Scalable Reaction Network Modeling with Automatic Validation of Consistency in Event-B

Constructing a large biological model is a difficult, error-prone process. Small errors in writing a part of the model cascade to the system level and their sources are difficult to trace back. In this paper we extend a recent approach based on Event-B, a state-based formal method with refinement as its central ingredient, allowing us to validate for model consistency step-by-step in an automated way. We demonstrate this approach on a model of the heat shock response and its scalability on a model of the ErbB signaling pathway, a key evolutionary pathway with a significant role in development and in many types of cancer. All consistency properties of the model were proved automatically with computer support.

The Role of miRNA-377 as a Tumor Suppressor in Lung Cancer by Negative Regulation of Genes Belonging to ErbB Signaling Pathway

The ErbB signaling pathway plays important role in the pathogenesis of lung cancer. We explored the role of miRNA-377 as a tumor suppressor in NSCLC through silencing of some genes in the ErbB pathway.Targeting the effect of miRNA-377 on EGFR, MAPK1, ABL2, and PAK2 was evaluated. The expression levels of these genes and miRNA-377 were surveyed in NSCLC and normal human tissues, Calu-6, and A549 cells. Real-time PCR was used to figure out whether miRNA-377 could decrease the target genes mRNAs in transfected lung cancer cell lines. The effects of miRNA-377 on apoptosis cell and proliferation were analyzed. We showed that miRNA-377 targets EGFR, MAPK1, and PAK2 mRNAs in in-silico and luciferase reporter assay. The expression of miRNA-377 was significantly downregulated in human NSCLC tissues, Calu-6 and A549 cells compared to their controls. We observed a negative correlation between EGFR, MAPK1, PAK2, and miRNA-377 expression in human NSCLC tissues. A significant reduction in EGFR, MAPK1, and PAK2 mRNA levels was detected, following miRNA-377 transfection in Calu-6 and A549 cells. The higher levels of miRNA-377 in Calu-6, and A549 cells induced apoptosis and reduced proliferation, significantly. All these data reveal that miRNA-377 functions as a tumor suppressor in NSCLC and may serve as a potential therapeutic target for the treatment of NSCLC.

Long Non-Coding RNA LINC01410 Promoted Tumor Progression via the ErbB Signaling Pathway by Targeting STAT5 in Gallbladder Cancer

ObjectivesLong non-coding RNAs (lncRNAs) have been recently emerging as crucial molecules in multiple human cancers. However, their expression patterns, roles as well as the underlying mechanisms in gallbladder cancer (GBC) remain largely unclear.Materials and MethodsThe expression of lncRNAs in GBC was downloaded from GEO database. Quantitative real-time polymerase chain reaction (qRT-PCR) and RNA in situ hybridization (ISH) were used to detect the expression of lncRNAs in GBC tissues. The full-sequence of LINC01410 was determined by RACE assay. Subcellular distribution of LINC01410 was examined by nuclear/cytoplasmic RNA fractionation analysis. Loss- and gain-of-function experiments were conducted to explore the biological functions of LINC01410 in vitro and in vivo. RNA pull-down, RNA immune-precipitation (RIP), and Western blot assay were conducted to investigate the mechanisms underlying the biological function of LINC01410 in GBC.ResultsLINC01410 was significantly upregulated in the GBC tissues compared to adjacent non-tumor tissues. High LINC01410 expression was significantly associated with poor prognosis of GBC patients. We identified LINC01410 to be 2,877 bp in length and mainly localized in the cytoplasm of GBC cells. Overexpression of LINC01410 promoted GBC cell proliferation, migration, and invasion in vitro and GBC progression in vivo, whereas LINC01410 downregulation rescued these effects in vitro. From RNA pull-down and RIP assay, we identified that STAT5 was a critical downstream target of LINC01410. Furthermore, ErbB signaling pathway was involved in the malignant phenotypes of GBC mediated by LINC01410.ConclusionsOur results suggested that LINC01410 was an important lncRNA that promoted GBC progression via targeting STAT5 and activating ErbB signaling pathway.

