Biological and Clinicopathological Significance of Cripto-1 Expression in the Progression of Human ESCC
Reports of biochemistry & molecular biology, 2017
Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic s... more Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic stem cell maintenance, and tumor progression. It also participates in multiple cell signaling pathways including Wnt, Notch, and TGF-β. Remarkably, it is expressed in cancer stem cell (CSC) compartments, boosting tumor cell migration, invasion, and angiogenesis. Although Cripto-1 is overexpressed in a variety of human malignant tumors, its expression in esophageal squamous cell carcinoma (ESCC) remains unclear. Our aim in this study was to evaluate the possible oncogenic role of Cripto-1 in ESCC progression and elucidate its association with clinicopathological parameters in patients. In this study, Cripto-1 expression in 50 ESCC tissue samples was analyzed and compared to corresponding margin-normal esophageal tissues using quantitative real-time PCR. Cripto-1 was overexpressed in nearly 40% of ESCC samples compared with normal tissue samples. Significant correlations were observed betwe...
BRUCE Protein, New Marker for Targeted Therapy of Gastric Carcinoma
Journal of Gastrointestinal Cancer, 2016
Evading apoptosis is one of the major hallmarks of cancer cells. Inhibitors of apoptosis (IAPs) p... more Evading apoptosis is one of the major hallmarks of cancer cells. Inhibitors of apoptosis (IAPs) proteins are considered as a most important gene families involved in apoptosis. BRUCE protein, a member of IAPs, is able to quench apoptosis as well as playing role in cell division. Our aim in this study was to analyze BRUCE protein expression in gastric carcinoma (GC) and its correlation with the clinicopathological features. Using immunohistochemistry, 52 GC specimens were studied for BRUCE protein expression. A validated scoring method was applied. BRUCE protein expression was detected in majority of tumor tissues (98.07 %). A significant correlation between gender and BRUCE expression (p = 0.024) was detected. Indeed, females showed higher level of BRUCE expression than male patients. Since specific expression of BRUCE protein was revealed in majority of GC tissues, BRUCE protein may be a useful therapeutic target for cancer therapy. Furthermore, based on the native role of BRUCE protein in inhibition of apoptosis, using this protein in targeted therapy of tumor cells may help to inhibit tumor cells growth and survival leading to rapid elimination of tumor mass.
Correlation of Wnt and NOTCH pathways in esophageal squamous cell carcinoma
Journal of Cell Communication and Signaling, 2016
There is an inevitable association between cell signaling pathways and tumorigenesis. Wnt and not... more There is an inevitable association between cell signaling pathways and tumorigenesis. Wnt and notch pathways play important roles during development and self-renewal. Beside the independent role of such pathways on tumor progression, different cross talks between these pathways through tumorigenesis are emphasized. In this study, we analyzed cross talk between Wnt and NOTCH signaling pathways through assessment of probable correlation between MAML1 and PYGO2 as the main transcription factors of these pathways, respectively in esophageal squamous cell carcinoma (ESCC) patients. Levels of MAML1 and PYGO2 mRNA expression in 48 ESCC patients were compared to the correlated margin normal tissues using real-time polymerase chain reaction (PCR). Eleven out of 48 patients (22.9 %) have shown the concomitant MAML1/PYGO2 over expression in significant correlation with tumor size (p = 0.046) and depth of tumor invasion (p = 0.050). We showed that there is a significant correlation and feedback between these markers during the ESCC progression and metastasis.
Role of Brg1 in progression of esophageal squamous cell carcinoma
Iranian Journal of Basic Medical Sciences, Nov 1, 2014
Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes ... more Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing. Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1. Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) compared with normal esophageal tissue of ESCC patients. Rate of transfection in KYSE30 was also between 40 to 50%, using the pSilencer-Brg1shRNA (1:1 ratio). Our data indicated that chromatin remodeling machinery is a novel aspect in tumor biology of ESCC, and overexpression of Brg1 as an important member of SWI/SNF might be involved in the migration and invasion of ESCC tumoral cells.
