The Ferroxidase Hephaestin in Lung Cancer: Pathological Significance and Prognostic Value.
Ontology highlight
ABSTRACT:
SUBMITTER: Zacchi P
PROVIDER: S-EPMC8170403 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Surfactant protein D (SP-D) is a pattern recognition molecule belonging to the Collectin (collagen-containing C-type lectin) family that has pulmonary as well as extra-pulmonary existence. In the lungs, it is a well-established opsonin that can agglutinate a range of microbes, and enhance their clearance via phagocytosis and super-oxidative burst. It can interfere with allergen-IgE interaction and suppress basophil and mast cell activation. However, it is now becoming evident that SP-D is likely to be an innate immune surveillance molecule against tumor development. SP-D has been shown to induce apoptosis in sensitized eosinophils derived from allergic patients and a leukemic cell line via p53 pathway. Recently, SP-D has been shown to suppress lung cancer progression via interference with the epidermal growth factor signaling. In addition, a truncated form of recombinant human SP-D has been reported to induce apoptosis in pancreatic adenocarcinoma via Fas-mediated pathway in a p53-independent manner. To further establish a correlation between SP-D presence/levels and normal and cancer tissues, we performed a bioinformatics analysis, using Oncomine dataset and the survival analysis platforms Kaplan-Meier plotter, to assess if SP-D can serve as a potential prognostic marker for human lung cancer, in addition to human gastric, breast, and ovarian cancers. We also analyzed immunohistochemically the presence of SP-D in normal and tumor human tissues. We conclude that (1) in the lung, gastric, and breast cancers, there is a lower expression of SP-D than normal tissues; (2) in ovarian cancer, there is a higher expression of SP-D than normal tissue; and (3) in lung cancer, the presence of SP-D could be associated with a favorable prognosis. On the contrary, at non-pulmonary sites such as gastric, breast, and ovarian cancers, the presence of SP-D could be associated with unfavorable prognosis. Correlation between the levels of SP-D and overall survival requires further investigation. Our analysis involves a large number of dataset; therefore, any trend observed is reliable. Despite apparent complexity within the results, it is evident that cancer tissues that produce less levels of SP-D compared to their normal tissue counterparts are probably less susceptible to SP-D-mediated immune surveillance mechanisms via infiltrating immune cells.
| S-EPMC6088209 | biostudies-literature
Project description:Hephaestin is a vertebrate multicopper ferroxidase important for the transfer of dietary iron from intestinal cells to the blood. Hephaestin is mutated in the sex-linked anemia mouse, resulting in iron deficiency. However, sex-linked anemia mice still retain some hephaestin ferroxidase activity. They survive, breed, and their anemia improves with age. To gain a better understanding of the role of hephaestin in iron homeostasis, we used the Cre-lox system to generate knockout mouse models with whole body or intestine-specific (Villin promoter) ablation of hephaestin. Both types of mice were viable, indicating that hephaestin is not essential and that other mechanisms, multicopper ferroxidase-dependent or not, must compensate for hephaestin deficiency. The knockout strains, however, both developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition. Consistent with this, the knockout mice accumulated iron in duodenal enterocytes and had reduced intestinal iron absorption. In addition, the similarities of the phenotypes of the whole body and intestine-specific hephaestin knockout mice clarify the important role of hephaestin specifically in intestinal enterocytes in maintaining whole body iron homeostasis. These mouse models will serve as valuable tools to study the role of hephaestin and associated proteins in iron transport in the small intestine and other tissues.
| S-EPMC4045767 | biostudies-literature
Project description:G9a, a H3K9 methyltransferase, shows elevated expression in many types of human cancers, particularly breast cancer. However, the tumorigenic mechanism of G9a is still far from clear. Here we report that G9a exerts its oncogenic function in breast cancer by repressing hephaestin and destruction cellular iron homeostasis. In the case of pharmacological inhibition or short hairpin RNA interference-mediated suppression of G9a, the expression and activity of hephaestin increases, leading to the observed decrease of intracellular labile iron content and the disturbance of breast cancer cell growth in vitro and in vivo. We also provide evidence that G9a interacts with HDAC1 and YY1 to form a multi-molecular complex that contributes to hephaestin silencing. Furthermore, high G9a expression and low hephaestin expression correlate with poor survival of breast cancer are investigated. All these suggest a G9a-dependent epigenetic program in the control of iron homeostasis and tumor growth in breast cancer.G9a is a histone methyltransferase highly expressed in several cancers including breast cancer. Here the authors propose a mechanism through which G9a promotes breast cancer by regulating iron metabolism through the repression of ferroxidase hephaestin.