Correlation of autophagy-related genes for predicting clinical prognosis in colorectal cancer

Aim: Autophagy plays a controversial role in cancer. The role of autophagy-related genes (ARGs) in colorectal cancer (CRC) was evaluated based on publicly available data from The Cancer Genome Atlas and the Human Autophagy Database. Materials & methods: After collecting CRC-related transcript and clinical data and a list of ARGs from public databases, the Wilcoxon test was used to identify the differentially expressed ARGs between CRC and paired normal tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were used to identify the major biological properties and pathways associated with these genes. Univariate Cox regression was used to identify the prognosis-associated ARGs, and a forest plot was used to visualize the results. Kaplan–Meier analysis of the 5-year survival rate was performed. Univariate and multivariate Cox analyses were used to verify the impact of the prognosis-associated ARGs. Results: A total of 36 differentially expressed genes (16 upregulated and 20 downregulated in CRC) were obtained from among 206 ARGs. There were 53 enriched pathways, including the p53 signaling pathway, platinum drug resistance, apoptosis, EGFR tyrosine kinase inhibitor resistance and ErbB signaling pathway (p- and q-values <0.05). Kaplan–Meier analysis showed that the 5-year survival rate was 46.0% (95% CI: 0.335–0.631) and 76.0% (95% CI: 0.651–0.886) in the high- and low-risk groups, respectively. The high-risk patients had worse survival probability (p = 6.256 × 10-5). Independent-samples t-tests revealed that MAP1LC3C expression was higher in patients aged ≤65 than >65 (p = 0.022); RAB7A expression was higher in patients aged ≤65 than >65 (p = 7.31 × 10-4), higher in M1 than M0 (p = 0.042), higher in N1–3 than N0 (p = 0.002) and higher in stage III and IV than I and II (p = 0.042); risk score was higher in N1–3 than N0 (p = 0.001) and in stage III and IV than I and II (p = 0.002); and WIPI2 expression was higher in M1 than M0 (p = 0.002), higher in N1–3 than N0 (p = 2.059 × 10-7) and higher in stage III and IV than I and II (p = 2.299 × 10-7). There were no differences in risk score between males and females (p = 0.593), T1–2 and T3–4 (p = 0.082) or M0 and M1 (p = 0.072). Univariate and multivariate Cox analyses showed that RAB7A was a lower-risk gene, while MAP1LC3C, WIPI2, DAPK1, ULK3 and PELP1 were high-risk genes. Conclusion: Certain ARGs are potential prognostic molecular markers of poor prognosis in CRC. Additionally, the p53 signaling pathway, platinum drug resistance, apoptosis, EGFR tyrosine kinase inhibitor resistance and ErbB signaling pathway may be critical pathways regulated by ARGs in CRC.

Dysregulation in EGF/ERBB signaling pathway may explain abnormalities in cellular migration in bipolar disorder in patient-derived neural precursors

ABSTRACTCellular migration is a ubiquitous feature of development that brings brain cells into appropriate spatial relationships. Cortical thinning has been reported in post-mortem brain samples of patients with bipolar disorder (BD). It could be that defective cellular migration during brain development is one of the contributing mechanisms in BD pathogenesis, leading to abnormalities reported at post-mortem, and during brain imaging. To probe the role of cellular migration in BD, we conducted time-lapse analysis of migration of neural precursor cells (NPCs) previously generated in our laboratory. Two NPC lines (B1 and B2) and one control line (C1) were used for the cell migration experiments. Time-lapse images were recorded every 15 min, for 15 hours, and analysed for speed and direction of cellular migration. Abnormalities in cellular migration was a common feature observed in both patient-derived NPCs. Consequently, we investigated underlying mechanistic irregularities in B1 and B2 lines that may contribute to the observed phenotype. To this end, transcriptional changes were compared between the patient-derived cells with the control line. Additionally, we examined exonic variations in genes related to cellular migration or motility. Our analysis showed downregulation of multiple genes that are all part of the EGF/ERBB signaling pathway. Collective dysregulation may be producing the defective cellular phenotype. These cellular migration abnormalities may be linked to structural changes in the brain reported in bipolar disorder.

Neuregulins in Neurodegenerative Diseases

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment.