The effects of ellagic acid and other pomegranate (Punica granatum L.) derivatives on human gastric cancer AGS cells.

Although surgery with or without (neo)adjuvant chemo/radiotherapy, as the standard treatments, can be suitable therapeutic strategies for gastric cancer, side effects and drug resistance are two main treatment obstacles. It has been discovered that pomegranate and its natural derivatives, especially ellagic acid (EA), offer significant anti-cancer effects while causing trivial side effects. In this study, we aimed to explore the anti-cancer effects of EA on a human gastric adenocarcinoma cell line (AGS) as well as in immunocompromised mice bearing human gastric tumors, for the first time. HPLC was used for determining EA in samples. MTT assay, apoptosis and scratch assay, gelatin zymography, and quantitative RT-PCR were used to determine the anti-cancer properties of different concentrations of pomegranate fruit juice, pomegranate peel extract, and EA. Furthermore, the effects of these compounds were investigated on immunosuppressed C57BL/6 mice carrying human gastric cancer tumors. EA could inhibit the proliferation and migration of gastric cancer cells. It also had significant effects on reducing both expression and activity of MMP-2 and MMP-9. Further, it was demonstrated that with alterations in the expression of genes involved in apoptosis and inflammation including P53, BAX, APAF1, BCL2, iNOS, NF-κB, IL-8, and TNF-α, EA treatment led to increased cancer cell death and reduced inflammation. Furthermore, its use in mice bearing gastric tumors resulted in a significant reduction in tumor volume without any obvious side effects. Ellagic acid exhibited anti-cancer effects on gastric adenocarcinoma, and can be considered as a safe anti-cancer agent for further preclinical studies on this cancer.

Ellagic acid and human cancers: a systems pharmacology and docking study to identify principal hub genes and main mechanisms of action.

Research on anticancer properties of natural compounds, as effective materials that are available while causing minimal side effects, is growing. Ellagic acid (EA) is a well-known polyphenolic compound, which has been found in both free and complex modes in several medicinal plants such as pomegranate, walnut, and berries. Although many articles have reported anticancer properties for this compound, its mechanism of action has not been fully elucidated. In this study, we used several online and offline bioinformatics tools and databases to identify the mechanism of action of EA on various types of human malignancies including bladder, blood, breast, cervical, colorectal, liver, pancreas, and prostate cancers. In this context, after identifying and extracting EA-affected human genes/proteins that have been reported in various references, we built the related gene networks and determined functional hub genes. In addition, docking was performed to recognize target proteins that react directly with EA and are in fact most affected by this compound. Our findings revealed that EA exerts its anticancer effects by influencing specific hub genes in various types of cancers. Moreover, different cellular signaling pathways are affected by this natural compound. Generally, it turned out that EA probably exerts most of its anticancer activities, through induction of apoptosis, as well as P53 and WNT signaling pathways, and also by affecting the expression of several hub genes such as CDKN1A, CDK4, CDK2, CDK6, TP53, JUN, CCNA2, MAPK14, CDK1, and CCNB1 and especially interactions with some related proteins including P53, CDK6, and MAPK14.

Salivary exosomes: properties, medical applications, and isolation methods.

Salivary exosomes are extracellular vesicles (EVs) with abundant CD63 immunoreactivity on their surface. Based on their size and protein composition, these exosomes can be categorized into two classes of exosomes I (mean diameter of 83.5 nm) and II (mean diameter of 40.5 nm). We have attempted to review the features of these exosomes, including origin, composition, separation methods, and their application in medicine. Not only the composition of salivary exosomes is invaluable in term of diagnosis, but can also afford an understanding in roles of the contents and components of these exosomes in the fundamental pathophysiologic processes of different diseases. since these EVs can cross the epithelial barriers they may be essential for transporting of multifarious components from the blood into saliva. Thus, in comparison to other bodily fluids, salivary exosomes are probably a better and accessible tool to examine the function of exosomes in the diagnosis and treatment of disease.

Impact of OCT4 and Its Related Signaling Pathways on Gastrointestinal Cancers: Focusing on Targeted Therapy.

There are many pieces of evidence support the effect of cancer stem cells on the initiation and progression of cancer. However, related mechanisms involved in these phenomena are far more complicated to understand. The function of different stemness factorsin cancer stem cells (CSCs) and their complex associations at different levels of cancer have been reported. Therefore, it seems that focusing on one master factor would be more helpful to complete the puzzle of singling pathways in these cells. Octamer-binding transcription factor 4 (OCT4) also known as POU domain, class 5, transcription factor 1(POU5F1), one of these key pluripotency factors, has important roles in both embryogenesis and tumorigenesis. In this review, we gathered information about the association of different markers with OCT4 expression in three types of gastrointestinal cancers including esophageal, gastric and colorectal cancers. OCT4 through different signaling pathways has an impact on different processes of gastrointestinal cancers such as proliferation, invasion, and metastasis. Based on the literature, OCT4 has great effects on cancer progression at different stages, therefore we suggested it has potential implications in therapeutic options.

