Genomic Instability and Carcinogenesis: An Update

Cancers arise as a result of stepwise accumulation of mutations which may occur at the nucleotide level and/or the gross chromosomal level. Many cancers particularly those of the colon display a form of genomic instability which may facilitate and speed up tumor initiation and development. In few instances, a “mutator mutation” has been clearly implicated in driving the accumulation of other carcinogenic mutations. For example, the post-replicative DNA mismatch repair deficiency results in dramatic increase in insertion/deletion mutations giving rise to the microsatellite instability (MSI) phenotype and may predispose to a spectrum of tumours when it occurs in the germline. Although many sporadic cancers show multiple mutations suggesting unstable genome, the role of this instability in carcinogenesis, as opposed to the power of natural selection, has been a matter of controversy. This review gives an update of the latest data on these issues particularly recent data from genome-wide, high throughput techniques as well as mathematical modelling. Throughout this review, reference will be made to the relevance of genomic instability to the pathogenesis of colorectal carcinoma particularly its hereditary and familial subsets

Oncogenic Potential of Bisphenol A and Common Environmental Contaminants in Human Mammary Epithelial Cells

There is an ample epidemiological evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the molecular mechanisms of their action are still not fully understood. Therefore, we sought to analyze the effects of three common contaminants (BPA; 4-tert-octylphenol, OP; hexabromocyclododecane, HBCD) on mammary epithelial cell (HME1) and MCF7 breast cancer cell line. We also supplied some data on methoxychlor, MXC; 4-nonylphenol, NP; and 2-amino-1-methyl-6-phenylimidazo [4–b] pyridine, PhIP. We focused on testing the prolonged (two months) exposure to low nano-molar concentrations (0.0015–0.0048 nM) presumed to be oncogenic and found that they induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and disrupted the cell cycle. Some agents induced epigenetic (methylation) changes of tumor suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13, and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that these agents increased cellular invasiveness through collagen. Cellular abilities to form colonies in soft agar were increased for MCF7. Toxic agents induced phosphorylation of protein kinase such as EGFR, CREB, STAT6, c-Jun, STAT3, HSP6, HSP27, AMPKα1, FAK, p53, GSK-3α/β, and P70S6 in HME1. Most of these proteins are involved in potential oncogenic pathways. Overall, these data clarify the molecular alterations that can be induced by some common environmental contaminants in mammary epithelial cells which could be a foundation to understand environmental carcinogenesis

Antiproliferative and proapoptotic activities of ferulic acid in breast and liver cancer cell lines

Purpose: To explore the potential anticancer activities of ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) on two different human cancers cell lines, viz, breast (MCF-7) and hepatocellular (HepG2). Methods: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cytotoxicity, Annexin V staining, enzyme-linked immunosorbent assay (ELISA), as well as caspase-8 and -9 activation assays were used to evaluate the proapoptotic and antiproliferative potentials of ferulic acid (FA) on MCF-7 and HepG2 cell lines. Results: Ferulic acid exerted cytotoxic effects on MCF-7 and HepG2 cell lines with half-maximal inhibitory concentration (IC50) of 75.4 and 81.38 μg/mL, respectively, at 48 h. Annexin V staining revealed evidence of apoptosis. Caspase-8 and-9 levels were elevated in both cell lines after incubation with ferulic acid. Conclusion: The findings of this study suggest that ferulic acid has promising therapeutic potentials for the treatment of breast and liver cancers by inducing apoptosis via activation of caspase-8 and -9 pathways

Differential roles of EPS8 in carcinogenesis: Loss of protein expression in a subset of colorectal carcinoma and adenoma

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Fermented Camel (Camelus dromedarius) and Bovine Milk Attenuate Azoxymethane-induced Colonic Aberrant Crypt Foci in Fischer 344 Rats