| S-EPMC5561105 | biostudies-literature
Project description:BackgroundEpithelial cadherin (E-cadherin), a calcium-dependent cell-cell adhesion molecule, as an important adhesion and signaling pathway mediator plays key roles in the maintenance of tissue integrity. However, the available results of E-cadherin expression and its prognostic value on non-small cell lung cancer (NSCLC) remain controversial. Therefore, a meta-analysis of published studies investigating the prognostic value of E-cadherin expression and its association with clinicopathological characteristics with NSCLC was performed.MethodsA literature search via PubMed, EMBASE, and MEDLINE (Ovid) databases was conducted. Data from eligible studies were extracted. Statistical analysis was performed using STATA 12.0.ResultsA total of 2412 patients from 15 studies were included in the meta-analysis. The results showed that the pooled hazard ratio (HR) for overall survival was 0.55 (95% confidence interval [CI]: 0.44-0.69) by univariate analysis and 0.68 (95% CI: 0.43-1.08) by multivariate analysis. In addition, the results showed a significant association between E-cadherin expression and the presence of lymph node metastasis (odds ratio = 0.37, 95% CI=0.05-0.69, P = 0.001).ConclusionOur study showed that positive expression of E-cadherin was associated with a favorable prognosis in patients with NSCLC, and might act as an inhibition factor of metastasis. However, adequately designed prospective studies are required to confirm this finding.
| S-EPMC4567004 | biostudies-literature
Project description:IntroductionThe cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).MethodsWe included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.ResultsIn ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).ConclusionsBreast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.
| S-EPMC3326560 | biostudies-literature
Project description:BackgroundThe eighth T classification excluded lepidic and ground-glass opacity (GGO) components. Current studies demonstrated lepidic and GGO components showed independent prognostic significances. This study elucidated the correlations and prognostic impacts of pathological and radiological T descriptors in invasive lung adenocarcinoma.MethodsA total of 1,490 patients with invasive lung adenocarcinoma were retrospectively reviewed. Correlation between pathological invasive size (PIS) and radiological solid size (RSS), and lepidic ratio and GGO ratio were comprehensively evaluated. Impacts of these pathological and radiological T descriptors on recurrence-free survival (RFS) were comparatively analyzed.ResultsClinical (c)T-stage was more frequently downstaged than upstaged comparing with the pathological (p)T-stage (28.4% vs. 18.2%). The correlation between PIS and RSS in solid nodule was stronger than that in part-solid nodule (solid: R2=0.750 vs. part-solid: R2=0.355). Some pathological invasive components except solid component were featured as GGO. Among T1 patients, lepidic absent GGO showed better RFS than lepidic present solid nodule (pT1: P=0.001; cT1: P=0.021). Multivariable analysis revealed GGO ratio was an independent prognostic factor for RFS in T1 invasive lung adenocarcinoma, whereas lepidic ratio was not.ConclusionsAmong T1 invasive lung adenocarcinoma, GGO ratio showed independent prognostic value for RFS, regardless of RSS. Meanwhile, lepidic ratio was not an independent RFS factor. GGO component rather than lepidic component should be considered as an additional T descriptor.
| S-EPMC10713262 | biostudies-literature
Project description:The feline sarcoma oncogene protein (FES) is a non-receptor tyrosine kinase implicated in both oncogenesis and tumor suppression. Here, cancer cell lines and human tissues were employed to clarify the pathological and prognostic significance of FES in bladder cancer.The relationship between FES expression and cancer aggressiveness was investigated using 3 cell lines (T24: corresponding to grade 3, 5637: corresponding to grade 2, and RT4: corresponding to grade 1) and 203 tissues derived from human bladder malignancies. Proliferation, invasion, and migration of cancer cells were assessed following the knockdown (KD) of FES expression by the siRNA method. Relationships between FES expression and pathological features, aggressiveness, and outcome were investigated.FES-KD inhibited the proliferation, migration, and invasion of T24 cells but not of RT4 cells and 5637 cells. Considering all patients, FES expression demonstrated a negative relationship with grade but no association with muscle invasion or cancer cell proliferation. However, it was positively correlated with pT stage and cell proliferation in high-grade tumors (p = 0.002); no such association was found for low-grade tumors. In addition, elevated FES expression was a negative prognostic indicator of metastasis after radical surgery for patients with high-grade tumors (p = 0.021) but not for those with low-grade malignancies.FES appeared to act as a suppressor of carcinogenesis, being associated with low tumor grade in the overall patient group. However, its expression correlated with cancer aggressiveness and poor outcome in high-grade bladder cancer. FES, therefore, represents a potential therapeutic target and useful prognostic factor for such patients.
