Host Transcriptional Regulatory Genes and Microbiome Networks Crosstalk through Immune Receptors Establishing Normal and Tumor Multiomics Metafirm of the Oral-Gut-Lung Axis.

The microbiome has shown a correlation with the diet and lifestyle of each population in health and disease, the ability to communicate at the cellular level with the host through innate and adaptative immune receptors, and therefore an important role in modulating inflammatory process related to the establishment and progression of cancer. The oral cavity is one of the most important interaction windows between the human body and the environment, allowing the entry of an important number of microorganisms and their passage across the gastrointestinal tract and lungs. In this review, the contribution of the microbiome network to the establishment of systemic diseases like cancer is analyzed through their synergistic interactions and bidirectional crosstalk in the oral-gut-lung axis as well as its communication with the host cells. Moreover, the impact of the characteristic microbiota of each population in the formation of the multiomics molecular metafirm of the oral-gut-lung axis is also analyzed through state-of-the-art sequencing techniques, which allow a global study of the molecular processes involved of the flow of the microbiota environmental signals through cancer-related cells and its relationship with the establishment of the transcription factor network responsible for the control of regulatory processes involved with tumorigenesis.

Lung Cancer Gene Regulatory Network of Transcription Factors Related to the Hallmarks of Cancer.

The transcriptomic analysis of microarray and RNA-Seq datasets followed our own bioinformatic pipeline to identify a transcriptional regulatory network of lung cancer. Twenty-six transcription factors are dysregulated and co-expressed in most of the lung cancer and pulmonary arterial hypertension datasets, which makes them the most frequently dysregulated transcription factors. Co-expression, gene regulatory, coregulatory, and transcriptional regulatory networks, along with fibration symmetries, were constructed to identify common connection patterns, alignments, main regulators, and target genes in order to analyze transcription factor complex formation, as well as its synchronized co-expression patterns in every type of lung cancer. The regulatory function of the most frequently dysregulated transcription factors over lung cancer deregulated genes was validated with ChEA3 enrichment analysis. A Kaplan-Meier plotter analysis linked the dysregulation of the top transcription factors with lung cancer patients' survival. Our results indicate that lung cancer has unique and common deregulated genes and transcription factors with pulmonary arterial hypertension, co-expressed and regulated in a coordinated and cooperative manner by the transcriptional regulatory network that might be associated with critical biological processes and signaling pathways related to the acquisition of the hallmarks of cancer, making them potentially relevant tumor biomarkers for lung cancer early diagnosis and targets for the development of personalized therapies against lung cancer.

Identification of the Transcriptional Regulatory Role of RUNX2 by Network Analysis in Lung Cancer Cells.

The use of a new bioinformatics pipeline allowed the identification of deregulated transcription factors (TFs) coexpressed in lung cancer that could become biomarkers of tumor establishment and progression. A gene regulatory network (GRN) of lung cancer was created with the normalized gene expression levels of differentially expressed genes (DEGs) from the microarray dataset GSE19804. Moreover, coregulatory and transcriptional regulatory network (TRN) analyses were performed for the main regulators identified in the GRN analysis. The gene targets and binding motifs of all potentially implicated regulators were identified in the TRN and with multiple alignments of the TFs' target gene sequences. Six transcription factors (E2F3, FHL2, ETS1, KAT6B, TWIST1, and RUNX2) were identified in the GRN as essential regulators of gene expression in non-small-cell lung cancer (NSCLC) and related to the lung tumoral process. Our findings indicate that RUNX2 could be an important regulator of the lung cancer GRN through the formation of coregulatory complexes with other TFs related to the establishment and progression of lung cancer. Therefore, RUNX2 could become an essential biomarker for developing diagnostic tools and specific treatments against tumoral diseases in the lung after the experimental validation of its regulatory function.

Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis.