Prognostic and Clinical Value of CD44 and CD133 in Esophageal Cancer: A Systematic Review and Meta-analysis.

Despite the importance of CD44 and CD133 in various cancers, the clinicopathological and prognostic values of these biomarkers in esophageal cancer remain debated. Hence, in this study, we did a meta-analysis to explore the correlation between overexpression of these markers and some clinicopathological features and their influence on the survival of esophageal cancer patients. A search in PubMed and Web of Science (among all articles published up to January 16, 2018) was done using the following keywords: esophageal cancer, CD44, CD133, prominin-1, AC133. Suitable studies, that were selected based on the criteria listed in the Materials and Methods section, were chosen and hazard ratios with 95% confidence intervals were estimated if available. Heterogeneity and sensitivity were also analyzed. Furthermore, publication bias was assessed using funnel plots, Egger, and Begg tests. The study included 1346 patients from 13 related studies. The median rates of marker expressions by immunohistochemistry were 35.7% (30%-76.6%) from 9 studies for CD44 and 31.9% (21%-44.2%) from 5 studies for CD133. The accumulative 5-year overall survival rates of CD44-positive and CD133-positive were 1.59% (1.22-2.06) and 1.27% (0.93-1.73), respectively. Meta-analysis showed that CD44 expression had a significant correlation with 5-year overall survival. CD44 overexpression showed a correlation with some clinicopathological features such as lymph node metastasis, vascular invasion, and recurrence of the disease, while it was not the case for coexpression of CD44 and CD133. In conclusion, CD44 overexpression was associated with a 5-year overall survival rate and thus this biomarker can be a suitable prognostic tool in esophageal cancer.

Cytotoxic activity of caffeic acid and gallic acid against MCF-7 human breast cancer cells: An in silico and in vitro study.

OBJECTIVE: Phenolic compounds have been considered inhibitors of various cancers. MATERIAL AND METHODS: In this study, caffeic acid and gallic acid were appraised for their possible effects on apoptotic genes expression in a breast cancer cell line in vitro. We also evaluated ligand interaction and ligand binding with estrogen receptor alpha by molecular docking. To determine half maximal inhibitory concentration, MCF-7 cells were treated with different concentrations of caffeic acid and gallic acid by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Furthermore, morphological changes in cells and alterations in P53, Mcl-1 and P21 gene expression were studied by real-time RT-PCR. Also, protein network and different interactions between the desired genes were analyzed using GeneMANIA database. RESULTS: Evaluation of cell survival by MTT assay revealed that the half-maximal inhibitory concentration values for caffeic acid and gallic acid against MCF-7 cells, were 159 and 18 µg/ml, respectively. These compounds were found to affect P53, Mcl-1 and P21 gene expression; this alteration in gene expression probably occurred along with the activation of intrinsic apoptotic signaling pathway. CONCLUSION: Via apoptosis induction, caffeic acid and gallic acid have induce toxic effects and morphological changes in breast cancer cells, suggesting their possible future application as antitumor agents.

Exosomes and their importance in metastasis, diagnosis, and therapy of colorectal cancer.

Extracellular vesicles are known as actual intermediaries of intercellular communications, such as biological signals and cargo transfer between different cells. A variety of cells release the exosomes as nanovesicular bodies. Exosomes contain different compounds such as several types of nucleic acids and proteins. In this study, we focused on exosomes in colorectal cancer as good tools that can be involved in various cancer-related processes. Furthermore, we summarize the advantages and disadvantages of exosome extraction methods and review related studies on the role of exosomes in colorectal cancer. Finally, we focus on reports available on relations between mesenchymal stem cell-derived exosomes and colorectal cancer. Several cancer-related processes such as cancer progression, metastasis, and drug resistance of colorectal cancer are related to the cargoes of exosomes. A variety of molecules, especially proteins, microRNAs, and long noncoding RNAs, play important roles in these processes. The microenvironment features, such as hypoxia, also have very important effects on the properties of the origin cell-derived exosomes. On the other hand, exosomes derived from colorectal cancer cells also interfere with cancer chemoresistance. Furthermore, today it is known that exosomes and their contents can likely be very effective in noninvasive colorectal cancer diagnosis and therapy. Thus, exosomes, and especially their cargoes, play different key roles in various aspects of basic and clinical research related to both progression and therapy of colorectal cancer.

7-Isopenthenyloxycoumarin, Arctigenin, and Hesperidin Modify Myeloid Cell Leukemia Type-1 (Mcl-1) Gene Expression by Hormesis in K562 Cell Line.