Abstract: Background and Objective: Camel milk is a folk remedy that includes valuable nutrients and bioactive zoochemicals. However, the chemopreventive potential of camel milk against colon carcinogenesis is poorly understood. This study was conducted to investigate the chemopreventive potential of camel (Camelus dromedarius) and bovine milk as well as the impact of fermenting these milks with Lactobacillus acidophilus and Streptococcus thermophilus against early colon carcinogenesis as measured by the reduction of aberrant crypt foci (ACF) in azoxymethane (AOM)-treated Fischer 344 rats. Methodology: Each of 60 weanling male rats was assigned to one of 6 experimental diet groups: Fermented and unfermented camel milk with AOM, fermented and unfermented bovine milk with AOM and positive (PC, AOM only) and negative (NC, saline vehicle only) control groups. The animals were fed the corresponding diets for 3 weeks and then received two subcutaneous injections of AOM or vehicle for 2 consecutive weeks and they were then placed on the corresponding diets for 11 weeks. At termination, all rats were euthanized, colons were harvested and the ACF counts were determined for all tested groups. Immunohistochemical testing was then performed to examine cell proliferation and apoptosis in the camel milk groups. Results: Significant reductions (p<0.05) (48.4-62.1%) in the total ACF count were observed in the colons of the rats fed all milk diets compared with rats fed on PC. However, significant differences were not observed in the total ACF between the camel and bovine milk diets or between the fermented and unfermented milk diets. In addition, significant changes were not observed in the apoptotic index for the camel milk diet compared with the index values for PC and β-catenin was generally localized to the membrane in all examined specimens. Conclusion: By virtue of its bioactive components, camel milk exhibited a chemopreventive potential against early colon carcinogenesis, however, fermentation did not improve its chemopreventive potential

Ore Genesis of the Abu Ghalaga Ferro-Ilmenite Ore Associated with Neoproterozoic Massive-Type Gabbros, South-Eastern Desert of Egypt: Evidence from Texture and Mineral Chemistry

Massif-type mafic intrusions (gabbro and anorthosite) are known for their considerable resources of vanadium-bearing iron–titanium oxide ores. Massive-type gabbroic and anorthosite rocks are frequently associated with magmatic rocks that have significant quantities of iron, titanium, and vanadium. The most promising intrusions that host Fe-Ti oxide ores are the gabbroic rocks in the south-eastern desert. The ilmenite ore deposits are hosted in arc gabbroic and anorthosite rocks. They are classified into three types, namely black ore, red ore, and disseminated ore. The black ilmenite ore is located at the deeper level, while the oxidized red ore is mainly located at or near the surface. Petrographically, the gabbro and ilmenite ores indicate a crystallization sequence of plagioclase, titaniferous pyroxene, and ilmenite. This reveals that the ilmenite is a magmatic deposit formed by the liquid gravity concentration of ilmenite following the crystallization of feldspar and pyroxene. Meanwhile, quartz, tremolite, zoisite, and opaque minerals are accessory minerals. The Fe-Ti ores are composed of ilmenite hosting exsolved hematite lamellae of variable sizes and shapes, gangue silicate minerals, and some sulfides. The X-ray diffraction (XRD) data reveal the presence of two mineral phases: ilmenite and hematite formed by the unmixing of the ferroilmenite homogeneous phase upon cooling. As a result, the ore is mostly made up of hemo-ilmenite. Using an electron microscope (SEM), as well as by observing the textures seen by the ore microscope, ilmenite is the dominant Fe-Ti oxide and contains voluminous hematite exsolved crystals. Under the scanning electron microscope, ilmenite contained intergrowths of hematite as a thin sandwich and lens shape. The formation of hematite lamellae indicates an oxidation process. Mineral chemistry-based investigations reveal late/post-magmatic activity at high temperatures. The examined ilmenite plots on the ferro-ilmenite line were created by continuous solid solution over 800 °C, whereas the analyzed magnetite and Ti-magnetite plot near the magnetite line and were formed by continuous solid solution exceeding 600 °C

Potential Adverse Effects of Resveratrol: A Literature Review.

