Origin of cells and network information

Abstract

All cells are derived from one cell, and the origin of different cell types is a subject of curiosity. Cells construct life through appropriately timed networks at each stage of development. Communication among cells and intracellular signaling are essential for cell differentiation and for life processes. Cellular molecular networks establish cell diversity and life. The investigation of the regulation of each gene in the genome within the cellular network is therefore of interest. Stem cells produce various cells that are suitable for specific purposes. The dynamics of the information in the cellular network changes as the status of cells is altered. The components of each cell are subject to investigation.

Key Words: Stem cell, Genome, Network information, Bioinformatics, Gene, Epithelial-mesenchymal transition

Core tip: The cells in the body orchestrate the unique roles of each organ through a cellular network. It is important to investigate alterations in cellular phenotypes and the regulation of genes, the genome and molecules in order to understand the origin of the cells. Insights into the changes in cellular features, including epithelial-mesenchymal transition, and recent database advances are described in this editorial.

THE GENOME AS A BLUEPRINT

Recently, pluripotent stem cells have played an increasing role in disease and developmental models, including the challenge of generating novel organs such as intestines[1]. Stem cell differentiation is one of the mechanisms by which regenerative tissues are produced. In each cell, the genome encodes the plan for the life of the cell and the path for organizing each tissue. The gene segments travel through the genome to settle at the gene loci[2]. Variations within the genome produce individual differences. Dramatic transitions of cellular phenotypes, such as the Warburg effect, occur in disease states such as cancer[3,4]. Epigenetic alterations provide cellular identity and phenotypic diversity. RNA transcription is altered in cancer; this alteration is caused by somatic DNA translocation or mutation[5]. Variants of genes such as BRCA2 and CHEK2 increase the risk of lung cancer[6]. Genome sequencing of normal cells has revealed the accumulation of mutations and differences in each cell lineage and tissue[7]. Genome editing has recently been developed. Additionally, gene therapy using clustered regularly interspaced short palindromic repeats/Cas9 is an emerging technique[8]. The construction and architecture of the genome are important for understanding the cell.

STEM CELL DIFFERENTIATION AND REPROGRAMMING

Definition of stem cells

Emerging roles for stem cells as sources for cell-based therapy remind us of the importance of the definition of stem cells[9]. Stem cells are generally defined as cells with self-renewal and differentiation potential[10]. Accumulating knowledge and insights have shown that stem cells are able to differentiate into several cell types in the body. However, a paradigm shift occurred after the discovery of induced pluripotent stem (iPS) cells that can be created by reprogramming differentiated cells with several factors[11]. This finding may allow for a shift in the cell type of stem cells derived from differentiated cells in the body. Thus, the range of stem cells needs to be defined. Stem cells can be classified into two categories (Figure 1): (1) pluripotent stem cells, such as embryonic stem cells or iPS cells[12-15]; or (2) tissue multipotent stem cells such as neural stem cells, hematopoietic stem cells or mesenchymal stem cells[16]. Recently, SNAI1 (SNAIL) has been reported to localize to the nucleus and to play a role in epithelial-mesenchymal transition (EMT) during the early stage of reprogramming of differentiated cells[17]. EMT and mesenchymal-epithelial transition processes may promote the reprogramming of differentiated cells toward stem cells[17]. Altered phenotypes and gene networks of stem cells have been reported, suggesting that the cells themselves have various gene dynamics during culture[18]. Cancer stem cells may be included as stem cells in cancer states. In some cases, engineered differentiated cells with gene modification or genome editing may also be included as stem cells if the cells are reprogrammed.

Figure 1 Current variations and definitions of stem cells. Pluripotent stem cells include embryonic stem cells and induced pluripotent stem cells, which will differentiate into all cells in the body. Multipotent stem cells, including tissue stem cells, differentiate into several types of cells to create the parts of organs or of the body. EMT: Epithelial-mesenchymal transition; iPS: Induced pluripotent stem; ES: Embryonic stem; TS: Tissue stem.

Cancer stem cell phenotype transition

The cell phenotype transition has been observed in cancer stem cells (CSCs)[19]. SOX2, which is a reprogramming factor, is a CSC biomarker in embryonal carcinoma cells and is related to stem-like cancer cells[20]. Genome analysis of SOX2-silenced human embryonal carcinoma cell lines has revealed that the cellular networks of these cells are enriched for microRNAs that are regulated by SOX2 and that are associated with EMT markers[20]. In contrast, an epidermal growth factor receptor exon 19-deleted lung cancer cell line was induced to exhibit CSC-like phenotypes and EMT by DDX3X transfection[21]. Moreover, DDX3X overexpression was reported to induce Sox2 up-regulation[21].

CSCs are related to chemotherapy and radiation resistance in squamous cell carcinomas (SCCs)[22]. The CSC population is diverse in SCCs; this diversity contributes to difficulty in cancer treatment[22]. Understanding the mechanisms of CSCs and EMT are important for the development of novel therapeutics.