Role of Msi1 and MAML1 in Regulation of Notch Signaling Pathway in Patients with Esophageal Squamous Cell Carcinoma
Journal of Gastrointestinal Cancer, 2015
Developmental pathways such as Wnt and Notch are involved in different cellular functions from th... more Developmental pathways such as Wnt and Notch are involved in different cellular functions from the cell cycle regulation to self-renewal. Therefore, aberrations in these pathways may cause tumorigenesis. Msi1 has a critical regulatory role for the Wnt and Notch pathways. In the present study, we have assessed the probable correlation between the Msi1 and MAML1 in esophageal squamous cell carcinoma (ESCC) progression and metastasis. Levels of Msi1 and MAML1 mRNA expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction (PCR). Nine out of 51 (17.6 %) cases had Msi1/MAML1 overexpression, and there was a significant correlation between such overexpressed cases and tumor location (p = 0.013). We showed that there is not any direct correlation and feedback between the Msi1 and MAML1 in ESCC patients.
Role of Brg1 in progression of esophageal squamous cell carcinoma
Iranian journal of basic medical sciences, 2014
Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes ... more Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing. Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1. Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) ...
Stem cell biology is one of the most important topics of the century in biology and medicine. Und... more Stem cell biology is one of the most important topics of the century in biology and medicine. Understanding the mechanisms by which stem cells self-regenerate in an undifferentiated state will improve our understanding of human development and diseases. Stem cells are known to have important characteristics such as self-renewal, in which they undergo unlimited asymmetric division [1, 2]. Somatic stem cells are able to maintain and regenerate normal tissues by means of asymmetric and self-renewing divisions; therefore, defects in their proliferation capacity may result in cell aging or tumorigenesis. In contrast to somatic stem cells, other cells within tissues are transient, have limited proliferation, and eventually differentiate.
HES1 as an Independent Prognostic Marker in Esophageal Squamous Cell Carcinoma
Journal of Gastrointestinal Cancer, 2014
Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, a... more Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, and its deregulation may lead to tumorigenesis. In this pathway, targeted to the CSL (CBF1, Suppressor of Hairless or Lag-1) complex, notch intracellular domain (NICD) releases corepressors and recruits MAML1 as coactivator triggering the activation of notch signaling transcription complex. Hairy enhance of split-1 (HES1) is one of the notch signaling target genes which is a basic helix-loop-helix (bHLH) transcription factor acting as a proliferation stimulator through the suppression of cell cycle inhibitors such as p27 and p21. In this study, we aimed to analyze the role of HES1 in the progression of esophageal squamous cell carcinoma (ESCC). Messenger RNA (mRNA) expression of HES1 in fresh tumoral tissues and their margin normal samples were assessed in 50 ESCC patients by real-time polymerase chain reaction (RT-PCR). Thirteen out of 50 cases (26 %) had HES1 underexpression, while HES1 overexpression was observed only in 4 (8 %) samples. HES1 underexpression was significantly correlated with tumor depth of invasion (P = 0.035). Although we have not observed any significant correlation between the HES1 expression and notch activation in ESCC, this study is the first report that elucidated the HES1 underexpression in ESCC and revealed its correlation with the invasiveness of ESCC.
The cancer stem cell theory is considered as the spotlight of cancer biology, in which a subpopul... more The cancer stem cell theory is considered as the spotlight of cancer biology, in which a subpopulation of tumor cells show unlimited proliferative and self renewal capacities. Post-transcriptional regulation is involved in different cellular functions such as cell differentiation and proliferation which results in cellular diversity. Musashi1 (Msi1) is one of the most important RNA-binding proteins (RBPs) which are involved in translational inhibition. Although, Msi1 targets are largely unknown, p21WAF-1, a cell cycle regulator, and Numb, inhibitor of notch signaling pathway, are well-known factors which are suppressed by the Msi1 in normal and cancer stem cells. Msi1 expression in tumor tissues from 53 ESCC patients was compared to normal tissues using realtime polymerase chain reaction (PCR). Msi1 was significantely overexpressed in 41.5 % of tumor samples and we observed a significant correlation between Msi1 expression and sex, in which the males had shown a higher level of Msi1 expression in comparison with the females (2.00 Vs 0.78 fold changes, p =0.05). In this study, we assessed whether Msi1 is expressed in ESCC samples suggesting this protein as a novel cancer stem cell marker which requires further studies.
