近年来，细胞自噬性存活和死亡的命运决定是肿瘤研究领域的热点和难点之一。我们前期的实验结果表明核蛋白因子p8通过调控自噬溶酶体途径的基因转录，维持自噬依赖的细胞存活；当下调该基因表达时，肺癌细胞出现囊泡化，并导致衰亡；动物实验也显示下调p8显著抑制肺癌细胞体内成瘤；分子机制上表明p8调控SNAP-25的转录，SNAP-25可能介导自噬溶酶体的外排，并且非小细胞肺癌临床样品中p8和SNAP-25表达显著增强，提示作为调控自噬途径的关键转录因子p8，调控细胞自噬性存活和死亡途径。本课题期望在现有实验基础上深入研究非小细胞肺癌发生发展过程中p8协调细胞自噬性存活和死亡的调控机制，依据实验结果阐明p8介导的自噬调控途径，并在非小细胞肺癌样品中加以验证，同时探讨基于p8生物学效应而进行的抑制肺癌细胞体内存活的可行性。研究结果将有助于了解非小细胞肺癌中细胞自噬调控途径，丰富对肺癌发生发展分子机制的认识。

Under a variety of stressful conditions, autophagy, a highly regulated cellular self-degradation process, is an obligate requirement for cancer cell survival. A aberrantly balance between autophagic survival and cell death is believed to drive all stages of cancer progression. However, the mechanisms of autophagic survival and cell death regulation in cancer cells which distinctly modulate cells to allow autophagic survival remain largely elusive. Our preliminary data showed that p8 (also called nuclear protein 1), a transcriptional regulator mediates autophagic survival in non-small cell lung cancer cells (NSCLCs) and plays an important role in NSCLC progression. Experimental validation shows that p8 regulates the late stages of autolysosomal process via SNAP-25-mediated autolysosomal exocytosis for cellular clearance as well as autophagic flux pathways. Inactivation of p8 causes enhanced autophagic flux alongside a persistent reduction in autolysosomal exocytosis and consequently triggers intrinsic senescent cell death with autolysosomal vacuolization, resulting in tumor suppression. Mechanistically, p8 knockdown impairs autophagic flux and lysosomal exocytosis, and induces rather autolysosome-dependent senescence than apoptosis, resulting in tumor suppression in vitro and in vivo. These findings indicate a significant and novel function of p8 as a potent regulator of autolysosomal process in diverse cancer cell demise decision. Along with our preliminary data demonstrating that p8 significantly correlates with NSCLCs, we propose here that inactivation of p8 expression and enhanced autophagy pathway might be a promising strategy to inhibit lung cancer survival. To test this hypothesis, we will use clinical lung cancer samples, lung cancer cell lines as well as mouse model to investigate the crosstalk between autophagic survival and autophagic cell death mediated by p8 in vitro and in vivo. The on-going project of p8 functional investigation will be initially focused on the interacting protein partners with p8 by Nano-HPLC/mass spectrometric analysis and their validation by DuoLink and co-immunoprecipitation, respectively. These interaction may regulate the downstream pathways of p8 which regulate autophagy at the transcription level. Based on our experimental data, the regulatory pathways of autophagic survival and cell death will be elucidated and evaluated in clinical NSCLC samples as new candidates for autophagic survival. Hopefully, we may gain significant insight into the autophagic survival and autophagic cell death events associated with lung cancer progression and add to means of assessing suppression of p8 and impaired autophagy for prevention of NSCLC incidence. Also, a better understanding of the role of p8 underlying autophagic survival and autophagic cell death including the determination of the upstream regulators and downstream effectors of p8 functional pathways may lead to the development of novel anti-tumor strategies.