| S-EPMC5756570 | biostudies-literature
Project description:Backgroud: Keratin 19 (KRT19) is the intermediate filament that constitutes the cytoskeleton and regulates cell-cycle and cell death. Objective: We aimed to assess whether KRT19 was involved in lung cancer development. Methods: The expression of KRT19 in lung cancer was evaluated from mRNA expression on open databse and protein abundance on tumor tissue array. Results: Using open microarray gene expression datasets and differential expression analysis, we found that KRT19 was upregulated in lung cancer compared with normal tissue. Further analysis suggested that KRT19 mRNA expression was correlated with tumor progression and overall survival in lung cancer patients. As KRT19 was overexpressed in adenocarcinoma (AC) and squamous cell carcinoma (SCC), we examined the prognostic value of KRT19 protein abundance by tissue microarray (TMA). The results suggested that protein expression of KRT19 was significantly associated with overall survival of SCC. Conclusions: Giving the prognostic role of KRT19 in lung cancer, KRT19 could be considered as an potential molecular marker in lung cancer, especially in SCC.
| S-EPMC7797641 | biostudies-literature
Project description:Functional nonsynonymous single-nucleotide polymorphisms (nsSNPs) of folate metabolism genes can influence the methylation of tumour suppressor genes, thereby potentially impacting on tumour behaviour. To investigate whether such polymorphisms influence lung cancer survival, we genotyped 14 nsSNPs mapping to methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR); DNA methyltransferase (DNMT2), methylenetetrahydrofolate dehydrogenase (MTHFD1) and methenyltetrahydrofolate synthetase (MTHFS) in 619 Caucasian women with incident disease, 465 with non-small cell (NSCLC) and 154 with small cell lung cancer (SCLC). The most significant association detected was with MTHFS Thr202Ala, with carriers of variant alleles having a worse prognosis (hazard ratio (HR)=1.49; 95% confidence interval: 1.14-1.94). Associations were also detected between overall survival (OS) in SCLC and homozygosity for MTHFR 222Val (HR=1.92; 1.03-3.58) and between OS from NSCLC and MTRR 175Leu carrier status (HR=1.36; 1.06-1.75). While there is evidence that variation in the folate metabolism genes may influence prognosis from lung cancer, current data are insufficiently robust to distinguish individual patient outcome.
| S-EPMC2360297 | biostudies-other
Project description:BackgroundAdditional histologic features of T3 colon cancer, such as tumour depth invasion beyond muscularis propria and elastic lamina invasion (ELI), have taken interest for a more accurate staging.MethodsPatients with pT3 and pT4a (control group) colon adenocarcinoma were retrospectively collected from our institutional database. The study group was divided according to depth of tumour invasion < 5 mm and ≥ 5 mm, and into ELI - and ELI + . Chi-square test was used to compare the clinicopathological characteristics. OS and DFS were estimated using Kaplan-Meier method and compared with the log-rank test. Univariable and multivariable Cox proportional hazard models were employed to assess the effect on OS and DFS.ResultsOut of 290 pT3 tumours, 168 (58%) had a depth of tumour invasion < 5 mm and 122 (42%) ≥ 5 mm. The 5-year OS and DFS were 85.2, 68.7 and 60.9%, and 81.4, 73.9 and 60.1% in pT3 < 5 mm, pT3 ≥ 5 mm, and pT4a respectively (p = 0.001, p = 0.072). Considering ELI - (n = 157, 54%) and ELI + (n = 133, 46%), the 5-year OS and DFS were 78.9, 76.7, and 60.9%, and 75.5, 81.5, and 60.1% in ELI - , ELI + and pT4a respectively (p = 0.955, p = 0.462). At multivariable analysis, the depth of invasion was found to be an independent predictive factor for OS (HR 2.04, 95%CI 1.28-3.24, p = 0.003) and DFS (HR 1.98, 95%CI 1.24-3.18, p = 0.004), while ELI did not result a prognostic factor for OS nor DFS.ConclusionIn pT3 colon cancer, depth of tumour invasion ≥ 5 mm is an independent risk factor for OS and DFS, whereas ELI did not result a prognostic factor affecting OS nor DFS.
| S-EPMC9393148 | biostudies-literature