X or Y Cancer: An Extensive Analysis of Sex Differences in Lung Adenocarcinoma.

Background: Cellular metabolism is a tightly controlled process during which cell growth and survival are maintained. Lung cancer is a disease with clear sex differences, where female patients have better survival rates than males. Evidence of sex differences is demonstrated in cancer risk, prognosis and response to different therapies, yet a sex-specific approach to cancer studies is not widely considered. These different tumour characteristics attributed to sex that impact disease outcome, including constitutional genetic and somatic molecular differences, make it essential to assess viral and hormonal influences. Methods: In silico analysis of lung adenocarcinoma (LUAD) TCGA data, including K-means clustering algorithm, dimensional reduction with principal component analysis and differential expression analysis using EdgeR (p < 0.05), were used to explore some robust sex differences in LUAD that exist in core signalling pathways and metabolic processes between males and females. The correlation of differentially expressed genes (DEGs) expression with immune abundance in the LUAD cohort was analysed on TIMER2.0 and adjusted by tumour purity utilising Cox proportional hazard. Multiple factorial analysis heatmap visualisation was used to examine endogenous steroid hormonal effects on LUAD patients with different smoking status and age groups. Results: We found 161 DEGs showing key differences in regulation of immune system and cellular homeostasis, key elements of divergent cancer progression, between the two sexes. We also found male and female LUAD patients to favour different metabolic intermediates for energy production to support tumourigenesis. Additionally, high levels of Tregs accompanied by DEGs correlated with better LUAD prognosis, and circulating hormonal transcriptional targets affect proliferation and progression in males and females differently. Finally, we examined the role of oestrogen protection in men and pre-/postmenopausal women. Conclusions: Further studies should focus on sex-specific changes and investigate sex-specific gene regulatory networks of these DEGs. Several lifestyle factors, including tobacco smoking and diet, differ between males and females. These factors might affect metabolic pathways and can influence the activity of epigenetic regulators, resulting in significant global epigenetic changes.

TGFα-EGFR pathway in breast carcinogenesis, association with WWOX expression and estrogen activation.

WWOX is a tumor-suppressive steroid dehydrogenase, which relationship with hormone receptors was shown both in animal models and breast cancer patients. Herein, through nAnT-iCAGE high-throughput gene expression profiling, we studied the interplay of estrogen receptors and the WWOX in breast cancer cell lines (MCF7, T47D, MDA-MB-231, BT20) under estrogen stimulation and either introduction of the WWOX gene by retroviral transfection (MDA-MB-231, T47D) or silenced with shRNA (MCF7, BT20). Additionally, we evaluated the consequent biological characteristics by proliferation, apoptosis, invasion, and adhesion assays. TGFα-EGFR signaling was found to be significantly affected in all examined breast cancer cell lines in response to estrogen and strongly associated with the level of WWOX expression, especially in ER-positive MCF7 cells. Under the influence of 17ß-estradiol presence, biological characteristics of the cell lines were also delineated. The study revealed modulation of adhesion, invasion, and apoptosis. The obtained results point at a complex role of the WWOX gene in the carcinogenesis of the breast tissue, which seems to be closely related to the presence of estrogen α and/or ß receptors.

Age- and Stage-Dependent Prostate Cancer Aggressiveness Associated with Differential Notch Signaling.

Prostate cancer (PC) remains a worldwide challenge, as does the question of how to distinguish its indolent from its aggressive form to reconcile proper management of the disease with age-related life expectations. This study aimed to differentiate the Notch-driven course of PC regarding patients' ages and stage of their disease. We analyzed 397 PC samples split into age subgroups of ≦55, 60−70, and >70 years old, as well as early vs. late stage. The clinical association of Notch signaling was evaluated by DFS and UpSet analyses. The clustering of downstream effectors was performed with ExpressCluster. Finally, for the most relevant findings, functional networks were constructed with MCODE and stringApp. The results have been validated with an independent cohort. We identified specific patterns of Notch expression associated with unfavorable outcomes, which were reflected by entering into a hybrid epithelial/mesenchymal state and thus reaching tumor plasticity with its all consequences. We characterized the molecular determinants of the age-related clinical behavior of prostate tumors that stem from different invasive properties depending on the route of the EMT program. Of the utmost relevance is the discovery of age- and stage-specific combinations of the Notch molecules predicting unfavorable outcomes and constituting a new prognostic and therapeutic approach for PCs.

Notch Signaling Pathway in Cancer-Review with Bioinformatic Analysis.

Notch signaling is an evolutionarily conserved pathway regulating normal embryonic development and homeostasis in a wide variety of tissues. It is also critically involved in carcinogenesis, as well as cancer progression. Activation of the Notch pathway members can be either oncogenic or suppressive, depending on tissue context. The present study is a comprehensive overview, extended with a bioinformatics analysis of TCGA cohorts, including breast, bladder, cervical, colon, kidney, lung, ovary, prostate and rectum carcinomas. We performed global expression profiling of the Notch pathway core components and downstream targets. For this purpose, we implemented the Uniform Manifold Approximation and Projection algorithm to reduce the dimensions. Furthermore, we determined the optimal cutpoint using Evaluate Cutpoint software to established disease-free and overall survival with respect to particular Notch members. Our results demonstrated separation between tumors and their corresponding normal tissue, as well as between tumors in general. The differentiation of the Notch pathway, at its various stages, in terms of expression and survival resulted in distinct profiles of biological processes such as proliferation, adhesion, apoptosis and epithelial to mesenchymal transition. In conclusion, whether oncogenic or suppressive, Notch signaling is proven to be associated with various types of malignancies, and thus may be of interest as a potential therapeutic target.

Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of Notch, Hedgehog, Wnt, and ErbB signalling.

Lung malignancies comprise lethal and aggressive tumours that remain the leading cancer-related death cause worldwide. Regarding histological classification, lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) account for the majority of cases. Surgical resection and various combinations of chemo- and radiation therapies are the golden standards in the treatment of lung cancers, although the five-year survival rate remains very poor. Notch, Hedgehog, Wnt and Erbb signalling are evolutionarily conserved pathways regulating pivotal cellular processes such as differentiation, proliferation, and angiogenesis during embryogenesis and post-natal life. However, to date, there is no study comprehensively revealing signalling networks of these four pathways in LUSC and LUAD. Therefore, the aim of the present study was the investigation profiles of downstream target genes of pathways that differ between LUSC and LUAD biology. Our results showed a few co-expression modules, identified through weighted gene co-expression network analysis (WGCNA), which significantly differentiated downstream signaling of Notch, ErbB, Hedgehog, and Wnt in LUSC and LUAD. Among co-expressed genes essential regulators of the cell cycle, DNA damage response, apoptosis, and proliferation have been found. Most of them were upregulated in LUSC compared to LUAD. In conclusion, identified downstream networks revealed distinct biological mechanisms underlying cancer development and progression in LUSC and LUAD that may diversify the clinical outcome of the disease.

Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis.

The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.