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Papers by abdel hady abdel Wahab

Solid State Phenomena, 2021

Graphene oxide (GO) is an oxidized nanosheets of graphite with a 2D planar structure. GO could be... more Graphene oxide (GO) is an oxidized nanosheets of graphite with a 2D planar structure. GO could be readily complexed with bio-entities as it possesses many oxygen-containing functionalities on its surface. The preparation process is fast, easy, and cost-effective. It was prepared using modified Hummers’ method in acidic solution as a primary solvent and potassium permanganate as an oxidizing agent. Afterwards, it was successfully characterized by FTIR, UV-visible spectroscopy, as well as XRD and Raman spectroscopy, and finally, SEM analysis. It was observed that the formed GO is mainly composed of carbon and oxygen elements rich in oxygen functional groups. Furthermore, the existence of (001) plane in XRD interprets the complete oxidation of graphite with d-spacing 9 Å. Moreover, Raman spectroscopy displayed the sp3 carbon hybridization, besides, the ID/IG ratio is found to be 0.84, which confirms the disorder between graphene oxide layers. The SEM images also pointed out that graph...

Radiation Research, 1994

The goal of these experiments was to investigate further the relationship between DNA double-stra... more The goal of these experiments was to investigate further the relationship between DNA double-strand breaks and cell killing in human tumor cells, first by comparing different cell lines, and second by radiomodification studies. Field-inversion gel electrophoresis was used to quantify double-strand breaks. Two subclones of the radioresistant human squamous cell carcinoma line SQ20B (SQD9 and SQG6) were compared. These subclones differed in DNA index by a factor of 1.7 but showed the same resistance to radiation as cells of the parental cell line. It was found that, although induction of DSBs was not significantly different in the two cell lines, the t1/2 of the fast component of repair was significantly shorter for SQD9 cells, leading to greater overall repair which was not reflected in increased survival. Caffeine and cysteamine were tested as modifiers of radiosensitivity, using the radioresistant SQ20B line and the radiosensitive SCC61 cell line. No effect of caffeine was seen when the drug was present only during irradiation. Postirradiation incubations with caffeine, however, resulted in a dose reduction factor greater than 2.0 in cell survival for both cell lines. In contrast, induction of DSBs was reduced by caffeine, and no effect on DSB repair was observed. Cysteamine led to a dose protection factor greater than 1.8 in cell survival in both cell lines. A reduction in induced DSBs was found at high doses corresponding approximately with the increase in cell survival. Over the same (low) dose range, however, the correlation between DSB induction and cell killing was poor. These data indicate that DSB induction does not correlate well with cell killing either for different cell lines, for radiochemical modification (cysteamine) or for some other types of modification (caffeine).

Asian Pacific Journal of Cancer Prevention, 2021

HCC patients received systemic chemotherapeutic agents (Liu et al., 2015). Sorafenib (Nexavar) is... more HCC patients received systemic chemotherapeutic agents (Liu et al., 2015). Sorafenib (Nexavar) is a multikinase inhibitor that targets both RAF and a number of tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptor-β (PDGFR-β) (Wilhelm et al., 2005). Despite the fact that sorafenib has been approved in several countries worldwide for advanced HCC patients still yet the drug show unsatisfied clinical outcomes due to its severe

BMC Urology, 2013

Background Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and meta... more Background Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and metastasis. Over-expression of different MMPs in tumor tissues can disturb the homeostasis and increase the level of various body fluids. Many MMPs including high molecular weights (HMWs) were detected in the urine of prostate and bladder cancer patients. Our aim here is to assess the usefulness of HMW MMPs as non invasive biomarkers in bilharzial bladder cancer in Egyptian patients. Methods The activity of different MMPs including HMW species was determined using zymographic analysis technique in the urine samples procured from sixty six bladder cancer patients (bilharzial and non-bilharzial) as well as hundred healthy control subjects. Also, the correlation between these HMW MMPs activities and different clinico-pathological parameters was investigated. Results High frequency of urine MMPs (uMMPs) activity was determined in 63.6% of examined tumor cases, however, none of the control cases ...

Cancer Research, 2016

Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal ... more Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal tumors worldwide, HCC is currently the fifth most common solid tumor worldwide and the fourth important cause of cancer-related death. Eighty percent of new cases found in developing countries as Egypt, but the incidence is increasing in economically developed regions, including Japan, Western Europe, and the United States. It has shown that expression level of different miRNAs was correlated with cellular liver processes such as inflammation, hepatocyte regeneration and apoptosis which indicate their important role in many liver diseases including hepatocellular carcinoma. The main objective of the present study is to correlate between the expression levels of liver specific miRNAs with different mitogen activated protein kinase (MAPK) pathway in primary HCC patients. Patients and Methods: The expression level of miRNA targeting MAPK pathway, Dual-Specificity Phosphatase 16 (DUSP16), c-...

