESCC following RT
Summary
Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. Chemoradiotherapy (CRT) remains an important treatment strategy in esophageal squamous cell carcinoma (ESCC); high heterogeneity with unclear molecular classifications leads to various treatment outcomes. NRF2 is an important transcription factor that regulates cellular antioxidant response [13] and is associated with radioresistance as illustrated in numerous studies [14,15,16]. Whether NRF2-induced radioresistance relates to SLC7A11-mediated ferroptosis regarding ESCC has not been elucidated; the interaction between hyperactive NRF2 nuclear expression and SLC7A11 on the efficacy of CRT in ESCC patients remains unclear
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