The bioinformatic pipeline previously developed in our research laboratory is used to identify potential general and specific deregulated tumor genes and transcription factors related to the establishment and progression of tumoral diseases, now comparing lung cancer with other two types of cancer. Twenty microarray datasets were selected and analyzed separately to identify hub differentiated expressed genes and compared to identify all the deregulated genes and transcription factors in common between the three types of cancer and those unique to lung cancer. The winning DEGs analysis allowed to identify an important number of TFs deregulated in the majority of microarray datasets, which can become key biomarkers of general tumors and specific to lung cancer. A coexpression network was constructed for every dataset with all deregulated genes associated with lung cancer, according to DAVID's tool enrichment analysis, and transcription factors capable of regulating them, according to oPOSSUM´s tool. Several genes and transcription factors are coexpressed in the networks, suggesting that they could be related to the establishment or progression of the tumoral pathology in any tissue and specifically in the lung. The comparison of the coexpression networks of lung cancer and other types of cancer allowed the identification of common connectivity patterns with deregulated genes and transcription factors correlated to important tumoral processes and signaling pathways that have not been studied yet to experimentally validate their role in lung cancer. The Kaplan-Meier estimator determined the association of thirteen deregulated top winning transcription factors with the survival of lung cancer patients. The coregulatory analysis identified two top winning transcription factors networks related to the regulatory control of gene expression in lung and breast cancer. Our transcriptomic analysis suggests that cancer has an important coregulatory network of transcription factors related to the acquisition of the hallmarks of cancer. Moreover, lung cancer has a group of genes and transcription factors unique to pulmonary tissue that are coexpressed during tumorigenesis and must be studied experimentally to fully understand their role in the pathogenesis within its very complex transcriptomic scenario. Therefore, the downstream bioinformatic analysis developed was able to identify a coregulatory metafirm of cancer in general and specific to lung cancer taking into account the great heterogeneity of the tumoral process at cellular and population levels.

Joint Transcriptomic Analysis of Lung Cancer and Other Lung Diseases.

Background: Epidemiological and clinical evidence points cancer comorbidity with pulmonary chronic disease. The acquisition of some hallmarks of cancer by cells affected with lung pathologies as a cell adaptive mechanism to a shear stress, suggests that could be associated with the establishment of tumoral processes. Objective: To propose a bioinformatic pipeline for the identification of all deregulated genes and the transcriptional regulators (TFs) that are coexpressed during lung cancer establishment, and therefore could be important for the acquisition of the hallmarks of cancer. Methods: Ten microarray datasets (six of lung cancer, four of lung diseases) comparing normal and diseases-related lung tissue were selected to identify hub differentiated expressed genes (DEGs) in common between lung pathologies and lung cancer, along with transcriptional regulators through the utilization of specialized libraries from R language. DAVID bioinformatics tool for gene enrichment analyses was used to identify genes with experimental evidence associated to tumoral processes and signaling pathways. Coexpression networks of DEGs and TFs in lung cancer establishment were created with Coexnet library, and a survival analysis of the main hub genes was made. Results: Two hundred ten DEGs were identified in common between lung cancer and other lung diseases related to the acquisition of tumoral characteristics, which are coexpressed in a lung cancer network with TFs, suggesting that could be related to the establishment of the tumoral pathology in lung. The comparison of the coexpression networks of lung cancer and other lung diseases allowed the identification of common connectivity patterns (CCPs) with DEGs and TFs correlated to important tumoral processes and signaling pathways, that haven´t been studied to experimentally validate their role in the early stages of lung cancer. Some of the TFs identified showed a correlation between its expression levels and the survival of lung cancer patients. Conclusion: Our findings indicate that lung diseases share genes with lung cancer which are coexpressed in lung cancer, and might be able to explain the epidemiological observations that point to direct and inverse comorbid associations between some chronic lung diseases and lung cancer and represent a complex transcriptomic scenario.

RUNX family: Oncogenes or tumor suppressors (Review).

Runt­related transcription factor (RUNX) proteins belong to a transcription factors family known as master regulators of important embryonic developmental programs. In the last decade, the whole family has been implicated in the regulation of different oncogenic processes and signaling pathways associated with cancer. Furthermore, a suppressor tumor function has been also reported, suggesting the RUNX family serves key role in all different types of cancer. In this review, the known biological characteristics, specific regulatory abilities and experimental evidence of RUNX proteins will be analyzed to demonstrate their oncogenic potential and tumor suppressor abilities during oncogenic processes, suggesting their importance as biomarkers of cancer. Additionally, the importance of continuing with the molecular studies of RUNX proteins' and its dual functions in cancer will be underlined in order to apply it in the future development of specific diagnostic methods and therapies against different types of cancer.