Mutagenesis, Jul 16, 2015

Galectin-4 is a member of the galectin family which consists of 15 galactoside-binding proteins. ... more Galectin-4 is a member of the galectin family which consists of 15 galactoside-binding proteins. Previously, galectin-4 has been shown to have a role in cancer progression and metastasis and it is found upregulated in many solid tumours, including colorectal cancer (CRC). Recently, the role in the metastatic process was suggested to be via promoting cancer cells to adhere to blood vascular endothelium. In the present study, the regulatory region of LGALS4 (galectin-4) in seven colon cell lines was investigated with respect to genetic variation that could be linked to expression levels and therefore a tumourigenic effect. Interestingly, qRT-PCR and sequencing results revealed that galectin-4 upregulation is associated with SNPs rs116896264 and rs73933062. By use of luciferase reporter- and pull-down assays, we confirmed the association between the gene upregulation and the two SNPs. Also, using pull-down assay followed by mass spectrometry, we found that the presence rs116896264 and ...

Hepatitis Monthly, 2016

Background: MicroRNAs (miRNAs) have been repeatedly shown to play important roles in liver pathol... more Background: MicroRNAs (miRNAs) have been repeatedly shown to play important roles in liver pathologies, including hepatitis, liver cirrhosis, and liver cancer. Egypt has the highest hepatitis C virus (HCV) infection rate worldwide, predominantly involving genotype-4. Objectives: In this study, we attempted to characterize the miRNA profile of the poorly studied genotype 4 of HCV in chronically infected Egyptian patients to obtain a better understanding of the disease and its complications and help in the design of better management protocols. Patients and Methods: We analyzed the expression levels of a selected panel of 94 miRNAs in fresh liver biopsies collected from 50 Egyptian patients diagnosed with chronic HCV infection using quantitative real-time polymerase chain reaction (PCR) assay. Nonparametric tests were used to analyze the expression level of each miRNA and association with the clinicopathological features of enrolled patients in this study. Results: Our results revealed differential expression levels of the analyzed miRNAs compared to the normal controls. Twenty-seven miRNAs (including miR-105, miR-147, miR-149-3p, and miR-196b) showed up-regulation, while 17 miRNAs (including miR-21, miR-122, miR-199a-3p, and miR-223) showed down-regulation. An inverse correlation was observed between levels of miR-95, miR-130a, and miR-142-5p with the blood albumin level. Increased expression levels of seven miRNAs (miR-29c, miR-30c, miR-126, miR-145, miR-199a, miR-199a-3p, and miR-222) were observed with severe chronic hepatic inflammation. Several deregulated miRNAs found in this study have been previously linked to chronic liver inflammation and the risk of hepatocellular carcinoma (HCC) development. Conclusions: The identified expression profiles of some examined miRNAs might offer important points to consider for the treatment of naive patients and the management of chronically infected HCV patients in Egypt and around the world.

Molecular and cellular biochemistry, 2012

Breast cancer (BC) is the most common neoplasm among women in most developed countries, including... more Breast cancer (BC) is the most common neoplasm among women in most developed countries, including Egypt. Elevated levels of certain proteins in human BC are associated with unfavorable prognosis and progressive stages of the disease. The aim of our study was to evaluate the protein expression profile and prognostic significance of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), MMP-9 and membrane type 1-MMP (MT1-MMP) and their interaction in operable BC patients. The protein expression of COX-2, MMP-2 and MT1-MMP were evaluated by western blot technique, whereas enzymatic activity of MMP-2 and MMP-9 was determined by zymography in 47 breast cancer patients as well as normal adjacent tissues. Also, the correlation between these proteins and age, tumor size, LN stage, TNM stage, estrogen receptor, progesterone receptor, disease-free survival, and overall survival (OS) has been investigated. As compared to adjacent normal tissues, COX-2, MMP-2 and MT1-MMP were over-expres...

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcrip... more MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcriptional interactions with mRNA. MiRNAs have recently considered as key regulators of various cancers including liver cancer. Sorafenib is one of the antitumor drugs for the treatment of advanced hepatocellular carcinoma. It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. This study tries to investigate a potential microRNA-based mechanism of action of the drug by studying the effect of sorafenib on miR-23a and miR-24 levels in HCC cell lines HepG2 /Huh7 and revealing the possible drug mechanism against these oncogenic miRNAS in this study cell viability of cultured HepG2 /Huh7 after treatment with sorafenib were evaluated using Sulphorhodamine-B (SRB) assay, cell cycle and apoptosis estimated by flow cytometry assay. The caspase-3 level was determined using the ELISA assay. Moreover, miR-23a and miR-24 expressions levels analyzed by qPCR. Finally, TGF-β le...

Arab Journal of Gastroenterology

Cells

Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its act... more Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastas...

