<b lang="uTL0N0xX"></b>
Skip to main page content (V体育官网)
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site VSports app下载. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2021 Dec 2:12:770857.
doi: 10.3389/fgene.2021.770857. eCollection 2021.

VSports - Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis

Jiajun He  1 , Hongjian Ding  1 , Huaqing Li  1 , Zhiyu Pan  1 , Qian Chen  1
Affiliations

Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis

Jiajun He et al. Front Genet. .

Abstract

While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis is regarded as a potent weapon in clearing cancer cells. The cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) is the core target for ferroptosis regulation, the overexpression of which dictates downregulated sensitivity to ferroptosis in cancer cells. Hence, we elaborated the pan-cancer level bioinformatic study and systematically elucidated the role of intra-tumoral expression of SLC7A11 in the survival of cancer patients and potential immunotherapeutic response. Specifically, 25/27 (92. 6%) cancers were featured with upregulated SLC7A11 expression, where SLC7A11 overexpression is a risk factor for worse overall survival in 8 cancers. We also validated SLC7A11 expression in multiple pancreatic cancer cell lines in vitro and found that it was upregulated in most pancreatic cancer cell lines (p < 0. 05). Single-cell sequencing method revealed the SLC7A11 was majorly expressed in cancer cells and mononuclear cells. To further explore the function of SLC7A11 in cancer progression, we analyzed the influence on cell proliferation after the knockdown or knockout of SLC7A11 by either CRISPR or RNAi methods. Besides, the association between SLC7A11 and drug resistance was characterized using bioinformatic approaches as well. We also analyzed the association between the expression of SLC7A11 in multi-omics level and the intra-tumoral infiltration of immune cells based on cell annotation algorithms. Moreover, the relationship between SLC7A11 and the expression of MHC, immune stimulators, immune inhibitors as well as the response to immunotherapy was investigated. In addition, the SLC7A11 expression in colon adenocarcinoma, uterine corpus endometrial carcinoma, and stomach adenocarcinoma (STAD) is also positively associated with microsatellite instability and that in head and neck squamous cell carcinoma, STAD, and prostate adenocarcinoma is positively associated with neoantigen level, which further revealed the potential relationship between SLC7A11 and immunotherapeutic response. VSports手机版.

Keywords: SLC7A11; drug resistance; ferroptosis; immune microenvironment; pan-cancer V体育安卓版. .

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The differential expression of SLC7A11 in distinct cancers. (A) The expression level of SLC7A11 in 33 normal organs. (B) The expression level of SLC7A11 in 21 cancer cell lines. (C) Investigation of the differential expression of SLC7A11 between cancers and normal tissues using TCGA data. (D) Investigation of the differential expression of SLC7A11 between cancers and normal tissues using the data from TCGA combined with GTEx. (E–J) Single-cell analysis and TIDE algorithms revealing the expression distribution and immunosuppressive characteristic of SLC7A11 in cell clusters. (K) Immunotherapy prolonged the survival expectancy only in patients with lower SLC7A11 expression. (L) SLC7A11 is associated with increased CTL cytotoxicity based on TIDE algorithm; CTL top referred to samples with higher CTL infiltration, while CTL bottom means lower CTL infiltration. The cut-off value to distinguish high and low CTL infiltration is just dependent on the Cox-PH model embedded in TIDE algorithm. (M) Comprehensive presentation of the influence on T-dysfunction and immunotherapeutic response associated with SLC7A11 by TIDE algorithm.
FIGURE 2
FIGURE 2
Correlation of the expression of SLC7A11 with the prognosis of distinct cancers. (A) The association between SLC7A11 level and overall survival of cancers. (B) The association between SLC7A11 level and disease-specific survival of cancers. (C) The association between SLC7A11 level and disease-free interval of cancers. (D) The association between SLC7A11 level and progression-free interval of cancers. (E–G) The survival curve revealed that SLC7A11 is significantly associated with the prognosis of several cancers.
FIGURE 3
FIGURE 3
Multi-omics data showed SLC7A11 expression was broadly associated with immune biomarkers but with tumor specificity. (A) MHC. (B) Chemokines. (C) Chemokine receptor. (D) GSEA to investigate which signal pathways were altered along with differential expression of SLC7A11 in cancers whose prognosis was associated with SLC7A11.
FIGURE 4
FIGURE 4
(A) SLC7A11 expression barely affects tumor cell proliferation in vitro. (B) SLC7A11 expression is associated with the sensitivity to multiple drugs. (C) Knockdown of SLC7A11. (D, E) CCK-8 and EDU analysis shows there are no obvious changes in cell proliferation after SLC7A11 knockdown in panc-1 cell.
FIGURE 5
FIGURE 5
(A) The correlation between SLC7A11 expression and immune and stromal score in distinct cancers. (B–D) Exploring the potential of SLC7A11 in anti-cancer immunity by evaluating its association with immune checkpoint, tumor mutation burden, and microsatellite instability across distinct cancers.
FIGURE 6
FIGURE 6
The expression of SLC7A11 is altered in different molecular and immune subtypes of cancers. (A, B) SLC7A11 expression in distinct molecular subtypes for cancers. (C, D) SLC7A11 expression in distinct immune subtypes for cancers.
See this image and copyright information in PMC

References (V体育官网入口)

    1. Badgley M. A., Kremer D. M., Maurer H. C., DelGiorno K. E., Lee H.-J., Purohit V., et al. (2020). Cysteine Depletion Induces Pancreatic Tumor Ferroptosis in Mice. Science 368, 85–89. 10.1126/science.aaw9872 - VSports app下载 - DOI - PMC - PubMed
    1. Bai Y. T., Chang R., Wang H., Xiao F. J., Ge R. L., Wang L. S., et al. (2018). ENPP2 Protects Cardiomyocytes from Erastin-Induced Ferroptosis. Biochem. Biophys. Res. Commun. 499, 44–51. 10.1016/j.bbrc.2018.03.113 - DOI - PubMed
    1. Boumahdi S., de Sauvage F. J. (2020). The Great Escape: Tumour Cell Plasticity in Resistance to Targeted Therapy. Nat. Rev. Drug Discovdrug Discovery 19, 39–56. 10.1038/s41573-019-0044-1 - "V体育安卓版" DOI - PubMed
    1. Burotto M., Wilkerson J., Stein W. D., Bates S. E., Fojo T. (2019). Adjuvant and Neoadjuvant Cancer Therapies: A Historical Review and a Rational Approach to Understand Outcomes. Semin. Oncol. 46, 83–99. 10.1053/j.seminoncol.2019.01.002 - "V体育安卓版" DOI - PubMed
    1. Dahlmanns M., Yakubov E., Chen D., Sehm T., Rauh M., Savaskan N., et al. (2017). Chemotherapeutic xCT Inhibitors Sorafenib and Erastin Unraveled with the Synaptic Optogenetic Function Analysis Tool. Cell Death Discov. 3, 17030. 10.1038/cddiscovery.2017.30 - DOI - PMC - PubMed