Hormesis is a new concept in dose-response relationship. Despite of traditional dose-response curves, there is a low-dose stimulation and a high-dose inhibition in this case. Hormesis effect in apoptosis induction/inhibition by natural compounds is reported previously. Here, we searched this effect for myeloid cell leukemia type-1 (Mcl-1) gene expression by phytochemicals 7-isopenthenyloxycoumarin (7-IP), arctigenin (Arg), and hesperidin (Hsp). For this purpose, first we tested the cytotoxicity of various doses of these compounds against K562 leukemia cell lines for different times by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. After that we explored the effect of various doses of these phytochemicals on Mcl-1 gene expression for different times by real-time polymerase chain reaction method. We found that these phytochemicals have cytotoxicity against K562 cell line. Hesperidin is the most cytotoxic agent. We also found that these natural compounds have hormetic effect on Mcl-1 gene expression. The hormetic model in Mcl-1 gene expression is overcompensation stimulation. This phenomenon is reported for the first time. We conclude that 7-IP, Arg, and Hsp are cytotoxic against K562 cancerous cells and induce/inhibit Mcl-1 gene expression by hormesis dose-response relationship.

Potential role of RAB6C-AS1 long noncoding RNA in different cancers.

BACKGROUND: Long noncoding RNAs (lncRNAs) refer to a group of non-protein-coding RNAs that are usually more than 200 nucleotides. These long transcripts play significant roles in diverse cellular processes, mostly through epigenetic mechanisms. Thus, dysregulation of lncRNAs is associated with various diseases, especially cancer. This study aims to investigate the probable roles of RAB6C-AS1 lncRNA in different cancers. METHODS: Real-time quantitative reverse transcription-polymerase chain reaction was applied for the analysis of RAB6C-AS1 lncRNA amplification in gastric cancer (GC) samples compared with normal ones. Also, several online and offline data sets and tools were used to analyze the relation between RAB6C-AS1 lncRNA and different cancers. RESULTS: The end result of our analyses indicated that RAB6C-AS1 was overexpressed in 40% of the investigated GC specimens. Also, the results demonstrated a true relation between RAB6C-AS1 overexpression and higher GC tumor grades. However, bioinformatic analyses showed that while RAB6C-AS1 possibly functions as an oncogene in some cancer types, including prostate and breast cancers, it might have a tumor suppressive function in some others including brain tumors. CONCLUSIONS: We found that RAB6C-AS1 lncRNA is mostly overexpressed in GC. Also, based on bioinformatic and systems biology analyses, RAB6C-AS1 might function either as an oncogenic factor or tumor suppressor in a tissue-specific manner. Thus, RAB6C-AS1 could be considered as a candidate biomarker for various malignancies, especially prostate and brain cancers. According to our results, RAB6C-AS1 has a notable prognostic value for patients with brain lower grade glioma.

SOX2 expression in gastrointestinal cancers of Iranian patients.

PURPOSE: Gastrointestinal (GI) malignancies are among the 5 most common cancers in Iran, and their high associated mortality rates are attributable to late diagnosis and poor treatment options. SOX2, a transcription factor necessary for maintenance and induction of pluripotency and self-renewal, has been identified as a lineage-survival oncogene in several cancers. In the present study, we examined SOX2 expression in esophageal squamous cell carcinoma (ESCC), gastric adenocarcinoma and colon squamous cell carcinoma (SCC), as well as normal GI tissues, in Iranian patients. METHODS: To elucidate the role of SOX2 in GI carcinogenesis, formalin-fixed tissues were analyzed using immunohistochemistry (IHC), while frozen ESCC samples were studied by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: IHC studies indicated presence of SOX2+ cells in a subset of cancerous and normal tissues of stomach and colon, while no significant difference was observed between groups, and no correlation was found between SOX2 expression and tumors grades. Nevertheless, studying ESCC samples with IHC and qRT-PCR revealed overexpression of SOX2 in comparison with normal adjacent tissues. CONCLUSIONS: The present results are in line with other studies and indicate SOX2 up-regulation in ESCC; however, due to our small sample size and contradictory reports, more research is needed to determine the importance of SOX2 in GI cancers.

Evaluating stem and cancerous biomarkers in CD15+CD44+ KYSE30 cells.

Digestive system cancers are listed among the ten top causes of cancer-related death worldwide. Cancer stem cells (CSCs) are malignant cells that share some of their characteristics with normal stem cells, including self-renewal and multipotency, and also cancer cells, such as drug resistance and metastasis. Despite many reports on CSCs with digestive system origin, identification and characterization of esophageal CSCs have remained elusive. To examine the validity of routine SC, cancer cell and CSC markers in KYSE30 cells, derived from esophageal carcinoma, cells were first characterized by immunofluorescence and RT-PCR techniques, and then the significance of candidate biomarkers was evaluated in retinoic acid-treated cells by flow cytometry and/or real-time RT-PCR. Meanwhile, to study CD15 (a newly introduced CSC marker) expression in digestive tract cancers, human normal and tumoral tissues of esophagus, stomach, and colon were analyzed by immunohistochemistry. Using several experimental approaches, we show that CD44, but not CD15, could serve as a reliable marker for undifferentiated malignant squamous cells of esophagus. In conclusion, our study confirms the role of CD44 as a CSC marker in KYSE30 cells, an esophageal squamous cell carcinoma cell line, and for the first time indicates the expression of CD15 in non-neural stem-like cancer cells. Although the importance of CD15 was not indicated in diagnosis of digestive cancers, further studies are needed to better understand the biological identity and function of this molecule in non-neural malignancies.