scholarly journals NR5A2 Is One of 12 Transcription Factors Predicting Prognosis in HNSCC and Regulates Cancer Cell Proliferation in a p53-Dependent Manner

2021 ◽  
Vol 11 ◽  
Author(s):  
Kun Zhang ◽  
Ming Xiao ◽  
Xin Jin ◽  
Hongyan Jiang

Head and neck squamous cell carcinoma (HNSCC) rank seventh among the most common type of malignant tumor worldwide. Various evidences suggest that transcriptional factors (TFs) play a critical role in modulating cancer progression. However, the prognostic value of TFs in HNSCC remains unclear. Here, we identified a risk model based on a 12-TF signature to predict recurrence-free survival (RFS) in patients with HNSCC. We further analyzed the ability of the 12-TF to predict the disease-free survival time and overall survival time in HNSCC, and found that only NR5A2 down-regulation was strongly associated with shortened overall survival and disease-free survival time in HNSCC. Moreover, we systemically studied the role of NR5A2 in HNSCC and found that NR5A2 regulated HNSCC cell growth in a TP53 status-dependent manner. In p53 proficient cells, NR5A2 knockdown increased the expression of TP53 and activated the p53 pathway to enhance cancer cells proliferation. In contrast, NR5A2 silencing suppressed the growth of HNSCC cells with p53 loss/deletion by inhibiting the glycolysis process. Therefore, our results suggested that NR5A2 may serve as a promising therapeutic target in HNSCC harboring loss-of-function TP53 mutations.

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Cory D. Bovenzi ◽  
James Hamilton ◽  
Patrick Tassone ◽  
Jennifer Johnson ◽  
David M. Cognetti ◽  
...  

Background. Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147.Methods. We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses.Results. Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p<0.001for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p<0.0001for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival.Conclusion. MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.


2010 ◽  
Vol 20 (5) ◽  
pp. 745-750 ◽  
Author(s):  
Fan-ling Meng ◽  
Ming-zhu Yin ◽  
Hong-tao Song ◽  
Hua Yang ◽  
Ge Lou ◽  
...  

Background:Lysosomal protein transmembrane 4 β-35 (LAPTM4B-35), a novel oncoprotein that belongs to the mammalian 4-tetratransmembrane spanning protein superfamily, has been implicated in oncogenesis and cancer progression in several solid malignances. However, the expression of LAPTM4B-35 and its role in endometrial cancer progression remain unknown.Materials and Methods:We investigated the expression of the LAPTM4B-35 protein by immunohistochemistry in 30 normal endometrium specimens and 165 endometrial carcinomas and analyzed its correlation with various clinicopathologic features, including patient outcome.Results:LAPTM4B-35 immunoreactivity was overexpressed in endometrial carcinoma cases compared with normal endometrium (P < 0.001). High LAPTM4B-35 expression was found in 117 (70.91%) of these 165 carcinomas and was positively correlated with the International Federation of Gynecology and Obstetrics stage, histological grade, depth of myometrial invasion, lymph node metastasis, lymph vascular space involvement, and recurrence, but not with age and histological type. Patients with high LAPTM4B-35 expression had significantly poorer overall survival and disease-free survival compared with patients with low expression of LAPTM4B-35 (P = 0.001 and P = 0.002, respectively). Multivariate analysis showed that high LAPTM4B-35 expression was an independent prognostic factor for both overall survival and disease-free survival of patients with endometrial carcinoma (both P = 0.005).Conclusions:These results showed that high LAPTM4B-35 expression was associated with progression and prognosis of endometrial carcinoma.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2689-2689
Author(s):  
Juan L Coelho-Silva ◽  
Diego A Pereira-Martins ◽  
Virginia Campos Silvestrini ◽  
Eduardo M Rego ◽  
Vitor Marcel Faca ◽  
...  