Only 10 % of cancer-related deaths result from primary tumors; most are caused by metastatic tumo... more Only 10 % of cancer-related deaths result from primary tumors; most are caused by metastatic tumors. It is believed that the metastatic power of tumor cells is attributed to features of a stem cell-like subpopulation of tumor cells known as cancer stem cells (CSCs). Cancer stem cells are resistant to chemotherapeutic treatments and can induce dormancy in tumor cells for long periods. Detection, isolation, and characterization of CSCs in solid tumors are hallmarks of cancer-targeted therapies in recent years. There are inevitable similarities between normal and cancer stem cells; therefore, finding specific methods or markers to differentiate them is critical to cancer therapies. Considering CSCs involvement in tumor relapse and chemotherapeutic resistance, identification of such cells in tumors is imperative for effective targeted therapy. The present review introduces practical and specific protocols used to isolate CSCs from solid tumors from colon, esophagus, liver, breast, brain, and cervix.
Role of hMLH1 and E-Cadherin Promoter Methylation in Gastric Cancer Progression
Journal of Gastrointestinal Cancer, 2013
Gastric cancer (GC) is one of the leading causes of cancer-related death in Iran. Genome stabilit... more Gastric cancer (GC) is one of the leading causes of cancer-related death in Iran. Genome stability is one of the main genetic issues in cancer biology which is governed via the different repair systems such as DNA mismatch repair (MMR). A clear correlation between MMR defects and tumor progression has been shown. Beside the genetic mutations, epigenetic changes also have a noticeable role in MMR defects. Here, we assessed promoter methylation status and the level of hMLH1mRNA expression as the main component of MMR system in 51 GC patients using the methylation-specific PCR and real-time PCR, respectively. Moreover, we performed a promoter methylation study of the E-cadherin gene promoter. It was observed that, 12 out of 39 cases (23.5%) had hMLH1 overexpression. Hypermethylation of hMLH1 and E-cadherin promoter regions were observed in 25.5 and 36.4%, respectively. Although, there was no significant correlation between hMLH1 mRNA expression and clinicopathological features, there are significant correlations between E-cadherin promoter methylation and tumor stage (p = 0.028) and location (p = 0.025). The rate of hMLH1 promoter methylation in this study was lower than that in the other population, showing the importance of the other mechanisms, in gastric tumorigenesis. The results of this study indicate that DNA repair system is adversely affected by hypermethylation of hMLH1 in a fraction of gastric cancer patients. Additionally, E-cadherin hypermethylation seen in a subset of our gastric cancer patients is consistent with other reports showing correlation with aggressiveness and metastasis of gastric cancer.
Wnt signaling is an important evolutionary conserved pathway that is not only involved in determi... more Wnt signaling is an important evolutionary conserved pathway that is not only involved in determination of cellular development, self-renewal, and fate, but also has significant roles in tumor development and progression. Deregulation of the Wnt/b-catenin signaling pathway and aberrant expression of its components is commonly observed in solid tumors. Such aberrant regulation of Wnt signaling is commonly related to either malfunction of its components or crosstalk with other cellular processes such as the epidermal growth factor receptor (EGFR) signaling cascade. Therefore, identification of the roles of major involved components may be useful to identify new therapeutic targets for cancer treatment. In this study, we assessed EGFR and PYGO2 mRNA expression in tumors and margin normal tissues from 55 esophageal squamous cell carcinoma (ESCC) patients using real-time qRT-PCR, and evaluated clinicopathology relative to the two genes' expression levels. Significant PYGO2 and EGFR overexpression was observed in 30.9 % (P = 0.017) and 38.2 % (P = 0.006) of tumors, respectively. PYGO2 and EGFR expression were significantly associated not only with each other (P \ 0.001), but also with tumor staging and depth (P \ 0.001). Furthermore, PYGO2 expression was significantly correlated with the tumor grade (P = 0.043) and size (P = 0.023). We identify PYGO2 as a new molecular marker of invasive tumors, introducing its probable oncogenic role in ESCC progression and aggressiveness. In line with other reports, we also illustrate the oncogenic function of EGFR in the development of ESCC through advance stages. We also observed a significant correlation between PYGO2 and EGFR in ESCC tumors, which reveals a mutual convergent influence of these factors in tumor progression and development. Considering aberrant expression, mutual positive feedback, and the significant clinical relevance of these genes in ESCC, we introduce them as appropriate therapeutic targets in adjuvant therapy of ESCC.