Nutrition and Cancer

Abstract Targeting altered metabolism in cancer provides a promising preventive and therapeutic a... more Abstract Targeting altered metabolism in cancer provides a promising preventive and therapeutic approach. Natural products interplay between gene expression and metabolism either by targeting altered metabolic enzymes and/or affecting the regulating miRNAs. Licorice is a widely known product used as flavoring agent. Glycyrrhizin and other metabolites were reported to exert several metabolic benefits. Here, we investigated the effect of licorice roots extract on some metabolic pathways and their regulating miRNAs in hepatocellular carcinoma cells. Our data showed various beneficial effects of licorice roots extract including induction of apoptosis and cell cycle arrest. Second, upregulating tumor suppressor miRNAs; let7a-3p, miR-34c-5p, miR-122-5p, miR-126-3p, miR195-5p, miR-199a-5p, miR-206, and miR-326-5p. Third, inhibiting HIF1α, PI3K and C-Myc and activating AMPK and p53. Fourth, inhibiting enzymes of glycolysis; HK-2, LDH-A and PK-M2; pentose phosphate pathway; G6PD and glutaminolysis; glutaminase. However, such an extract upregulated oncogenic miRNAs; miR-21, miR-221, and miR-222. Although the present data highlights the ability of licorice roots extract to enhance apoptosis and cell cycle arrest and correct altered metabolism, it warns against its unfavorable effects, hence, its use for prevention and therapy should proceed with caution. Further experiments are required to investigate whether a specific bioactive ingredient is responsible for upregulating the oncogenic miRNAs.

Anti-Cancer Agents in Medicinal Chemistry

Background: Doxorubicin (DOX) is the most common drugs used in cancer therapy, including Hepatoce... more Background: Doxorubicin (DOX) is the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance, is one of chemotherapy’s significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic. Objective: Investigating the role of miR-520c-3p in enhancement of anti-tumor effect of DOX against HepG2 cells. Methods: Expression profile for liver related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. Expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and TP53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using western blot technique. Results: The pres...

The Medical Journal of Cairo University

Background: Epigenetic gene regulation is important in human cancer. Aim of Study: We investigate... more Background: Epigenetic gene regulation is important in human cancer. Aim of Study: We investigated the possible role of acetylation level in the regulation of microRNAs (miRNAs) expression in hepatocellular carcinoma. Material and Methods: We first determined the inhibitory concentration (IC20, IC35 and IC50) of the histone deacetylase inhibitor Sodium Butyrate (SB) in HepG2 and Huh7 cells. Then, we analyzed the expression level of five miRNAs (miR-133b, miR-122-5p, miR-26a-5p, miR-539-5p and miR-518f-3p after treatment using qRT-PCR assay. MiRTarBase, MiROB and GeneCards databases were used for the identification of strong validated targets of examined microRNAs, and the detection of possible functions of the selected targets and related pathways. Results: SB revealed an anti-proliferative effect in both HepG2 and Huh7 cells, with IC50 values of 6.7mM and 9.2mM, respectively. MiR-133b showed up-regulation in HepG2 and miR-122-5p was down-regulated in HepG2 and Huh7 (29.5 and 1000 folds) in a dose dependent manner. MiR-26a-5p exhibited decrease in its level in both cell lines at IC35, but was increased at IC50 in HepG2 cells. MiR-518f-3p showed increase in its level during various doses of SB in both cell lines. Finally, miR-539-5p showed down expression in both cell lines. Prediction pathway analysis referred to the important role of each of miR-133b, miR-122-5p and miR-26a-5p in proliferation, apoptosis, angiogenesis and metastasis. Conclusion: Sub-lethal doses of SB have significant effects on miRNAs expression in human hepatocellular carcinoma cells. Understanding the epigenetic regulation of miRNAs may enhance the development of therapeutic strategies against HCC.

Biochemistry Letters

Triple negative breast cancer PARP, poly ADP-ribose polymerase ATM, ataxia telangiectasia mutated... more Triple negative breast cancer PARP, poly ADP-ribose polymerase ATM, ataxia telangiectasia mutated Background: spotting the scope on triple-negative breast cancer (TNBC) as the most aggressive type of breast cancer, with no targeted therapeutic options. TNBC is often characterized by having defects in DNA repair due to defects in BRCA making this cancer a rational target for the synthetic lethality of olaparib, as an inhibitory target agent of the alternative DNA repair pathway (poly ADP-ribose polymerase "PARP" inhibitor). Objectives: the present study aims to evaluate the value of miRNAs-181a/b as potential biomarkers in predicting the response of TNBC to olaparib. Methods: anti-miRNAs-181a/b was transfected into MDA-MB-231 cell line using HiPerFect transfection reagent, the transfected and untransfected cells were subjected to olaparib. The effect of miRNAs-181a/b on MDA-MB-231 treated cells with olaparib was evaluated through the detection of essential proteins involved in apoptosis and cell proliferation including Caspase-8, Bcl-2, and Ki-67. Further, the expression level of ataxia telangiectasia mutated (ATM) was determined as a functional target of miRNAs-181a/b. Results: a significant decrease in Caspase-8 activity, and Bcl-2, but a significant increase in cell survival, cell proliferation, and ATM protein were observed upon suppression of miRNAs-181a/b by their inhibitors followed by treatment with olaparib for TNBC cell line (MDA-MB-231 cells). Conclusions: our data confirmed that miRNA-181a and miRNA-181b play a critical role for detecting the sensitivity of TNBC cells to olaparib. As well as miRNAs-181a/b could be used as a potentially predictive biomarkers for response to olaparib.

Arab Journal of Gastroenterology

Background and study aims: Hepatocellular carcinoma (HCC) is one of the most common cancers world... more Background and study aims: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with highest incidence in Asia and Africa. MicroRNAs (miRNAs), a class of non-coding single stranded RNA, which not only post transcriptionally regulate gene expression but also respond to signaling molecules to affect cell functions such as Wnt/b-catenin signaling specifically in HCC. The goal of this study is to investigate the crosstalk between Wnt/b-catenin signaling proteins and microRNAs expression in HCC patients. Patients and methods: Fresh tissue samples of 30 primary HCC patients and 10 control subjects were included. Expression level of 13 different miRNAs (miR-10a-miR-106b-miR-99a-miR-148a-miR-125b-miR-30e-miR-183-miR-155-miR-199a-miR-199a3p-miR-24-miR-122 and miR-215) were examined using real-time PCR assay. Five proteins involved in the Wnt/b-catenin pathway (b-catenin, APC, c-myc, survivin and cyclin D1) were analysed by immunohistochemistry technique. The correlation between miRNAs expression levels with protein expressions was assessed. Results: Up-regulation of miR-155 and miR-183 was reported in HCC patients compared to normal controls and this up-regulation was significantly correlated with liver cirrhosis in the case of miR-155 (p < 0.05) referring to their oncogenic activity. Down-regulation was observed for 11 miRNAs in HCC indicating their tumour suppression activity. MiRNA-10a, miR-30e, miR-215, miR-125b and miR-148a were significantly correlated with the expression of important players in Wnt/b-catenin pathway including b-catenin, APC and c-myc (p < 0.05). Detailed analysis revealed that miR-215 is associated with the grade of the disease and miR-125b is associated with HCV infection. Conclusion: Collectively, our data showed potential role of miR-10a, miR-30e, miR-215, miR-125b and miR-148a as important mediators in HCC progression. Furthermore, their association with Wnt/ b-catenin cascade proteins could be exploited to develop new therapeutic target strategies in HCC.

International Journal of Ophthalmology

• AIM: To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor ... more • AIM: To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor for success rates in the surgical management of Egyptian congenital glaucoma patients. • METHODS: Totally 42 eyes of 29 primary congenital glaucoma patients were operated on with combined trabeculotomy/trabeculectomy with mitomycin-C and followed up at 1d, 1wk, 1, 6 and 12mo postoperatively. Genomic DNA was extracted from peripheral blood leukocytes. Coding regions of CYP1B1 gene were amplified using 13 pairs of primers, screened for mutations using single-strand conformation polymorphism followed by sequencing of both strands. Efficacy of the operation was graded as either a success [maintaining intraocular pressure (IOP) less than 21 mm Hg with or without antiglaucoma medication], or a failure (IOP more than 21 mm Hg with topical antiglaucoma medications). • RESULTS: Seven novel mutations out of a total of 15 different mutations were found in the CYP1B1 genes of 14 patients (48.2%). The presence of CYP1B1 gene mutations did not correlate with the failure of the surgery (P=0.156, odds ratio=3.611, 95%CI, 0.56 to 22.89); while the positive consanguinity strongly correlated with failure of the initial procedure (P=0.016, odds ratio=11.25, 95%CI, 1.57 to 80.30). However, the Kaplan-Meier survival analysis revealed a significantly lower time of IOP control in the subgroup with mutations in CYP1B1 versus the congenital primary glaucoma group without mutations (log rank test, P=0.015). • CONCLUSION: Seven new CYP1B1 mutations are identified in Egyptian patients. Patients harboring confirmed mutations suffered from early failure of the initial surgery. CYP1B1 mutations could be considered as a prognostic factor for surgery in primary congenital glaucoma.

Journal of Medical Biochemistry

Summary Background To date few reports have pointed out the role of circulating miRNAs in discrim... more Summary Background To date few reports have pointed out the role of circulating miRNAs in discriminating metastatic liver tumors from primary hepatocellular (HCC) tumors. Such discrimination will have significant therapeutic and prognostic implications. The purpose of this study was to evaluate the potential value of a panel of HCC-related circulating miRNAs (miR-142, miR-182, miR-200a, mir-210, miR-211, miR-302b, miR-324, miR-338, miR-340 and miR-1246) as noninvasive biomarkers for discriminating primary HCC from metastatic tumors in the liver. Methods The expression level of the selected miRNAs was quantified by quantitative real time PCR in 33 patients with HCC, 22 patients with metastatic tumors in the liver, and 30 healthy volunteers as control. Mann-Whitney U test was used to evaluate the difference in miRNAs expression between primary and metastatic liver tumors and to study the associations between their relative expression levels and the clinicopathological factors. Receive...

Solid State Phenomena, 2021

Graphene oxide (GO) is an oxidized nanosheets of graphite with a 2D planar structure. GO could be... more Graphene oxide (GO) is an oxidized nanosheets of graphite with a 2D planar structure. GO could be readily complexed with bio-entities as it possesses many oxygen-containing functionalities on its surface. The preparation process is fast, easy, and cost-effective. It was prepared using modified Hummers’ method in acidic solution as a primary solvent and potassium permanganate as an oxidizing agent. Afterwards, it was successfully characterized by FTIR, UV-visible spectroscopy, as well as XRD and Raman spectroscopy, and finally, SEM analysis. It was observed that the formed GO is mainly composed of carbon and oxygen elements rich in oxygen functional groups. Furthermore, the existence of (001) plane in XRD interprets the complete oxidation of graphite with d-spacing 9 Å. Moreover, Raman spectroscopy displayed the sp3 carbon hybridization, besides, the ID/IG ratio is found to be 0.84, which confirms the disorder between graphene oxide layers. The SEM images also pointed out that graph...

Radiation Research, 1994

The goal of these experiments was to investigate further the relationship between DNA double-stra... more The goal of these experiments was to investigate further the relationship between DNA double-strand breaks and cell killing in human tumor cells, first by comparing different cell lines, and second by radiomodification studies. Field-inversion gel electrophoresis was used to quantify double-strand breaks. Two subclones of the radioresistant human squamous cell carcinoma line SQ20B (SQD9 and SQG6) were compared. These subclones differed in DNA index by a factor of 1.7 but showed the same resistance to radiation as cells of the parental cell line. It was found that, although induction of DSBs was not significantly different in the two cell lines, the t1/2 of the fast component of repair was significantly shorter for SQD9 cells, leading to greater overall repair which was not reflected in increased survival. Caffeine and cysteamine were tested as modifiers of radiosensitivity, using the radioresistant SQ20B line and the radiosensitive SCC61 cell line. No effect of caffeine was seen when the drug was present only during irradiation. Postirradiation incubations with caffeine, however, resulted in a dose reduction factor greater than 2.0 in cell survival for both cell lines. In contrast, induction of DSBs was reduced by caffeine, and no effect on DSB repair was observed. Cysteamine led to a dose protection factor greater than 1.8 in cell survival in both cell lines. A reduction in induced DSBs was found at high doses corresponding approximately with the increase in cell survival. Over the same (low) dose range, however, the correlation between DSB induction and cell killing was poor. These data indicate that DSB induction does not correlate well with cell killing either for different cell lines, for radiochemical modification (cysteamine) or for some other types of modification (caffeine).

Asian Pacific Journal of Cancer Prevention, 2021

HCC patients received systemic chemotherapeutic agents (Liu et al., 2015). Sorafenib (Nexavar) is... more HCC patients received systemic chemotherapeutic agents (Liu et al., 2015). Sorafenib (Nexavar) is a multikinase inhibitor that targets both RAF and a number of tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs), and platelet-derived growth factor receptor-β (PDGFR-β) (Wilhelm et al., 2005). Despite the fact that sorafenib has been approved in several countries worldwide for advanced HCC patients still yet the drug show unsatisfied clinical outcomes due to its severe

BMC Urology, 2013

Background Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and meta... more Background Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and metastasis. Over-expression of different MMPs in tumor tissues can disturb the homeostasis and increase the level of various body fluids. Many MMPs including high molecular weights (HMWs) were detected in the urine of prostate and bladder cancer patients. Our aim here is to assess the usefulness of HMW MMPs as non invasive biomarkers in bilharzial bladder cancer in Egyptian patients. Methods The activity of different MMPs including HMW species was determined using zymographic analysis technique in the urine samples procured from sixty six bladder cancer patients (bilharzial and non-bilharzial) as well as hundred healthy control subjects. Also, the correlation between these HMW MMPs activities and different clinico-pathological parameters was investigated. Results High frequency of urine MMPs (uMMPs) activity was determined in 63.6% of examined tumor cases, however, none of the control cases ...

Cancer Research, 2016

Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal ... more Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal tumors worldwide, HCC is currently the fifth most common solid tumor worldwide and the fourth important cause of cancer-related death. Eighty percent of new cases found in developing countries as Egypt, but the incidence is increasing in economically developed regions, including Japan, Western Europe, and the United States. It has shown that expression level of different miRNAs was correlated with cellular liver processes such as inflammation, hepatocyte regeneration and apoptosis which indicate their important role in many liver diseases including hepatocellular carcinoma. The main objective of the present study is to correlate between the expression levels of liver specific miRNAs with different mitogen activated protein kinase (MAPK) pathway in primary HCC patients. Patients and Methods: The expression level of miRNA targeting MAPK pathway, Dual-Specificity Phosphatase 16 (DUSP16), c-...

Mutagenesis, Jul 16, 2015

Galectin-4 is a member of the galectin family which consists of 15 galactoside-binding proteins. ... more Galectin-4 is a member of the galectin family which consists of 15 galactoside-binding proteins. Previously, galectin-4 has been shown to have a role in cancer progression and metastasis and it is found upregulated in many solid tumours, including colorectal cancer (CRC). Recently, the role in the metastatic process was suggested to be via promoting cancer cells to adhere to blood vascular endothelium. In the present study, the regulatory region of LGALS4 (galectin-4) in seven colon cell lines was investigated with respect to genetic variation that could be linked to expression levels and therefore a tumourigenic effect. Interestingly, qRT-PCR and sequencing results revealed that galectin-4 upregulation is associated with SNPs rs116896264 and rs73933062. By use of luciferase reporter- and pull-down assays, we confirmed the association between the gene upregulation and the two SNPs. Also, using pull-down assay followed by mass spectrometry, we found that the presence rs116896264 and ...

Hepatitis Monthly, 2016

Background: MicroRNAs (miRNAs) have been repeatedly shown to play important roles in liver pathol... more Background: MicroRNAs (miRNAs) have been repeatedly shown to play important roles in liver pathologies, including hepatitis, liver cirrhosis, and liver cancer. Egypt has the highest hepatitis C virus (HCV) infection rate worldwide, predominantly involving genotype-4. Objectives: In this study, we attempted to characterize the miRNA profile of the poorly studied genotype 4 of HCV in chronically infected Egyptian patients to obtain a better understanding of the disease and its complications and help in the design of better management protocols. Patients and Methods: We analyzed the expression levels of a selected panel of 94 miRNAs in fresh liver biopsies collected from 50 Egyptian patients diagnosed with chronic HCV infection using quantitative real-time polymerase chain reaction (PCR) assay. Nonparametric tests were used to analyze the expression level of each miRNA and association with the clinicopathological features of enrolled patients in this study. Results: Our results revealed differential expression levels of the analyzed miRNAs compared to the normal controls. Twenty-seven miRNAs (including miR-105, miR-147, miR-149-3p, and miR-196b) showed up-regulation, while 17 miRNAs (including miR-21, miR-122, miR-199a-3p, and miR-223) showed down-regulation. An inverse correlation was observed between levels of miR-95, miR-130a, and miR-142-5p with the blood albumin level. Increased expression levels of seven miRNAs (miR-29c, miR-30c, miR-126, miR-145, miR-199a, miR-199a-3p, and miR-222) were observed with severe chronic hepatic inflammation. Several deregulated miRNAs found in this study have been previously linked to chronic liver inflammation and the risk of hepatocellular carcinoma (HCC) development. Conclusions: The identified expression profiles of some examined miRNAs might offer important points to consider for the treatment of naive patients and the management of chronically infected HCV patients in Egypt and around the world.

Molecular and cellular biochemistry, 2012

Breast cancer (BC) is the most common neoplasm among women in most developed countries, including... more Breast cancer (BC) is the most common neoplasm among women in most developed countries, including Egypt. Elevated levels of certain proteins in human BC are associated with unfavorable prognosis and progressive stages of the disease. The aim of our study was to evaluate the protein expression profile and prognostic significance of cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2), MMP-9 and membrane type 1-MMP (MT1-MMP) and their interaction in operable BC patients. The protein expression of COX-2, MMP-2 and MT1-MMP were evaluated by western blot technique, whereas enzymatic activity of MMP-2 and MMP-9 was determined by zymography in 47 breast cancer patients as well as normal adjacent tissues. Also, the correlation between these proteins and age, tumor size, LN stage, TNM stage, estrogen receptor, progesterone receptor, disease-free survival, and overall survival (OS) has been investigated. As compared to adjacent normal tissues, COX-2, MMP-2 and MT1-MMP were over-expres...

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcrip... more MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through post-transcriptional interactions with mRNA. MiRNAs have recently considered as key regulators of various cancers including liver cancer. Sorafenib is one of the antitumor drugs for the treatment of advanced hepatocellular carcinoma. It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. This study tries to investigate a potential microRNA-based mechanism of action of the drug by studying the effect of sorafenib on miR-23a and miR-24 levels in HCC cell lines HepG2 /Huh7 and revealing the possible drug mechanism against these oncogenic miRNAS in this study cell viability of cultured HepG2 /Huh7 after treatment with sorafenib were evaluated using Sulphorhodamine-B (SRB) assay, cell cycle and apoptosis estimated by flow cytometry assay. The caspase-3 level was determined using the ELISA assay. Moreover, miR-23a and miR-24 expressions levels analyzed by qPCR. Finally, TGF-β le...

Arab Journal of Gastroenterology

Cells

Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its act... more Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastas...

Nutrition and Cancer

Abstract Targeting altered metabolism in cancer provides a promising preventive and therapeutic a... more Abstract Targeting altered metabolism in cancer provides a promising preventive and therapeutic approach. Natural products interplay between gene expression and metabolism either by targeting altered metabolic enzymes and/or affecting the regulating miRNAs. Licorice is a widely known product used as flavoring agent. Glycyrrhizin and other metabolites were reported to exert several metabolic benefits. Here, we investigated the effect of licorice roots extract on some metabolic pathways and their regulating miRNAs in hepatocellular carcinoma cells. Our data showed various beneficial effects of licorice roots extract including induction of apoptosis and cell cycle arrest. Second, upregulating tumor suppressor miRNAs; let7a-3p, miR-34c-5p, miR-122-5p, miR-126-3p, miR195-5p, miR-199a-5p, miR-206, and miR-326-5p. Third, inhibiting HIF1α, PI3K and C-Myc and activating AMPK and p53. Fourth, inhibiting enzymes of glycolysis; HK-2, LDH-A and PK-M2; pentose phosphate pathway; G6PD and glutaminolysis; glutaminase. However, such an extract upregulated oncogenic miRNAs; miR-21, miR-221, and miR-222. Although the present data highlights the ability of licorice roots extract to enhance apoptosis and cell cycle arrest and correct altered metabolism, it warns against its unfavorable effects, hence, its use for prevention and therapy should proceed with caution. Further experiments are required to investigate whether a specific bioactive ingredient is responsible for upregulating the oncogenic miRNAs.

Anti-Cancer Agents in Medicinal Chemistry

Background: Doxorubicin (DOX) is the most common drugs used in cancer therapy, including Hepatoce... more Background: Doxorubicin (DOX) is the most common drugs used in cancer therapy, including Hepatocellular Carcinoma (HCC). Drug resistance, is one of chemotherapy’s significant problems. Emerging studies have shown that microRNAs (miRNAs) could participate in regulating this mechanism. Nevertheless, the impact of miRNAs on HCC chemoresistance is still enigmatic. Objective: Investigating the role of miR-520c-3p in enhancement of anti-tumor effect of DOX against HepG2 cells. Methods: Expression profile for liver related miRNAs (384 miRNAs) has been analyzed on HepG2 cells treated with DOX using qRT-PCR. miR-520c-3p, the most deregulated miRNA, was selected for combination treatment with DOX. Expression level for LEF1, CDK2, CDH1, VIM, Mcl-1 and TP53 was evaluated in miR-520c-3p transfected cells. Cell viability, colony formation, wound healing as well as apoptosis assays have been demonstrated. Furthermore, Mcl-1 protein level was measured using western blot technique. Results: The pres...

The Medical Journal of Cairo University

Background: Epigenetic gene regulation is important in human cancer. Aim of Study: We investigate... more Background: Epigenetic gene regulation is important in human cancer. Aim of Study: We investigated the possible role of acetylation level in the regulation of microRNAs (miRNAs) expression in hepatocellular carcinoma. Material and Methods: We first determined the inhibitory concentration (IC20, IC35 and IC50) of the histone deacetylase inhibitor Sodium Butyrate (SB) in HepG2 and Huh7 cells. Then, we analyzed the expression level of five miRNAs (miR-133b, miR-122-5p, miR-26a-5p, miR-539-5p and miR-518f-3p after treatment using qRT-PCR assay. MiRTarBase, MiROB and GeneCards databases were used for the identification of strong validated targets of examined microRNAs, and the detection of possible functions of the selected targets and related pathways. Results: SB revealed an anti-proliferative effect in both HepG2 and Huh7 cells, with IC50 values of 6.7mM and 9.2mM, respectively. MiR-133b showed up-regulation in HepG2 and miR-122-5p was down-regulated in HepG2 and Huh7 (29.5 and 1000 folds) in a dose dependent manner. MiR-26a-5p exhibited decrease in its level in both cell lines at IC35, but was increased at IC50 in HepG2 cells. MiR-518f-3p showed increase in its level during various doses of SB in both cell lines. Finally, miR-539-5p showed down expression in both cell lines. Prediction pathway analysis referred to the important role of each of miR-133b, miR-122-5p and miR-26a-5p in proliferation, apoptosis, angiogenesis and metastasis. Conclusion: Sub-lethal doses of SB have significant effects on miRNAs expression in human hepatocellular carcinoma cells. Understanding the epigenetic regulation of miRNAs may enhance the development of therapeutic strategies against HCC.

Biochemistry Letters

Triple negative breast cancer PARP, poly ADP-ribose polymerase ATM, ataxia telangiectasia mutated... more Triple negative breast cancer PARP, poly ADP-ribose polymerase ATM, ataxia telangiectasia mutated Background: spotting the scope on triple-negative breast cancer (TNBC) as the most aggressive type of breast cancer, with no targeted therapeutic options. TNBC is often characterized by having defects in DNA repair due to defects in BRCA making this cancer a rational target for the synthetic lethality of olaparib, as an inhibitory target agent of the alternative DNA repair pathway (poly ADP-ribose polymerase "PARP" inhibitor). Objectives: the present study aims to evaluate the value of miRNAs-181a/b as potential biomarkers in predicting the response of TNBC to olaparib. Methods: anti-miRNAs-181a/b was transfected into MDA-MB-231 cell line using HiPerFect transfection reagent, the transfected and untransfected cells were subjected to olaparib. The effect of miRNAs-181a/b on MDA-MB-231 treated cells with olaparib was evaluated through the detection of essential proteins involved in apoptosis and cell proliferation including Caspase-8, Bcl-2, and Ki-67. Further, the expression level of ataxia telangiectasia mutated (ATM) was determined as a functional target of miRNAs-181a/b. Results: a significant decrease in Caspase-8 activity, and Bcl-2, but a significant increase in cell survival, cell proliferation, and ATM protein were observed upon suppression of miRNAs-181a/b by their inhibitors followed by treatment with olaparib for TNBC cell line (MDA-MB-231 cells). Conclusions: our data confirmed that miRNA-181a and miRNA-181b play a critical role for detecting the sensitivity of TNBC cells to olaparib. As well as miRNAs-181a/b could be used as a potentially predictive biomarkers for response to olaparib.

Arab Journal of Gastroenterology

Background and study aims: Hepatocellular carcinoma (HCC) is one of the most common cancers world... more Background and study aims: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with highest incidence in Asia and Africa. MicroRNAs (miRNAs), a class of non-coding single stranded RNA, which not only post transcriptionally regulate gene expression but also respond to signaling molecules to affect cell functions such as Wnt/b-catenin signaling specifically in HCC. The goal of this study is to investigate the crosstalk between Wnt/b-catenin signaling proteins and microRNAs expression in HCC patients. Patients and methods: Fresh tissue samples of 30 primary HCC patients and 10 control subjects were included. Expression level of 13 different miRNAs (miR-10a-miR-106b-miR-99a-miR-148a-miR-125b-miR-30e-miR-183-miR-155-miR-199a-miR-199a3p-miR-24-miR-122 and miR-215) were examined using real-time PCR assay. Five proteins involved in the Wnt/b-catenin pathway (b-catenin, APC, c-myc, survivin and cyclin D1) were analysed by immunohistochemistry technique. The correlation between miRNAs expression levels with protein expressions was assessed. Results: Up-regulation of miR-155 and miR-183 was reported in HCC patients compared to normal controls and this up-regulation was significantly correlated with liver cirrhosis in the case of miR-155 (p < 0.05) referring to their oncogenic activity. Down-regulation was observed for 11 miRNAs in HCC indicating their tumour suppression activity. MiRNA-10a, miR-30e, miR-215, miR-125b and miR-148a were significantly correlated with the expression of important players in Wnt/b-catenin pathway including b-catenin, APC and c-myc (p < 0.05). Detailed analysis revealed that miR-215 is associated with the grade of the disease and miR-125b is associated with HCV infection. Conclusion: Collectively, our data showed potential role of miR-10a, miR-30e, miR-215, miR-125b and miR-148a as important mediators in HCC progression. Furthermore, their association with Wnt/ b-catenin cascade proteins could be exploited to develop new therapeutic target strategies in HCC.

International Journal of Ophthalmology

• AIM: To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor ... more • AIM: To identify CYP1B1 gene mutations and evaluate their possible role as a prognostic factor for success rates in the surgical management of Egyptian congenital glaucoma patients. • METHODS: Totally 42 eyes of 29 primary congenital glaucoma patients were operated on with combined trabeculotomy/trabeculectomy with mitomycin-C and followed up at 1d, 1wk, 1, 6 and 12mo postoperatively. Genomic DNA was extracted from peripheral blood leukocytes. Coding regions of CYP1B1 gene were amplified using 13 pairs of primers, screened for mutations using single-strand conformation polymorphism followed by sequencing of both strands. Efficacy of the operation was graded as either a success [maintaining intraocular pressure (IOP) less than 21 mm Hg with or without antiglaucoma medication], or a failure (IOP more than 21 mm Hg with topical antiglaucoma medications). • RESULTS: Seven novel mutations out of a total of 15 different mutations were found in the CYP1B1 genes of 14 patients (48.2%). The presence of CYP1B1 gene mutations did not correlate with the failure of the surgery (P=0.156, odds ratio=3.611, 95%CI, 0.56 to 22.89); while the positive consanguinity strongly correlated with failure of the initial procedure (P=0.016, odds ratio=11.25, 95%CI, 1.57 to 80.30). However, the Kaplan-Meier survival analysis revealed a significantly lower time of IOP control in the subgroup with mutations in CYP1B1 versus the congenital primary glaucoma group without mutations (log rank test, P=0.015). • CONCLUSION: Seven new CYP1B1 mutations are identified in Egyptian patients. Patients harboring confirmed mutations suffered from early failure of the initial surgery. CYP1B1 mutations could be considered as a prognostic factor for surgery in primary congenital glaucoma.

Journal of Medical Biochemistry

Summary Background To date few reports have pointed out the role of circulating miRNAs in discrim... more Summary Background To date few reports have pointed out the role of circulating miRNAs in discriminating metastatic liver tumors from primary hepatocellular (HCC) tumors. Such discrimination will have significant therapeutic and prognostic implications. The purpose of this study was to evaluate the potential value of a panel of HCC-related circulating miRNAs (miR-142, miR-182, miR-200a, mir-210, miR-211, miR-302b, miR-324, miR-338, miR-340 and miR-1246) as noninvasive biomarkers for discriminating primary HCC from metastatic tumors in the liver. Methods The expression level of the selected miRNAs was quantified by quantitative real time PCR in 33 patients with HCC, 22 patients with metastatic tumors in the liver, and 30 healthy volunteers as control. Mann-Whitney U test was used to evaluate the difference in miRNAs expression between primary and metastatic liver tumors and to study the associations between their relative expression levels and the clinicopathological factors. Receive...