CELLULAR NETWORK INFORMATION

Epithelial-mesenchymal transition

Cellular networks characterize both cells and the body, and gene combinations are critical for the presentation of phenotypes[23]. EMT is one of the mechanisms by which the cell phenotype transitions; dihydropyrimidine has been reported to induce EMT[24]. EMT is associated with metastasis in tumor progression and is induced by Notch activation and p53 deletion in mice[25]. Erythropoietin-producing hepatoma (EPH) receptors, which are receptor tyrosine kinases related to cancer, may be related to EMT signaling[26]. EPH receptor A2 induces EMT viaβ-catenin activation, followed by Snail expression and cadherin 1, type 1, E-cadherin (epithelial) (CDH1) suppression[26]. Wnt/β-catenin signaling is inhibited by SOX10, leading to the inhibition of the growth and metastasis of digestive cancers[27]. SRY (sex determining region Y)-box 10 (SOX10) inhibits EMT, which may be one of the possible mechanisms of cancer inhibition[27]. Frizzled2, the Wnt receptor, induces EMT and cell migration through the noncanonical pathway[28]. EMT is monitored by cell rigidity, and human equilibrative nucleoside transporter-1 suppression induces EMT in pancreatic cancer cells[29]. EMT characterization is needed for further understanding cell type transition and cancer progression.

Classification of EMT features

EMT can be characterized by the following three features: (1) changes in cellular morphology; (2) increases in cellular motility; and (3) alterations in the expression of E-cadherin and N-cadherin[29]. Cellular morphological changes are typically observed in the transition from connective-like cells to mesenchymal-like cells[29]. The expression of CDH1 is usually up-regulated in connective- or epithelial-like cells, whereas the expression of N-cadherin (CDH2) is up-regulated in mesenchymal-like cells[29,30]. EMT is associated with tumor metastasis[30]. The metastasis potential or invasiveness of cancer can be measured by the mechanical rigidity of the cells[31,32]. Several genes are involved in EMT, including BMI1 proto-oncogene, polycomb ring finger (BMI1), hypoxia inducible factor 1, alpha subunit (HIF1A, HIF-1α) and twist family bHLH transcription factor 1 (TWIST1, Twist)[33]. HIF-1α, which is a key transcription factor, is up-regulated in gastric cancer. Additionally, network pathway genes, such as NFκB1, BRCA1, STAT3 and STAT1, and network hub genes, such as MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS and TFF3, have been identified[34].

GENE REGULATION IN DISEASE

Gene and molecule alterations

An abundant number of genes are regulated in cancer. Genes are regulated not only by transcription factors but also by microRNAs (miRNAs). miRNA-9 is up-regulated in esophageal squamous cell carcinoma, which may induce EMT and metastasis in cancer[35]. CD151, which is a regulator of laminin-binding integrin function and signaling, represses EMT and canonical Wnt signaling, leading to the inhibition of ovarian tumor growth[36]. Wnt/β-catenin signaling is involved in EMT induction by the parathyroid hormone in human renal proximal tubular cells[37]. Endothelin-1 and endothelin A receptor signaling, together with Wnt signaling, regulate EMT in epithelial ovarian cancer[38]. Endothelin/β-arrestin signaling and Wnt/β-catenin signaling may be involved in chemotherapy resistance in cancer[38]. Hypoxia-inducible factors (HIFs) play roles in Wnt signaling in human colon cancer cells[39]. HIF-1α depletion induces the reversal of EMT, and HIF-2α silencing affects the expression of stem cell markers and increases β-catenin transcriptional activity under hypoxic conditions[39]. The roles of HIFs in Wnt/β-catenin signaling and in the surrounding networks are essential for understanding cancer cell phenotypes. The silencing of β-catenin via promoter methylation is also involved in the enhancement of non-small cell lung cancer invasiveness[40].

Notch1, which is one of the important molecules in cancer signaling, is involved in Ras/phosphoinositide 3 kinase (PI3K)/Akt signaling in T-cell acute lymphoblastic leukemia (T-ALL)[41], and PI3K and Notch1 may be targets for drug resistance in T-ALL[41]. Sox2, which is one of the reprogramming factors used to produce iPS cells, may be a regulator of EMT during neural crest development[42]. The Wnt pathway induces the EMT pathway, and the inhibition of the Wnt pathway may be involved in the re-differentiation of human islet β-cells[43]. Thus, the investigation of the molecules associated with EMT and disease is of interest[44].

MOLECULAR COMMUNICATION

The gene and genome networks

Several megaprojects have been established in response to the genome projects, one of which is called the ENCyclopedia Of DNA Elements (ENCODE) Project, which aims to translate the human genome sequence into biological and health mechanisms[45]. The ENCODE Project has identified functional elements in the genome (http://www.genome.gov/ENCODE/)[46,47].

The cross-cancer alteration of genes and their networks can be examined in cBioPortal, which is a cancer genomics database (http://www.cbioportal.org/public-portal/)[48,49]. The cBioPortal includes network analysis for the visualization of networks that are altered in cancer[49]. The precise information obtained through network analysis has been reported in several studies[50-53]. The sources of the networks are derived from pathways and interactions from the Human Reference Protein Database[53], Reactome[51], the Pathway Interaction Database created by the National Cancer Institute in collaboration with Nature Publishing Group (http://pid.nci.nih.gov/)[52], and the Memorial Sloan-Kettering Cancer Center Cancer Cell Map, which are all included as source information in the Pathway Commons Project (http://www.pathwaycommons.org)[50]. Pathway Commons is an open pathway that includes interaction information for multiple species, such as humans and model organisms[50].

The web interface called Gene Expression Commons is an interesting tool for gene expression analysis and microarray data that can be analyzed with reference data to model biological relationships (https://gexc.stanford.edu/)[54]. The amount of data available in these databases is increasing and includes data from microarrays, next-generation sequencing, and clinical data.

CONCLUSION

The cell is the fundamental unit of life. The investigation of gene and genome regulation is critical for a deep understanding of phenotypic alterations and of the origin of cells. The transition of cell characteristics, including differentiation, reprogramming and EMT, and cell-to-cell communications requires further investigation to reveal the cell of origin.