2. Academic Validation
  3. Analysis of multiple programmed cell death-related prognostic genes and functional validations of necroptosis-associated genes in oesophageal squamous cell carcinoma

Analysis of multiple programmed cell death-related prognostic genes and functional validations of necroptosis-associated genes in oesophageal squamous cell carcinoma

  • EBioMedicine. 2023 Dec 14:99:104920. doi: 10.1016/j.ebiom.2023.104920.
Kui Cao 1,  Jinhong Zhu 2,  Mengdi Lu 1,  Jinfeng Zhang 1,  Yingnan Yang 1,  Xiaodong Ling 1,  Luquan Zhang 1,  Cuicui Qi 1,  Shenshui Wei 3,  Yanqiao Zhang 4,  Jianqun Ma 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China.
  • 2 Biobank, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China; Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China.
  • 3 Biobank, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China.
  • 4 Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China; Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China; Key Laboratories of Tumor Immunology in Heilongjiang, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China. Electronic address: yanqiaozhang@ems.hrbmu.edu.cn.
  • 5 Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, Heilongjiang, China. Electronic address: jianqunma@hrbmu.edu.cn.
PMID: 38101299 DOI: 10.1016/j.ebiom.2023.104920
Abstract

Background: Oesophageal squamous cell carcinoma (ESCC) is a lethal malignancy. Immune Checkpoint inhibitors (ICIs) showed great clinical benefits for patients with ESCC. We aimed to construct a model predicting prognosis and response to ICIs by integrating diverse programmed cell death (PCD) forms.

Methods: Genes related to 14 PCDs were collected to generate multi-gene signatures, including Apoptosis, Necroptosis, Pyroptosis, Ferroptosis, and Cuproptosis. Bulk and single-cell RNA transcriptome datasets were used to develop and validate the model. We assessed the functions of two necroptosis-related genes in ESCC cells by Western blot, co-immunoprecipitation (Co-IP), LDH release assay, CCK-8, and migration assay, followed by immunohistochemistry (IHC) staining on samples of patients with ESCC (n = 67).

Findings: We built and validated a 16-gene prognostic combined cell death index (CCDI) by combining immunogenic cell death (ICD) and Necroptosis signatures. The CCDI could also predict response to ICIs in Cancer, as shown by Tumour Immune Dysfunction and Exclusion (TIDE) analysis, confirmed in four independent ICI clinical trials. Trajectory analysis revealed that HOOK1 and CUL4A might affect ESCC cell fate. We found that HOOK1 induced Necroptosis and inhibited the proliferation and migration of ESCC cells, while CUL4A exhibited the opposite effects. Co-IP assay confirmed that HOOK1 and CUL4A promoted and reduced necrosome formation in ESCC cells. Data from patients with ESCC further supported that HOOK1 and CUL4A might be a tumour suppressor and oncogene, respectively.

Interpretation: We constructed a CCDI model with potential in predicting prognosis and response to ICIs in Cancer. HOOK1 and CUL4A in the CCDI model are crucial prognostic biomarkers in ESCC.

Funding: The Natural Science Foundation of China [82172786], The National Cancer Center Climbing Fund of China [NCC201908B06], The Natural Science Foundation of Heilongjiang Province [LH2021H077].

Keywords

ESCC; Immune checkpoint inhibitor; Programmed cell death; Single-cell RNA-Seq.

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