Due to its health benefits, resveratrol (RE) is one of the most researched natural polyphenols. Resveratrol's health benefits were first highlighted in the early 1990s in the French paradox study, which opened extensive research activity into this compound. Ever since, several pharmacological activities including antioxidant, anti-aging, anti-inflammatory, anti-cancerous, anti-diabetic, cardioprotective, and neuroprotective properties, were attributed to RE. However, results from the available human clinical trials were controversial concerning the protective effects of RE against diseases and their sequelae. The reason for these conflicting findings is varied but differences in the characteristics of the enrolled patients, RE doses used, and duration of RE supplementation were proposed, at least in part, as possible causes. In particular, the optimal RE dosage capable of maximizing its health benefits without raising toxicity issues remains an area of extensive research. In this context, while there is a consistent body of literature on the protective effects of RE against diseases, there are relatively few reports investigating its possible toxicity. Indeed, toxicity and adverse effects were reported following consumption of RE; therefore, extensive future studies on the long-term effects, as well as the in vivo adverse effects, of RE supplementation in humans are needed. Furthermore, data on the interactions of RE when combined with other therapies are still lacking, as well as results related to its absorption and bioavailability in the human body. In this review, we collect and summarize the available literature about RE toxicity and side effects. In this process, we analyze in vitro and in vivo studies that have addressed this stilbenoid. These studies suggest that RE still has an unexplored side. Finally, we discuss the new delivery methods that are being employed to overcome the low bioavailability of RE

A Novel P@SiO2 Nano-Composite as Effective Adsorbent to Remove Methylene Blue Dye from Aqueous Media

This work aims to prepare a novel phosphate-embedded silica nanoparticles (P@SiO2) nanocomposite as an effective adsorbent through a hydrothermal route. Firstly, a mixed solution of sodium silicate and sodium phosphate was passed through a strong acidic resin to convert it into hydrogen form. After that, the resultant solution was hydrothermally treated to yield P@SiO2 nanocomposite. Using kinetic studies, methylene blue (MB) dye was selected to study the removal behavior of the P@SiO2 nanocomposite. The obtained composite was characterized using several advanced techniques. The experimental results showed rapid kinetic adsorption where the equilibrium was reached within 100 s, and the pseudo-second-order fitted well with experimental data. Moreover, according to Langmuir, one gram of P@SiO2 nanocomposite can remove 76.92 mg of the methylene blue dye. The thermodynamic studies showed that the adsorption process was spontaneous, exothermic, and ordered at the solid/solution interface. Finally, the results indicated that the presence of NaCl did not impact the adsorption behavior of MB dye. Due to the significant efficiency and promising properties of the prepared P@SiO2 nanocomposite, it could be used as an effective adsorbent material to remove various cationic forms of pollutants from aqueous solutions in future works

Emerging role of caldesmon in cancer: A potential biomarker for colorectal cancer and other cancers

Colorectal cancer (CRC) is a devastating disease, mainly because of metastasis. As a result, there is a need to better understand the molecular basis of invasion and metastasis and to identify new biomarkers and therapeutic targets to aid in managing these tumors. The actin cytoskeleton and actin-binding proteins are known to play an important role in the process of cancer metastasis because they control and execute essential steps in cell motility and contractility as well as cell division. Caldesmon (CaD) is an actin-binding protein encoded by the CALD1 gene as multiple transcripts that mainly encode two protein isoforms: High-molecular-weight CaD, expressed in smooth muscle, and low-molecular weight CaD (l-CaD), expressed in nonsmooth muscle cells. According to our comprehensive review of the literature, CaD, particularly l-CaD, plays a key role in the development, metastasis, and resistance to chemoradiotherapy in colorectal, breast, and urinary bladder cancers and gliomas, among other malignancies. CaD is involved in many aspects of the carcinogenic hallmarks, including epithelial mesenchymal transition via transforming growth factor-beta signaling, angiogenesis, resistance to hormonal therapy, and immune evasion. Recent data show that CaD is expressed in tumor cells as well as in stromal cells, such as cancerassociated fibroblasts, where it modulates the tumor microenvironment to favor the tumor. Interestingly, CaD undergoes selective tumor-specific splicing, and the resulting isoforms are generally not expressed in normal tissues, making these transcripts ideal targets for drug design. In this review, we will analyze these features of CaD with a focus on CRC and show how the currently available data qualify CaD as a potential candidate for targeted therapy in addition to its role in the diagnosis and prognosis of cancer

Germline Mutation of RPS20, Encoding a Ribosomal Protein, Causes Predisposition to Hereditary Nonpolyposis Colorectal Carcinoma Without DNA Mismatch Repair Deficiency

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