Expression of potassium channel genes predicts clinical outcome in lung cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Ko EA
PROVIDER: S-EPMC6819903 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Expression of potassium channel genes predicts clinical outcome in lung cancer.
Ko Eun-A EA Kim Young-Won YW Lee Donghee D Choi Jeongyoon J Kim Seongtae S Seo Yelim Y Bang Hyoweon H Kim Jung-Ha JH Ko Jae-Hong JH
The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 20191024 6
Lung cancer is the most common cause of cancer deaths worldwide and several molecular signatures have been developed to predict survival in lung cancer. Increasing evidence suggests that proliferation and migration to promote tumor growth are associated with dysregulated ion channel expression. In this study, by analyzing high-throughput gene expression data, we identify the differentially expressed K<sup>+</sup> channel genes in lung cancer. In total, we prioritize ten dysregulated K<sup>+</sup ...[more]
Similar Datasets
Project description:BACKGROUND: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. METHODS: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman's rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. RESULTS: 22, 24, and 30 ion channel genes are found to be differentially expressed with a change in p53 mutation status, ER status, and tumor histological grade in the discovery cohort. We assign the 30 tumor grade associated ion channel genes as the IC30 gene signature. We find that IC30 risk score predicts clinical outcome (P < 0.05) in the discovery cohort and 6 out of 7 validation cohorts. Multivariate and univariate tests conducted in two validation cohorts indicate that IC30 is a robust prognostic biomarker, which is independent of standard clinical and pathological prognostic factors including patient age, lymph node status, tumor size, tumor grade, estrogen and progesterone receptor status, and p53 mutation status. CONCLUSIONS: We identified a molecular gene signature IC30, which represents a promising diagnostic and prognostic biomarker in breast cancer. Our results indicate that information regarding the expression of ion channels in tumor pathology could provide new targets for therapy in human cancers.
| S-EPMC3849355 | biostudies-literature
Project description:LRP1 (low-density lipoprotein receptor-related protein 1), a multifunctional endocytic receptor, has recently been identified as a hub within a biomarker network for multi-cancer clinical outcome prediction. As its role in colon cancer has not yet been characterized, we here investigate the relationship between LRP1 and outcome.Materials and methodsLRP1 mRNA expression was determined in colon adenocarcinoma and paired colon mucosa samples, as well as in stromal and tumor cells obtained after laser capture microdissection. Clinical potential was further investigated by immunohistochemistry in a population-based colon cancer series (n = 307). LRP1 methylation, mutation and miR-205 expression were evaluated and compared with LRP1 expression levels.ResultsLRP1 mRNA levels were significantly lower in colon adenocarcinoma cells compared with colon mucosa and stromal cells obtained after laser capture microdissection. Low LRP1 immunohistochemical expression in adenocarcinomas was associated with higher age, right-sided tumor, loss of CDX2 expression, Annexin A10 expression, CIMP-H, MSI-H and BRAFV600E mutation. Low LRP1 expression correlated with poor clinical outcome, especially in stage IV patients. While LRP1 expression was downregulated by LRP1 mutation, LRP1 promoter was never methylated.ConclusionsLoss of LRP1 expression is associated with worse colon cancer outcomes. Mechanistically, LRP1 mutation modulates LRP1 expression.
| S-EPMC5823651 | biostudies-literature
Project description:One of the major problems in management of prostate cancer is the lack of reliable genetic markers predicting the clinical course of the disease. We analyzed expression profiles of 12,625 transcripts in prostate tumors from patients with distinct clinical outcomes after therapy as well as metastatic human prostate cancer xenografts in nude mice. We identified small clusters of genes discriminating recurrent versus nonrecurrent disease with 90% and 75% accuracy in two independent cohorts of patients. We examined one group of samples (21 tumors) to discover the recurrence predictor genes and then validated the predictive power of these genes in a different set (79 tumors). Kaplan-Meier analysis demonstrated that recurrence predictor signatures are highly informative (P < 0.0001) in stratification of patients into subgroups with distinct relapse-free survival after therapy. A gene expression-based recurrence predictor algorithm was informative in predicting the outcome in patients with early-stage disease, with either high or low preoperative prostate-specific antigen levels and provided additional value to the outcome prediction based on Gleason sum or multiparameter nomogram. Overall, 88% of patients with recurrence of prostate cancer within 1 year after therapy were correctly classified into the poor-prognosis group. The identified algorithm provides additional predictive value over conventional markers of outcome and appears suitable for stratification of prostate cancer patients at the time of diagnosis into subgroups with distinct survival probability after therapy.
| S-EPMC362118 | biostudies-literature
Project description:Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients.
