Lim Jun Hyeok, Oh Sekyung, Kim Lucia, Suh Young Ju, Ha Yu-Jin, Kim Jung Soo, Kim Hyun-Jung, Park Mi Hwa, Kim Young Sam, Cho Yunjung, Kwak Seung Min, Lee Hong Lyeol, Kim You-Sun, Ryu Jeong-Seon
Department of Internal Medicine, Inha University Hospital, Incheon, South Korea.
Department of Medical Sciences, Catholic Kwandong University College of Medicine, Incheon, South Korea.
Transl Lung Cancer Res. 2021 Mar;10(3):1221-1230. doi: 10.21037/tlcr-20-1027.
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.
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.
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 low-level 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.
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.
程序性细胞死亡途径坏死性凋亡可能与DNA损伤反应（DDR）协同作用以对抗肿瘤进展。虽然我们对坏死性凋亡细胞死亡的基本机制理解迅速发展，但其在癌症中的预后意义尚未得到充分研究。
我们纳入了1997年1月1日至2011年12月31日期间接受手术肿瘤切除的394例I期非小细胞肺癌（NSCLC）患者，并使用组织微阵列测量了394例患者原发样本中参与坏死性凋亡和DDR的9种蛋白质的表达水平。使用H评分法评估的蛋白质表达以中位数进行二分法划分。以总生存期为终点，从诊断时间计算至最后一次随访或死亡时间。
我们发现坏死性凋亡标志物RIPK3和PELI1的低水平表达与患者死亡的高风险相关。关键DDR因子p53的高水平表达与RIPK3或PELI1的低水平表达相结合会进一步增加风险。这些基因表达效应似乎特别发生在I期NSCLC的鳞状细胞癌（SCC）亚型中，而在非SCC亚型中未观察到。
RIPK3和PELI1等坏死性凋亡因子的低水平表达与DDR因子p53的高水平表达相结合可作为预测I期NSCLC患者SCC亚型生存期的关键指标。