Background : Mutations of the FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) occur in approximately in 30% of AML patients, and is considered a driver mutation that presents a high leukemic burden and confers a poor prognosis. Insulin-like growth factor 1 receptor/insulin receptor substrates (IGF1R/IRS) signaling has been implicated to the malignant phenotype in myeloid neoplasms. However, how extend is the participation of IGF1R/IRS signaling in FLT3-mutated transformation is still an open question. Aims: To determine the clinical impact of IGF1R-IRS1/2 signaling component in FLT3-mutated AML patients and to investigate the therapeutic opportunity of pharmacological inhibition of IGF1R-IRS1/2 in preclinical models of FLT3-mutated AML. Material and methods: Clinical and molecular data from AML patients were obtained from Gene Expression Omnibus (GEO-GSE 6891; n=406, median age 44 years) and TCGA AML study (n=173, median age 58 years). For survival analysis in FLT3-mutated patients, IGF1R, IGF2R, IRS1 and IRS2 mRNA expression levels from 150 and 49 patients from GSE6891 and TCGA patients were included, respectively. MOLM-13 and MV4;11 FLT3-mutated cell lines were submitted to FLT3 inhibitors (midostaurin and quizartinib) and/or Linsitinib (IGF1R/IR inhibitor: 0.5 to 40 µM) or NT157 (IGF1R-IRS1/2 inhibitor: 0.25 to 10 µM) until 72 hours and evaluated for cell viability (MTT), apoptosis (Annexin V/PI), proliferation (CFSE), and protein expression/activation (western blot and proteomics). Statistical analyses were performed using ANOVA or Mann-Whitney. For survival analysis, Kaplan-Meier curves were compared with the log-rank test, and multivariate analysis was performed by Proportional Hazard Cox regression. Results: IGF1R, INSR, IGF1, IGF2, IRS1, and IRS2 were all downregulated in FLT3-mutated in comparison with wild-type in both AML cohorts (all P<0.05). Higher IGF1R expression (overall survival [OS] median time [MT]: low 23.6 months [mos] vs. high 8.9 mos, P=0.003; disease-free survival [DFS]: 34.2 vs. 10.5, P=0.03), as well as reduced IRS2 (OS: 8.3 vs. 17.2, P=0.001; DFS: 8.8 vs. 28.2, P=0.05) expression were associated with shorter disease-free survival and overall survival in GSE 6891 cohort. In the TCGA cohort, higher IGF1R expression predicted shorter DFS (20.6 vs. 7.3, P=0.03) but did not predict OS. Both linsitinib and NT157 significantly reduced cell viability in MOLM13 (IC50 for Linsinitinb 24, 48 and 72 hours:12.6, 11.2 and 8.1 µM, and for NT157: 0.9, 0.8 and 0.7 µM) and MV4;11 cells (IC50 for Linsinitinb 24, 48 and 72 hours:14.9, 11.2 and 9.5 µM, and for NT157: 1.2, 1.4 and 1.0 µM). Linsitinib (>5µM) and NT157 (>0.5 µM) significantly induced apoptosis in a dose-dependent manner in both cell lines (all P<0.05), but showed no additive effect in cotreatment with midostaurin and quizartinib, suggesting that both classes of inhibitors acting in similar intracellular targets. As demonstrated by CFSE assay, linsitinib (>2.5 µM) and NT157 (>0.5 µM) significantly reduced cell proliferation in a dose-dependent-manner. Linsitinib and NT157 inhibited IGF1R and IRS1/2 activation, as well as its related signaling pathways as demonstrated by reduced activation/expression of FLT3 (Y591), AKT1/2/3 (S473), mTOR (S2448), STAT5 (Y694). Linsitinb acted as a cytostatic drug by inducing autophagy, as determined by mTORC1 inhibition and mTORC2 activation, as well as p62 degradation and LC3B-I conversion into LC3BII. NT157 was more cytotoxic activating AP-1 system, as evidenced by p-JNK/SAPK and P38 MAPK and more prominent cleavage of CASP3 and PARP1 and reducing BCL-xL expression. A better characterization of the molecular context of IGF1R-IRS1/2 pharmacological inhibition will be allowed by proteomic of total extract of MOLM13 and MV4;11 cells treated with linsitinb (10 µM) or NT157 (1 µM) that will be presented at the meeting. Midostaurin ≥2.5 nM and quizartinib ≥0.5 nM treatment abolished IGF1R activation and IRS1 and IRS2 expression, as well as induced autophagy as demonstrated by the degradation of p62 and accumulation of Beclin 1. Conclusion: In FLT3-mutated AML, expression of IGF1R-IRS1/2 signaling components are deregulated and high IGF1R expression predicted dismal prognosis. Pharmacological inhibition of IGF1R-IRS1/2 exerted antineoplastic activity in cellular models and arises as a promising therapeutic target for FLT3-mutated AML patients. Disclosures No relevant conflicts of interest to declare.


PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256139
Author(s):  
Hannah Able ◽  
Amber Wolf-Ringwall ◽  
Aaron Rendahl ◽  
Christopher P. Ober ◽  
Davis M. Seelig ◽  
...  

Quantitative analysis of computed tomography (CT) radiomic features is an indirect measure of tumor heterogeneity, which has been associated with prognosis in human lung carcinoma. Canine lung tumors share similar features to human lung tumors and serve as a model in which to investigate the utility of radiomic features in differentiating tumor type and prognostication. The purpose of this study was to correlate first-order radiomic features from canine pulmonary tumors to histopathologic characteristics and outcome. Disease-free survival, overall survival time and tumor-specific survival were calculated as days from the date of CT scan. Sixty-seven tumors from 65 dogs were evaluated. Fifty-six tumors were classified as primary pulmonary adenocarcinomas and 11 were non-adenocarcinomas. All dogs were treated with surgical resection; 14 dogs received adjuvant chemotherapy. Second opinion histopathology in 63 tumors confirmed the histologic diagnosis in all dogs and further characterized 53 adenocarcinomas. The median overall survival time was longer (p = 0.004) for adenocarcinomas (339d) compared to non-adenocarcinomas (55d). There was wide variation in first-order radiomic statistics across tumors. Mean Hounsfield units (HU) ratio (p = 0.042) and median mean HU ratio (p = 0.042) were higher in adenocarcinomas than in non-adenocarcinomas. For dogs with adenocarcinoma, completeness of excision was associated with overall survival (p<0.001) while higher mitotic index (p = 0.007) and histologic score (p = 0.037) were associated with shorter disease-free survival. CT-derived tumor variables prognostic for outcome included volume, maximum axial diameter, and four radiomic features: integral total, integral total mean ratio, total HU, and max mean HU ratio. Tumor volume was also significantly associated with tumor invasion (p = 0.044). Further study of radiomic features in canine lung tumors is warranted as a method to non-invasively interrogate CT images for potential predictive and prognostic utility.


2005 ◽  
Vol 23 (3) ◽  
pp. 502-509 ◽  
Author(s):  
Julien Taïeb ◽  
Pascal Artru ◽  
François Paye ◽  
Christophe Louvet ◽  
Nathalie Perez ◽  
...  

Purpose To evaluate the efficacy and tolerability of the metastatic irinotecan plus oxaliplatin (MIROX) strategy (adjuvant FOLFOX-7 followed by FOLFIRI), in patients with resectable metastatic colorectal cancer. Patients and Methods Forty-seven patients with resectable metastases of colorectal cancer were prospectively enrolled onto this study. Treatment consisted of six cycles of leucovorin 400 mg/m2, oxaliplatin 130 mg/m2 in a 120-minute infusion, and fluorouracil (FU) 2,400 mg/m2 in a 46-hour infusion, every 2 weeks (FOLFOX-7), followed by six cycles of leucovorin 400 mg/m2, irinotecan 180 mg/m2 in a 90-minute infusion, bolus FU 400 mg/m2, and FU 2,400 mg/m2 as a 46-hour infusion, every 2 weeks (FOLFIRI). Surgery was performed before chemotherapy in 25 patients and after six cycles of FOLFOX-7 in 22 patients (six cycles of FOLFIRI were administered after surgery). Results All but one of the patients underwent curative surgery. Two patients refused postoperative chemotherapy. Tolerability was generally good. The main toxicities were grade 3 to 4 neutropenia (13%) and thrombocytopenia (11%); no febrile neutropenia or bleeding occurred, and there were no deaths caused by toxicity. Two pathologically confirmed complete responses and 15 partial responses were obtained with FOLFOX-7 in the 22 patients who received this regimen before surgery (overall response rate, 77%; 95% CI, 68 to 86). The median disease-free survival time was 21 months; the median overall survival has not yet been reached. The 2-year overall and disease-free survival rates were 89% and 47%, respectively. Conclusion The MIROX strategy is feasible and well tolerated by patients with resectable metastatic colorectal cancer. Progression-free and overall survival rates are promising, with a median of 38 months of follow-up. This strategy currently is being compared with the leucovorin and FU regimen in a phase III trial.