| S-EPMC8910917 | biostudies-literature
Project description:Despite improvements in early diagnosis and treatment, breast cancer is still a major health problem worldwide. Among breast cancer subtypes, the most challenging and harder to treat is represented by triple-negative molecular subtype. Due to its intrinsic features this subtype cannot be treated neither with hormonal therapy (since it does not express estrogen or progesterone receptors) nor with epidermal growth factor receptor 2 (HER2) inhibitors (as it does not express high levels of this protein). For these reasons, the standard of care for these patients is represented by a combination of surgery, radiation therapy and chemotherapy. In this scenario, searching for novel biomarkers that might help both in diagnosis and therapy is mandatory. In the last years, it was shown that different families of potassium channels are overexpressed in primary breast cancers. The altered ion channel expression may be useful for diagnostic and therapeutic purposes due to some peculiar characteristics of this class of molecules. Ion channels are defined as pore-forming transmembrane proteins regulating passive ion fluxes in the cells. Ion channels represent good potential markers since, being localized at the plasma membrane level, their detection and block with specific drugs and antibodies might be fast and tunable. This review focuses on triple-negative breast cancers and recapitulates the current knowledge about potassium channels' clinical relevance and their potential use in the clinical setting, for triple-negative breast cancer diagnosis and therapy.
| S-EPMC7251142 | biostudies-literature
Project description:Non-small-cell lung cancer (NSCLC) is characterized by abnormalities of numerous signaling proteins that play pivotal roles in cancer development and progression. Many of these proteins have been reported to be correlated with clinical outcomes of NSCLC. However, none of them could provide adequate accuracy of prognosis prediction in clinical application.A total of 384 resected NSCLC specimens from two hospitals in Beijing (BJ) and Chongqing (CQ) were collected. Using immunohistochemistry (IHC) staining on stored formalin-fixed paraffin-embedded (FFPE) surgical samples, we examined the expression levels of 75 critical proteins on BJ samples. Random forest algorithm (RFA) and support vector machines (SVM) computation were applied to identify protein signatures on 2/3 randomly assigned BJ samples. The identified signatures were tested on the remaining BJ samples, and were further validated with CQ independent cohort.A 6-protein signature for adenocarcinoma (ADC) and a 5-protein signature for squamous cell carcinoma (SCC) were identified from training sets and tested in testing sets. In independent validation with CQ cohort, patients can also be divided into high- and low-risk groups with significantly different median overall survivals by Kaplan-Meier analysis, both in ADC (31 months vs. 87 months, HR 2.81; P?<? 0.001) and SCC patients (27 months vs. not reached, HR 9.97; P?<? 0.001). Cox regression analysis showed that both signatures are independent prognostic indicators and outperformed TNM staging (ADC: adjusted HR 3.07 vs. 2.43, SCC: adjusted HR 7.84 vs. 2.24). Particularly, we found that only the ADC patients in high-risk group significantly benefited from adjuvant chemotherapy (P?=?0.018).Both ADC and SCC protein signatures could effectively stratify the prognosis of NSCLC patients, and may support patient selection for adjuvant chemotherapy.
| S-EPMC5840771 | biostudies-literature
Project description:Clinical significance of Notch1 activation in gastric cancer has been elucidated in our previous study, but the role of its ligands remains obscure. This study aims to evaluate the prognostic value of Jagged1 expression in patients with gastric cancer.We examined Jagged1 expression in tumor and nontumor tissues in retrospectively enrolled 302 patients with gastric cancer undergoing gastrectomy at Zhongshan Hospital of Fudan University in 2008 by immunohistochemical staining. The Kaplan-Meier method and Cox regression models were used to evaluate the prognostic value of Jagged1 expression and its association with clinicopathological features. We created a predictive nomogram by integrating Jagged1 expression with the TNM staging system for overall survival of gastric cancer patients.Jagged1 expression in gastric cancer was decreased compared with that in nontumor tissues. Low expression of Jagged1 in tumor and nontumor both predicted a dismal outcome. The Jagged1 risk derived from Jagged1 expression in tumor/nontumor tissue gave a further discrimination for the prognosis of gastric cancer patients. By Cox multivariate analysis, the Jagged1 risk was defined as an independent prognostic factor. The generated nomogram performed well in predicting the 3- and 5-year overall survival of gastric cancer patients.Jagged1 is a potential prognostic biomarker for overall survival, which could be integrated with TNM stage to give a better risk stratification for gastric cancer patients.
| S-EPMC4658849 | biostudies-other
Project description:LRP1 (low-density lipoprotein receptor-related protein 1) is a broadly expressed receptor that binds multiple extracellular ligands and participates in protein clearance. It is expressed in numerous cancers, but its role in lung cancer has not been characterized. Here, we investigate the relationship between LRP1 and lung cancer.LRP1 mRNA levels were determined in lung tumors from several large, multicenter studies. LRP1 protein localization was determined by immunohistochemical analysis of lung tumor microarrays. Normal fibroblasts, fibroblasts treated with the LRP1 inhibitor RAP (receptor-associated protein), and Lrp1 null fibroblasts were cocultured with 3 independent lung cancer cell lines to investigate the role of LRP1 on tumor cell proliferation.LRP1 mRNA levels are significantly decreased in lung tumors relative to nontumorous lung tissue. Lower expression of LRP1 in lung adenocarcinomas correlates with less favorable clinical outcome in a cohort of 439 patients. Immunohistochemical analysis shows that LRP1 is primarily expressed in stromal cells in 94/111 lung cancers, with very little protein found in cancer cells. A growth-suppressive function of mouse embryonic fibroblast (MEF) cells was observed in 3 lung cancer cell lines tested (H460, H2347, and HCC4006 cells); growth suppression was blocked by the LRP1 inhibitor RAP. Lrp1 deletion in fibroblasts reduced the ability of MEF cells to suppress tumor cell mitosis. In a validation set of adenocarcinomas, we confirmed a significant, positive correlation between both LRP1 mRNA and protein levels and favorable clinical outcomes.LRP1 expression is associated with improved lung cancer outcomes. Mechanistically, stromal LRP1 may non-cell autonomously suppress lung tumor cell proliferation.
| S-EPMC3079007 | biostudies-literature
Project description:Eosinophil peroxidase (EPO), a heme protein abundantly expressed in eosinophils, involves in the catalysis of cytotoxic oxidants associated with the pathogenesis of cancer, asthma, and allergic inflammatory disorders. To date, its roles in the pathogenesis of lung cancer are still not known. We determined the expression of EPO in the lung adenocarcinoma tissues and the normal adjacent lung tissues using Real-time PCR and Western blotting analysis, respectively. Also, EPO protein expression in 90 lung adenocarcinoma (AD) samples were confirmed with immunohistochemistry (IHC) using tissue microarrays. Meanwhile, we investigated the association between EPO and the clinicopathological characteristics and disease prognosis in the pulmonary adenocarcinoma patients, which demonstrated that EPO mRNA and protein were significantly higher in lung AD tissues that those of the adjacent normal lung tissues (P<0.05). EPO overexpression was significantly correlated with pathologic-tumour nodes metastasen stage (p-TNM stage, P=0.017) and lymph node metastasis (P=0.027). Patients with EPO overexpression showed shorter survival time than those with low EPO levels (P=0.017), according to the Kaplan-Meier survival curve. Furthermore, a multivariate Cox regression model was utilized to analyze the prognostic factors, which indicated that N stage (HR=0.965, 95% CI=0.328-1.359, P=0.008), p-TNM Stage (HR=3.127, 95% CI =2.463-5.015, P=0.021) and high EPO protein expression (HR=3.145, 95% CI=2.016-5.519, P=0.018) were independent factors for the prognosis of lung AD. In conclusion, increased EPO expression could be used as a biomarker for lung AD patients with poor prognosis.
| S-EPMC6400814 | biostudies-literature
Project description:A gene expression signature indicative of activated wound responses is common to more than 90% of non-neoplastic tissues adjacent to breast cancer, but these tissues also exhibit substantial heterogeneity. We hypothesized that gene expression subtypes of breast cancer microenvironment can be defined and that these microenvironment subtypes have clinical relevance.Gene expression was evaluated in 72 patient-derived breast tissue samples adjacent to invasive breast cancer or ductal carcinoma in situ. Unsupervised clustering identified two distinct gene expression subgroups that differed in expression of genes involved in activation of fibrosis, cellular movement, cell adhesion and cell-cell contact. We evaluated the prognostic relevance of extratumoral subtype (comparing the Active group, defined by high expression of fibrosis and cellular movement genes, to the Inactive group, defined by high expression of claudins and other cellular adhesion and cell-cell contact genes) using clinical data. To establish the biological characteristics of these subtypes, gene expression profiles were compared against published and novel tumor and tumor stroma-derived signatures (Twist-related protein 1 (TWIST1) overexpression, transforming growth factor beta (TGF-?)-induced fibroblast activation, breast fibrosis, claudin-low tumor subtype and estrogen response). Histological and immunohistochemical analyses of tissues representing each microenvironment subtype were performed to evaluate protein expression and compositional differences between microenvironment subtypes.Extratumoral Active versus Inactive subtypes were not significantly associated with overall survival among all patients (hazard ratio (HR) = 1.4, 95% CI 0.6 to 2.8, P = 0.337), but there was a strong association with overall survival among estrogen receptor (ER) positive patients (HR = 2.5, 95% CI 0.9 to 6.7, P = 0.062) and hormone-treated patients (HR = 2.6, 95% CI 1.0 to 7.0, P = 0.045). The Active subtype of breast microenvironment is correlated with TWIST-overexpression signatures and shares features of claudin-low breast cancers. The Active subtype was also associated with expression of TGF-? induced fibroblast activation signatures, but there was no significant association between Active/Inactive microenvironment and desmoid type fibrosis or estrogen response gene expression signatures. Consistent with the RNA expression profiles, Active cancer-adjacent tissues exhibited higher density of TWIST nuclear staining, predominantly in epithelium, and no evidence of increased fibrosis.These results document the presence of two distinct subtypes of microenvironment, with Active versus Inactive cancer-adjacent extratumoral microenvironment influencing the aggressiveness and outcome of ER-positive human breast cancers.
| S-EPMC3446385 | biostudies-literature