Cancer cells have countless behaviors of pluripotent embryonic stem cells and germ line cells, su... more Cancer cells have countless behaviors of pluripotent embryonic stem cells and germ line cells, such as unlimited proliferation, self-renewal, and migration. Expression of specific germ line and embryonic genes in tumor cells may be associated with indefinite growth and invasiveness of such cells. Developmental pluripotency factor 2 (DPPA2) and HIWI are two important developmental genes which are involved in embryonic and germ line stem cell properties. Deciphering the role of these genes seems to be necessary for understanding cancer initiation and progression. Tumoral and normal tissues from 46 colorectal cancer (CRC) patients were subjected to gene expression analysis using quantitative real-time reverse transcription-polymerase chain reaction, prior to any therapeutic intervention. Overexpression of DPPA2 and HIWI was detected in 26.1 and 34.8 % of specimens, respectively. Significant correlation between DPPA2 overexpression and lymph node metastasis of the tumor cells (P=0.049) was seen in the samples with advanced stages (III/IV) of the tumor development. HIWI mRNA expression was significantly associated to the depth of tumor invasion (P = 0.020) and the stage of tumorigenesis progression (P=0.030). In samples with overexpression of at least one gene, DPPA2 mRNA expression was significantly correlated to the stage of tumor (P=0.017). In the same samples, a significant correlation was observed between mRNA expression of HIWI and the stage of tumor cells (P=0.034). These results documented the important role of HIWI and DPPA2 in tumorigenesis and also in lymph node metastasis of tumor cells. Further evaluation is required to uncover the detailed role of HIWI and DPPA2 and their interactions in tumorigenesis of CRC.
Porphyrias are rare metabolic hereditary diseases originating from defects in specific enzymes in... more Porphyrias are rare metabolic hereditary diseases originating from defects in specific enzymes involved in the heme biosynthesis pathway. Congenital erythropoietic porphyria (CEP) is the rarest autosomal recessive porphyria resulting from a deficiency of uroporphyrinogen III cosynthase (UROS), the fourth enzyme in heme biosynthesis. CEP leads to an excessive production and accumulation of type I porphyrins in bone marrow, skin and several other tissues. Clinical manifestations are presented in childhood with severe cutaneous photosensitivity, blistering, scarring and deformation of the hands and the loss of eyebrows and eyelashes. Less than 200 cases of CEP have been reported to date. Four CEP patients and their family members were studied for the first time in Iran. A missense mutation in the UROS gene was identified in this family. A, T to C change at nucleotide 34313, leading to a substitution of Leucine by Proline at codon 237, was observed in the homozygous state in these 4 patients and heterozygous state in their parents. Our data from the Iranian population emphasizes the importance of codon 237 alone, given the rarity of this disease. This fact can be taken into consideration in the mutational analysis of UROS. This work emphasizes the advantages of molecular genetic techniques as diagnostic tools for the detection of clinically asymptomatic heterozygous mutation carriers as well as CEP within families.
Background: Human cancer cells resemble stem cells in expression signatures leading them to share... more Background: Human cancer cells resemble stem cells in expression signatures leading them to share some features, most notably, self-renewal. A complex network of transcription factors and signaling molecules are required for continuance of this trait. SALL4 is a zinc finger transcriptional activator crucial for maintenance of self-renewal in stem cells; however, its expression level has not yet been elucidated in colorectal tumor cells. To determine this level and probable clinicopathological consequences, its expression was analyzed.
Background Colorectal cancer (CRC) remains the third most common cancer in the world. Approximate... more Background Colorectal cancer (CRC) remains the third most common cancer in the world. Approximately in 50 percent of patients, metastatic disease is a major cause of death. Therefore, early diagnosis of CRC is crucial for a successful outcome. For the detection of circulating cancer cells, this study applied a sensitive method that employed specific tumor markers for early detection. Methods A total of 80 blood samples from 40 CRC patients and 40 age-matched healthy controls were collected for the study. The circulating mRNA levels of two CRC tumor markers, tumor endothelial marker 8 (TEM-8) and carcinoembryogenic antigen (CEA) were evaluated using an absolute quantitative real-time PCR assay in a Stratagene Mx-3000P real-time PCR system. GAPDH was used as the endogenous control.
Biological and Clinicopathological Significance of Cripto-1 Expression in the Progression of Human ESCC
Reports of biochemistry & molecular biology, 2017
Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic s... more Human Cripto-1, a member of the EGF-CFC family, is involved in embryonic development, embryonic stem cell maintenance, and tumor progression. It also participates in multiple cell signaling pathways including Wnt, Notch, and TGF-β. Remarkably, it is expressed in cancer stem cell (CSC) compartments, boosting tumor cell migration, invasion, and angiogenesis. Although Cripto-1 is overexpressed in a variety of human malignant tumors, its expression in esophageal squamous cell carcinoma (ESCC) remains unclear. Our aim in this study was to evaluate the possible oncogenic role of Cripto-1 in ESCC progression and elucidate its association with clinicopathological parameters in patients. In this study, Cripto-1 expression in 50 ESCC tissue samples was analyzed and compared to corresponding margin-normal esophageal tissues using quantitative real-time PCR. Cripto-1 was overexpressed in nearly 40% of ESCC samples compared with normal tissue samples. Significant correlations were observed betwe...
BRUCE Protein, New Marker for Targeted Therapy of Gastric Carcinoma
Journal of Gastrointestinal Cancer, 2016
Evading apoptosis is one of the major hallmarks of cancer cells. Inhibitors of apoptosis (IAPs) p... more Evading apoptosis is one of the major hallmarks of cancer cells. Inhibitors of apoptosis (IAPs) proteins are considered as a most important gene families involved in apoptosis. BRUCE protein, a member of IAPs, is able to quench apoptosis as well as playing role in cell division. Our aim in this study was to analyze BRUCE protein expression in gastric carcinoma (GC) and its correlation with the clinicopathological features. Using immunohistochemistry, 52 GC specimens were studied for BRUCE protein expression. A validated scoring method was applied. BRUCE protein expression was detected in majority of tumor tissues (98.07 %). A significant correlation between gender and BRUCE expression (p = 0.024) was detected. Indeed, females showed higher level of BRUCE expression than male patients. Since specific expression of BRUCE protein was revealed in majority of GC tissues, BRUCE protein may be a useful therapeutic target for cancer therapy. Furthermore, based on the native role of BRUCE protein in inhibition of apoptosis, using this protein in targeted therapy of tumor cells may help to inhibit tumor cells growth and survival leading to rapid elimination of tumor mass.
Correlation of Wnt and NOTCH pathways in esophageal squamous cell carcinoma
Journal of Cell Communication and Signaling, 2016
There is an inevitable association between cell signaling pathways and tumorigenesis. Wnt and not... more There is an inevitable association between cell signaling pathways and tumorigenesis. Wnt and notch pathways play important roles during development and self-renewal. Beside the independent role of such pathways on tumor progression, different cross talks between these pathways through tumorigenesis are emphasized. In this study, we analyzed cross talk between Wnt and NOTCH signaling pathways through assessment of probable correlation between MAML1 and PYGO2 as the main transcription factors of these pathways, respectively in esophageal squamous cell carcinoma (ESCC) patients. Levels of MAML1 and PYGO2 mRNA expression in 48 ESCC patients were compared to the correlated margin normal tissues using real-time polymerase chain reaction (PCR). Eleven out of 48 patients (22.9 %) have shown the concomitant MAML1/PYGO2 over expression in significant correlation with tumor size (p = 0.046) and depth of tumor invasion (p = 0.050). We showed that there is a significant correlation and feedback between these markers during the ESCC progression and metastasis.
Role of Brg1 in progression of esophageal squamous cell carcinoma
Iranian Journal of Basic Medical Sciences, Nov 1, 2014
Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes ... more Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing. Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1. Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) compared with normal esophageal tissue of ESCC patients. Rate of transfection in KYSE30 was also between 40 to 50%, using the pSilencer-Brg1shRNA (1:1 ratio). Our data indicated that chromatin remodeling machinery is a novel aspect in tumor biology of ESCC, and overexpression of Brg1 as an important member of SWI/SNF might be involved in the migration and invasion of ESCC tumoral cells.
Role of Msi1 and MAML1 in Regulation of Notch Signaling Pathway in Patients with Esophageal Squamous Cell Carcinoma
Journal of Gastrointestinal Cancer, 2015
Developmental pathways such as Wnt and Notch are involved in different cellular functions from th... more Developmental pathways such as Wnt and Notch are involved in different cellular functions from the cell cycle regulation to self-renewal. Therefore, aberrations in these pathways may cause tumorigenesis. Msi1 has a critical regulatory role for the Wnt and Notch pathways. In the present study, we have assessed the probable correlation between the Msi1 and MAML1 in esophageal squamous cell carcinoma (ESCC) progression and metastasis. Levels of Msi1 and MAML1 mRNA expression in 51 ESCC patients were compared to the normal tissues using real-time polymerase chain reaction (PCR). Nine out of 51 (17.6 %) cases had Msi1/MAML1 overexpression, and there was a significant correlation between such overexpressed cases and tumor location (p = 0.013). We showed that there is not any direct correlation and feedback between the Msi1 and MAML1 in ESCC patients.
Role of Brg1 in progression of esophageal squamous cell carcinoma
Iranian journal of basic medical sciences, 2014
Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes ... more Epigenetic regulation of gene expression can be carried out through chromatin remodeling enzymes such as SWI/SNF. Brg1 also known as SMARCA4 is a catalytic subunit of SWI/SNF, which is necessary for MMPs expression. Matrix metalloproteinases (MMPs) are known as important player enzymes during tumor progression and metastasis. Aberrant epigenetic modification of chromatin should be precisely clarified to reveal probable unknown pathways in ESCC progression. Probable role of Brg1 in ESCC tumorigenesis and metastasis was studied through the assessment of Brg1 mRNA expression in KYSE30, and further evaluation about the biology of Brg1 was performed through the Brg1 silencing. Level of Brg1 mRNA expression in KYSE30 was compared to normal tissues using the real time polymerase chain reaction (PCR). Moreover, KYSE30 cells were transfected with Brg1-siRNA to silence the Brg1. Our results showed for the first time that Brg1 mRNA expression was increased in KYSE30 cell line (ESCC cell line) ...
Stem cell biology is one of the most important topics of the century in biology and medicine. Und... more Stem cell biology is one of the most important topics of the century in biology and medicine. Understanding the mechanisms by which stem cells self-regenerate in an undifferentiated state will improve our understanding of human development and diseases. Stem cells are known to have important characteristics such as self-renewal, in which they undergo unlimited asymmetric division [1, 2]. Somatic stem cells are able to maintain and regenerate normal tissues by means of asymmetric and self-renewing divisions; therefore, defects in their proliferation capacity may result in cell aging or tumorigenesis. In contrast to somatic stem cells, other cells within tissues are transient, have limited proliferation, and eventually differentiate.
HES1 as an Independent Prognostic Marker in Esophageal Squamous Cell Carcinoma
Journal of Gastrointestinal Cancer, 2014
Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, a... more Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, and its deregulation may lead to tumorigenesis. In this pathway, targeted to the CSL (CBF1, Suppressor of Hairless or Lag-1) complex, notch intracellular domain (NICD) releases corepressors and recruits MAML1 as coactivator triggering the activation of notch signaling transcription complex. Hairy enhance of split-1 (HES1) is one of the notch signaling target genes which is a basic helix-loop-helix (bHLH) transcription factor acting as a proliferation stimulator through the suppression of cell cycle inhibitors such as p27 and p21. In this study, we aimed to analyze the role of HES1 in the progression of esophageal squamous cell carcinoma (ESCC). Messenger RNA (mRNA) expression of HES1 in fresh tumoral tissues and their margin normal samples were assessed in 50 ESCC patients by real-time polymerase chain reaction (RT-PCR). Thirteen out of 50 cases (26 %) had HES1 underexpression, while HES1 overexpression was observed only in 4 (8 %) samples. HES1 underexpression was significantly correlated with tumor depth of invasion (P = 0.035). Although we have not observed any significant correlation between the HES1 expression and notch activation in ESCC, this study is the first report that elucidated the HES1 underexpression in ESCC and revealed its correlation with the invasiveness of ESCC.
The cancer stem cell theory is considered as the spotlight of cancer biology, in which a subpopul... more The cancer stem cell theory is considered as the spotlight of cancer biology, in which a subpopulation of tumor cells show unlimited proliferative and self renewal capacities. Post-transcriptional regulation is involved in different cellular functions such as cell differentiation and proliferation which results in cellular diversity. Musashi1 (Msi1) is one of the most important RNA-binding proteins (RBPs) which are involved in translational inhibition. Although, Msi1 targets are largely unknown, p21WAF-1, a cell cycle regulator, and Numb, inhibitor of notch signaling pathway, are well-known factors which are suppressed by the Msi1 in normal and cancer stem cells. Msi1 expression in tumor tissues from 53 ESCC patients was compared to normal tissues using realtime polymerase chain reaction (PCR). Msi1 was significantely overexpressed in 41.5 % of tumor samples and we observed a significant correlation between Msi1 expression and sex, in which the males had shown a higher level of Msi1 expression in comparison with the females (2.00 Vs 0.78 fold changes, p =0.05). In this study, we assessed whether Msi1 is expressed in ESCC samples suggesting this protein as a novel cancer stem cell marker which requires further studies.
Only 10 % of cancer-related deaths result from primary tumors; most are caused by metastatic tumo... more Only 10 % of cancer-related deaths result from primary tumors; most are caused by metastatic tumors. It is believed that the metastatic power of tumor cells is attributed to features of a stem cell-like subpopulation of tumor cells known as cancer stem cells (CSCs). Cancer stem cells are resistant to chemotherapeutic treatments and can induce dormancy in tumor cells for long periods. Detection, isolation, and characterization of CSCs in solid tumors are hallmarks of cancer-targeted therapies in recent years. There are inevitable similarities between normal and cancer stem cells; therefore, finding specific methods or markers to differentiate them is critical to cancer therapies. Considering CSCs involvement in tumor relapse and chemotherapeutic resistance, identification of such cells in tumors is imperative for effective targeted therapy. The present review introduces practical and specific protocols used to isolate CSCs from solid tumors from colon, esophagus, liver, breast, brain, and cervix.
