Abstract
RIPK3 is a key regulator of necroptosis, which plays a double-edged sword role in tumor progression. CHIP is an E3 ubiquitin ligase that regulates necroptosis by degrading RIPK3. Here, we investigated the prognostic value of RIPK3 and CHIP expression in 404 patients with non-small cell lung cancer (NSCLC). Expressions of CHIP and RIPK3 showed opposite correlations with survival. CHIP expression was associated with the longer overall survival (OS), whereas RIPK3 expression was associated with the shorter OS. RIPK3 positivity showed marginal association with shorter OS and disease-free survival (DFS) in adjuvant radiotherapy recipients but not in non-recipients, suggesting that necroptosis may induce radioresistance. In multivariate analysis, CHIP expression was associated with longer OS. Compared with other patients, CHIP(−)/RIPK3(+) patients had shorter OS and DFS. In summary, in patients with NSCLC, the expression of CHIP was an independent favorable prognostic factor while that of RIPK3 was an adverse prognostic factor.
Highlights
Necroptosis, a caspase-independent programmed cell death modality [1], has recently gained considerable attention as an alternative form of cell death that may overcome the resistance of tumor cells toward apoptosis [2], thereby augmenting antitumor immune responses in cancer patients [3].Morphologically, necroptosis bears similarities to necrosis such as rupture of the plasma membrane as well as swelling of cells and organelles [4]
As necroptosis has been reported to display both pro- and anti-tumoral effects during cancer progression and/or metastasis [3,20,21,22], we investigated the prognostic impact of necroptosis in non-small cell lung cancer (NSCLC), which is one of the most common and lethal cancers with a
In lung cancer, carboxyl terminus of Hsp70-interacting protein (CHIP) has been implicated in the proteasomal degradation of oncogenic tyrosine kinase Met receptor, which was demonstrated in an NSCLC xenograft model [24]
Summary
Necroptosis, a caspase-independent programmed cell death modality [1], has recently gained considerable attention as an alternative form of cell death that may overcome the resistance of tumor cells toward apoptosis [2], thereby augmenting antitumor immune responses in cancer patients [3].Morphologically, necroptosis bears similarities to necrosis such as rupture of the plasma membrane as well as swelling of cells and organelles [4]. Necroptosis bears similarities to apoptosis by sharing a portion of signaling pathways [5]. In sharp contrast to apoptosis, necroptosis does not result in the activation of caspases—instead, the amyloid-like signaling complex “necrosome,”. Which involves the phosphorylated forms of receptor-interacting serine/threonine kinase 1 (RIPK1). Receptor-interacting serine/threonine kinase 3 (RIPK3), is assembled [6]. Upon activation of the necrosome, the downstream effectors of RIPK3 induce the loss of cell and organelle integrity, thereby. Cancers 2020, 12, 1496 resulting in the release of endogenous immunomodulatory molecules known as damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein and mitochondrial DNA to trigger robust inflammatory responses [7,8,9]. GSK2982772 developed by GlaxoSmithKline has been advanced into phase 2 clinical trials for psoriasis, ulcerative colitis, and rheumatoid arthritis [9,10,11,12], and DNL747 developed by Sanofi and Denali Therapeutics is in phase 1 clinical trials for Alzheimer’s disease, amyotrophic lateral sclerosis and multiple sclerosis [12]
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