Low-level expression of necroptosis factors indicates a poor prognosis of the squamous cell carcinoma subtype of non-small-cell lung cancer

Abstract

Background: The programmed cell death pathway necroptosis may synergize with the DNA damage response (DDR) in opposing tumor progression. While our basic mechanistic understanding of the necroptotic cell death advances rapidly, its prognostic implications have not been thoroughly examined in cancers.Methods: We included 394 patients with stage I non-small-cell lung cancer (NSCLC) who underwent surgical tumor resection between 1 January 1997 and 31 December 2011 and measured expression levels of nine proteins involved in necroptosis and the DDR in primary samples from 394 patients using tissue microarray. Protein expression evaluated by using an H-score method was dichotomized by the median value. The overall survival as the endpoint was calculated from the time of diagnosis to the time of the last follow-up or death.Results: We find that low-level expression of the necroptosis markers RIPK3 and PELI1 is associated with high risk of patient death. High-level expression of the key DDR factor p53 in combination with lowlevel expression of either RIPK3 or PELI1 increases the risk further. These gene expression effects appear to occur specifically in the squamous cell carcinoma (SCC) subtype of stage I NSCLC, while not observed in the non-SCC subtypes.Conclusions: Low-level expression of such necroptosis factors as RIPK3 and PELI1 in combination with high-level expression of the DDR factor p53 can serve as a critical indicator in predicting survival of stage I NSCLC patients with the SCC subtype.

Identification of necroptosis‐related gene signature and characterization of tumour microenvironment infiltration in non‐small‐cell lung cancer

“…On the other hand, necroptosis helps to strengthen the immune ability of anticancer drugs 11 . Decreased expression of necroptosis factors has been found in NSCLC tissues and was associated with worse prognosis in NSCLC patients 12,13 . The activation of necroptosis pathway has been shown to remarkably increased the killing ability of lung cancer cell mediated by chemotherapy drugs or radiation 14–16 .…”

“…11 Decreased expression of necroptosis factors has been found in NSCLC tissues and was associated with worse prognosis in NSCLC patients. 12,13 The activation of necroptosis pathway has been shown to remarkably increased the killing ability of lung cancer cell mediated by chemotherapy drugs or radiation. [14][15][16] Collectively, necroptosis may become a novel approach in cancer therapy.…”

Necroptosis is Related to Anti-PD-1 Treatment Response and Influences the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma

“…Several studies reported that some necroptosis-related molecules were biomarkers for prognostic ( Gong et al, 2019 ; Lim et al, 2021 ). In order to select the most likely candidate prognostic necroptosis-related genes, we performed the LASSO algorithm to identify a set of 26 necroptosis-related genes ( Figures 6A–B ).…”

Construction of a Necroptosis-Associated Long Non-Coding RNA Signature to Predict Prognosis and Immune Response in Hepatocellular Carcinoma

“…As an alternative mode of programmed cell death, necroptosis overcomes apoptosis resistance and may trigger and amplify anti-tumor immunity in cancer therapy ( Gong et al, 2019 ). Further, necroptosis is not only an important cellular process that regulates the evolution of cancer, but is also closely associated with the prognosis of many tumors ( Lim et al, 2021 ; Xin et al, 2022 ). In HCC, necroptosis driver genes correlate with tumor-infiltrating lymphocyte density, with CD8 + T cells clustering in tumors with higher expression of necroptosis-related genes ( Nicolè et al, 2022 ).…”