2020 ◽  
Vol 66 (7) ◽  
pp. 948-953
Author(s):  
Xue-Ying Ren ◽  
Wei-Bin Yang ◽  
Yun Tian

SUMMARY OBJECTIVE Long noncoding RNAs (lncRNAs) have been shown to play a critical role in tumor progression. Abnormal expression of LncRNA PTPRG antisense RNA 1 (PTPRG-AS1) has been reported in several tumors. Hence, we aimed to determine the expression and clinical significance of PTPRG-AS1 in epithelial ovarian cancer (EOC) patients. METHODS The expressions of PTPRG-AS1 were assessed in 184 pairs of EOC tumor specimens and adjacent normal tissues. The levels of target lncRNAs and GAPDH were examined using standard SYBR-Green methods. The relationships between the expressions of PTPRG-AS1 and the clinicopathological features were analyzed using the chi-square test. Multivariate analysis using the Cox proportional hazards model was performed to assess the prognostic value of PTPRG-AS1 in EOC patients. RESULTS We confirmed that the expressions of PTPRG-AS1 were distinctly higher in the EOC tissue compared with the adjacent non-tumor specimens (p < 0.01). Higher levels of PTPRG-AS1 in EOC patients were associated with advanced FIGO stage (p = 0.005), grade (p = 0.006), and distant metastasis (p = 0.005). Survival analyses revealed that patients with high expressions of PTPRG-AS1 had a distinctly decreased overall survival (p = 0.0029) and disease-free survival (p = 0.0009) compared with those with low expressions of PTPRG-AS1. Multivariate assays indicated that PTPRG-AS1 expression was an independent prognostic factor for both overall survival and disease-free survival in EOC (Both p < 0.05). CONCLUSIONS Our study suggests that PTPRG-AS1 may serve as a novel prognostic biomarker for EOC patients.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4302-4302
Author(s):  
Nobuaki Nakano ◽  
Yosifusa Takatsuka ◽  
Shogo Takeuchi ◽  
Masahito Tokunaga ◽  
Mayumi Tokunaga ◽  
...  

Abstract Abstract 4302 Introductions Allogenic stem cell transplantaion (allo-SCT) for non-Hodgkin's lymphomas (NHLs) may be curative for chemorefractory patients, but few studies are available to guide transplant decision making in this setting. It would be very important to assess the eligibilities of allo-SCT for NHLs. To clarify the possibilities and eligibilities of allo-SCT for aggressive NHLs and come out the better prognostic factors, we analyzed 18 NHL patients who underwent allo-SCT in our institute retrospectively. Design and methods There were 55 NHL patients who had been undergone allo-SCT in our institute from August 2001 to March 2009. Thirty-seven patients out of 55 were adult T-cell leukemia/lymphoma (ATLL) patients, and we excluded these 37 ATLL patients in this study so that eliminate selection bias. We analyzed about rest of 18 patents. We analyzed 3 years overall survival (OS), disease free survival (DFS), related factors such as gender, age, diagnosis, disease status, IPI, HCT-CI score, transplantation methods, acute GVHD, chronic GVHD, and causes of death. Results Median age was 37.5 years old (19-63). Thirteen patients were male and 5 female. Diagnosis included FL (n=4), PTCL-u (n=3), MNKL (n=3), BL (n=2), DLBCL (n=2), ALCL (n=1), T-LBL (n=1), hepatosplenic lymphoma (n=1), and MF (n=1). Median overall survival time and disease free survival time after SCT were 215.5 days (6-2436) and 73 days (2-2436). Overall survival rate after SCT was 38.9%. IPI was Low in 2 patients, 8 L-I, 5 H-I, and 3 High. Low/L-I group showed significantly superior OS, DFS compare to H-I/High group (54% vs 0% p=0.0014, 56.3% vs 0% p=0.0112). HCT-CI scoring 0 in 12 patients, five 1, and only one patient scored over 2. HCT-CI score significantly related to OS after SCT in our cases (p=0.024). There were 13 sibling donors (included 5 HLA haplo-identical donors) and 5 unrelated donors (URD) (included 2 cord blood donors) in our cases. Ten patients received myeloablative conditioning and 8 reduced intensity conditioning (RIC). Disease status at SCT was CR in 5 patients, 7 PR, and 6 PD. Eleven patients died after SCT (3 a-GVHD, 2 disease progression, 2 sepsis, 1 TMA, 1 pneumonia, 1 invasive aspergillosis, and 1 liver failure). Five patients died within 100 days after SCT (three patients died within day 30). Six patients have been alive over 3 years (3 yrs OS, DFS: 33.3%, 27.8%). Seven patients were complicated grade 0-1 a-GVHD and 9 grade 2-4. Grade 0-1 group patients showed significantly superior DFS compare to grade 2-4 (p=0.0314). Five patients complained limited c-GVHD and 3 extensive. The patients group complained with c-GVHD showed better OS and DFS than asymptomatic group (53.6% vs 12.0% p=0.0062, 58.3% vs 12.5% p=0.0267). Four patients suffered relapse or progressive disease after SCT. Two out of these 4 patients showed GVL effect only with reducing immunosuppressive therapies. Discussion and conclusion Interestingly, about a-GVHD, grade 2-4 group obtained poor prognostic result compared to grade 0-1 group. On the other hand, the group which showed c-GVHD obtained better survival results. Our study was based on relatively small numbers of cases, but it might be showed that c-GVHD is important and GVL effect would be possibly existed. 3 years OS and DFS of allo-SCT for chemorefractory NHL in our institute were 33.3%, 27.8%, and NRM was 50%. Although it was not acceptable results, in some groups such as IPI Low/L-I, low scored HCT-CI groups, allo-SCT would be acceptable. Further studies including large patients numbers will be required. Disclosures: No relevant conflicts of interest to declare.


Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 285
Author(s):  
Malgorzata Gajdzis ◽  
Stamatios Theocharis ◽  
Jerzy Klijanienko ◽  
Nathalie Cassoux ◽  
Sophie Gardrat ◽  
...  

Background: Uveal melanoma is the most common primary intraocular malignancy in adults. In advanced cases, the prognosis is very poor. Thus far, no effective methods of pharmacotherapy of this cancer have been found. The aim of the study was to evaluate the expression of PARP-1, the best-known member of the family of poly(ADP-ribose) polymerases, in uveal melanoma and its associations with clinicopathological parameters, overall survival, and disease-free survival. Methods: The study included 91 patients who underwent enucleation due to uveal melanoma. PARP-1 expression was assessed by immunohistochemistry. Results: High PARP-1 expression was associated with more frequent chromosome 3 loss, higher histopathological grade, bigger tumor size, and absence of intrascleral extension. High PARP-1 expression was associated with shorter overall survival time and disease-free survival time. Conclusions: The above findings indicate that high expression of PARP-1 can be considered as an unfavorable prognostic factor in uveal melanoma.


Author(s):  
Zhen Yang ◽  
Hengjun Gao ◽  
Jun Lu ◽  
Zheyu Niu ◽  
Huaqiang Zhu ◽  
...  

Abstract Objective There are limited data from retrospective studies on whether therapeutic outcomes after regular pancreatectomy are superior to those after enucleation in patients with small, peripheral and well-differentiated non-functional pancreatic neuroendocrine tumors. This study aimed to compare the short- and long-term outcomes of regular pancreatectomy and enucleation in patients with non-functional pancreatic neuroendocrine tumors. Methods Between January 2007 and July 2020, 227 patients with non-functional pancreatic neuroendocrine tumors who underwent either enucleation (n = 89) or regular pancreatectomy (n = 138) were included. Perioperative complications, disease-free survival, and overall survival probabilities were compared. Propensity score matching was performed to balance the baseline differences between the two groups. Results The median follow-up period was 60.76 months in the enucleation group and 43.29 months in the regular pancreatectomy group. In total, 34 paired patients were identified after propensity score matching. The average operative duration in the enucleation group was significantly shorter than that in the regular pancreatectomy group (147.94 ± 42.39 min versus 217.94 ± 74.60 min, P &lt; 0.001), and the estimated blood loss was also significantly lesser (P &lt; 0.001). The matched patients who underwent enucleation displayed a similar overall incidence of postoperative complications (P = 0.765), and a comparable length of hospital stay (11.12 ± 3.90 days versus 9.94 ± 2.62 days, P = 0.084) compared with those who underwent regular pancreatectomy. There were no statistically significant differences between the two groups in disease-free survival and overall survival after propensity score matching. Conclusion Enucleation in patients with non-functional pancreatic neuroendocrine tumors was associated with shorter operative time, lesser intraoperative bleeding, similar overall morbidity of postoperative complications, and comparable 5-year disease-free survival and overall survival when compared with regular pancreatectomy.


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