Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer

Abstract

Background: Accumulating evidence suggests that necroptosis, or programmed necrotic cell death, may play a significant role in cancer. We evaluated the expression of key molecules in necroptosis and their association with clinical features and prognosis in NSCLC. Methods: A total of 253 NSCLC patients (96 squamous cell carcinoma [SCC] cases and 157 adenocarcinoma [AC] cases) who underwent curative resection were included. Tumor tissues and corresponding normal tissues were investigated for relative mRNA expression levels of RIPK1, RIPK3, and MLKL. Difference in disease free survival (DFS) was analyzed according to the expression levels of these molecules in tumor tissues. Results: NSCLC tissues had significantly lower expression of RIPK1, RIPK3, and MLKL than normal tissues (P = 1 x 10-4 , P = 8 x 10-6 , and P = 4 x 10-8 , respectively). In subgroup analysis, SCCs had significantly lower RIPK1, RIPK3, and MLKL expression (P = 5 x 10-4 , P = 3 x 10-15 , P = 1 x 10-5 , respectively), and ACs had significantly lower RIPK1 and MLKL expression (P = 0.01 and P = 6 x 10-4 , respectively) than normal tissues. Low expression of RIPK1, RIPK3, and MLKL in tumors was associated with a worse DFS (HR = 1.71, P = 0.01; HR = 1.53, P = 0.04; and HR = 1.53, P = 0.04, respectively) in a multivariate analysis. In SCC, none of the RIPK1, RIPK3, and MLKL expression was significantly associated with DFS. However, in AC, low expression of RIPK1, RIPK3, and MLKL was significantly associated with worse DFS (HR = 1.67, P = 0.03; HR = 1.70, P = 0.03; and HR = 1.81, P = 0.02, respectively). Conclusions: Key regulatory genes in necroptosis, RIPK1, RIPK3, and MLKL, were downregulated in NSCLC, and their lower expression in NSCLC may be used to predict early recurrence after curative resection, especially in AC.

Identification and Verification of Necroptosis-Related Gene Signature and Associated Regulatory Axis in Breast Cancer

“…With the characteristics of both necrosis and apoptosis, necroptosis may trigger and amplify antitumor immunity in the immunotherapy of malignancy ( Gong et al, 2019 ). Moreover, some necroptosis regulators may serve as prognosis markers for cancer and other diseases ( Zhang et al, 2018 ; Park et al, 2020 ). Thus, necroptosis-related genes may also be of vital significance in the prognosis of BRCA.…”

Programmed Cell Death Tunes Tumor Immunity

“…Necroptosis has been found to have both pro- and anti-tumor roles in TME ( 94 ). On one hand, low expression of necroptosis regulators RIP(K)3 and MLKL correlated with poor prognosis in various types of solid tumors ( 95 – 97 ). Specifically, necroptotic cells have been shown to promote dendric cell maturation ( 98 ) and determined cross-priming efficiency thus anti-tumor immunity of CD8+ T cells through RIPK1 and NF-κB signaling ( 99 ).…”

Necroptosis in Pulmonary Diseases: A New Therapeutic Target

“…et al, 2018 ). In another situation, low RIPK3 showed worse disease-free survival (DFS) after curative resection in patients with NSCLC ( Park et al, 2020 ). Similarly, patients with NSCLC who have lower RIPK3 expression have worse chemotherapy responses ( Wang Q. et al, 2020 ).…”