The transcriptional regulator nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3) is constitutively activated in several cancer types and plays important roles in cancer development and progression. Heavily phosphorylated NFATc3 resides in the cytoplasm of resting cells, and dephosphorylated NFATc3 translocates to the nucleus to activate expression of target genes in cells exposed to stimuli, for instance, hypoxia. Apart from phosphorylation, various post-translational modifications have been reported to regulate NFAT transcriptional activity. However, the mechanisms remain elusive. Here, we have demonstrated that NFATc3 is activated in human pancreatic ductal adenocarcinoma (PDAC) cells and that excessive activation of NFATc3 is correlated to advanced stages of PDAC and short survival time of PDAC patients. NFATc3 is deSUMOylated at K384 by SENP3 under hypoxia, which impairs the interaction between NFATc3 and phosphokinase GSK-3β, subsequently decreases NFATc3 phosphorylation and increases its nuclear occupancy. Knockdown of SENP3 greatly decreased hypoxia-induced NFATc3 nuclear occupancy. Our results highlight that SENP3-mediated deSUMOylation acts as an essential modulator of NFATc3, which is instrumental in PDAC tumor progression under hypoxia.

Background As the number of cancer survivors increases, the prevalence of the second type of primary cancer will increase. In clinical trials, patients with a history of malignant tumors in the past are usually excluded. It is unknown whether previous cancers affect survival outcomes. The purpose of this study was to investigate the impact of previous malignant tumors on the long-term prognosis of patients with gallbladder cancer. Methods By using the Surveillance, Epidemiology and END Results (SEER) database, we collect patient data and obtain patients who had gallbladder cancer diagnosed in 2004–2015 and had an adaption and contrast 1:1 with cases. We applied the Kaplan–Meier analysis and Cox regression models to assess the influence of prior malignancy on gallbladder cancer survival outcomes. Results Among 8338 patients who had mainly gallbladder cancer, 525 (6.3%) suffered prior cancer. Prostate cancer (22.29%), Breast cancer (21.14%), and Genitourinary (14.67%) are the most common types. Before propensity score matching (PSM), two groups of different Kaplan–Meier curves were obtained by classifying previous cancer history, and by comparison, the all-cause difference in the group with previous cancer history was not salience ( P = 0.31), but there is a protective effect on the Cancer-specific fatality rate ( p < 0.001). Similar results were obtained after propensity score matching (PSM). Among the multivariate Cox analysis, previous malignancy had no obvious relation, including all causes (HR = 0.98, 95% CI: 0.86–1.12, p = 0.70) but a better gallbladder cancer-specific survival (HR =0.64, 95% CI: 0.55–0.75, P < 0.001). Conclusion Prior cancer may not be an obvious factor impacting the survival of cancers of all-cause including the gallbladder. In clinical trials of gallbladder cancer, exclusion criteria based on cancer history should be assessed.

Purpose The association between post-resection radiotherapy for primary gynecological malignant neoplasms (GMNs) and the development of secondary primary malignancies (SPMs) remains a subject of debate. This study represents the first population-based analysis employing a multivariate competitive risk model to assess risk factors for this relationship and to develop a comprehensive competing-risk nomogram for quantitatively predicting SPM probabilities. Materials and methods In our study, data on patients with primary GMNs were retrospectively collected from the Epidemiology, Surveillance and End Results (SEER) database from 1973 to 2015. The incidence of secondary malignant tumors diagnosed at least six months after GMN diagnosis was compared to determine potential risk factors for SPMs in GMN patients using the Fine and Gray proportional sub-distribution hazard model. A competing-risk nomogram was constructed to quantify SPM probabilities. Results A total of 109,537 patients with GMNs were included in the study, with 76,675 and 32,862 GMN patients in the training and verification sets, respectively. The competing-risk model analysis identified age, primary tumor location, tumor grade, disease stage, chemotherapy, and radiation as risk factors for SPMs in GMN patients. Calibration curves and ROC curves in both training and verification cohorts demonstrated the predictive accuracy of the established nomogram, which exhibited a good ability to predict SPM occurrence. Conclusions This study presents the nomogram developed for quantitatively predicting SPM probabilities in GMN patients for the first time. The constructed nomogram can assist clinicians in designing personalized treatment strategies and facilitate clinical decision-making processes.