Role of hMLH1 and E-Cadherin Promoter Methylation in Gastric Cancer Progression
Journal of Gastrointestinal Cancer, 2013
Gastric cancer (GC) is one of the leading causes of cancer-related death in Iran. Genome stabilit... more Gastric cancer (GC) is one of the leading causes of cancer-related death in Iran. Genome stability is one of the main genetic issues in cancer biology which is governed via the different repair systems such as DNA mismatch repair (MMR). A clear correlation between MMR defects and tumor progression has been shown. Beside the genetic mutations, epigenetic changes also have a noticeable role in MMR defects. Here, we assessed promoter methylation status and the level of hMLH1mRNA expression as the main component of MMR system in 51 GC patients using the methylation-specific PCR and real-time PCR, respectively. Moreover, we performed a promoter methylation study of the E-cadherin gene promoter. It was observed that, 12 out of 39 cases (23.5%) had hMLH1 overexpression. Hypermethylation of hMLH1 and E-cadherin promoter regions were observed in 25.5 and 36.4%, respectively. Although, there was no significant correlation between hMLH1 mRNA expression and clinicopathological features, there are significant correlations between E-cadherin promoter methylation and tumor stage (p = 0.028) and location (p = 0.025). The rate of hMLH1 promoter methylation in this study was lower than that in the other population, showing the importance of the other mechanisms, in gastric tumorigenesis. The results of this study indicate that DNA repair system is adversely affected by hypermethylation of hMLH1 in a fraction of gastric cancer patients. Additionally, E-cadherin hypermethylation seen in a subset of our gastric cancer patients is consistent with other reports showing correlation with aggressiveness and metastasis of gastric cancer.
Wnt signaling is an important evolutionary conserved pathway that is not only involved in determi... more Wnt signaling is an important evolutionary conserved pathway that is not only involved in determination of cellular development, self-renewal, and fate, but also has significant roles in tumor development and progression. Deregulation of the Wnt/b-catenin signaling pathway and aberrant expression of its components is commonly observed in solid tumors. Such aberrant regulation of Wnt signaling is commonly related to either malfunction of its components or crosstalk with other cellular processes such as the epidermal growth factor receptor (EGFR) signaling cascade. Therefore, identification of the roles of major involved components may be useful to identify new therapeutic targets for cancer treatment. In this study, we assessed EGFR and PYGO2 mRNA expression in tumors and margin normal tissues from 55 esophageal squamous cell carcinoma (ESCC) patients using real-time qRT-PCR, and evaluated clinicopathology relative to the two genes' expression levels. Significant PYGO2 and EGFR overexpression was observed in 30.9 % (P = 0.017) and 38.2 % (P = 0.006) of tumors, respectively. PYGO2 and EGFR expression were significantly associated not only with each other (P \ 0.001), but also with tumor staging and depth (P \ 0.001). Furthermore, PYGO2 expression was significantly correlated with the tumor grade (P = 0.043) and size (P = 0.023). We identify PYGO2 as a new molecular marker of invasive tumors, introducing its probable oncogenic role in ESCC progression and aggressiveness. In line with other reports, we also illustrate the oncogenic function of EGFR in the development of ESCC through advance stages. We also observed a significant correlation between PYGO2 and EGFR in ESCC tumors, which reveals a mutual convergent influence of these factors in tumor progression and development. Considering aberrant expression, mutual positive feedback, and the significant clinical relevance of these genes in ESCC, we introduce them as appropriate therapeutic targets in adjuvant therapy of ESCC.
Cancer cells have countless behaviors of pluripotent embryonic stem cells and germ line cells, su... more Cancer cells have countless behaviors of pluripotent embryonic stem cells and germ line cells, such as unlimited proliferation, self-renewal, and migration. Expression of specific germ line and embryonic genes in tumor cells may be associated with indefinite growth and invasiveness of such cells. Developmental pluripotency factor 2 (DPPA2) and HIWI are two important developmental genes which are involved in embryonic and germ line stem cell properties. Deciphering the role of these genes seems to be necessary for understanding cancer initiation and progression. Tumoral and normal tissues from 46 colorectal cancer (CRC) patients were subjected to gene expression analysis using quantitative real-time reverse transcription-polymerase chain reaction, prior to any therapeutic intervention. Overexpression of DPPA2 and HIWI was detected in 26.1 and 34.8 % of specimens, respectively. Significant correlation between DPPA2 overexpression and lymph node metastasis of the tumor cells (P=0.049) was seen in the samples with advanced stages (III/IV) of the tumor development. HIWI mRNA expression was significantly associated to the depth of tumor invasion (P = 0.020) and the stage of tumorigenesis progression (P=0.030). In samples with overexpression of at least one gene, DPPA2 mRNA expression was significantly correlated to the stage of tumor (P=0.017). In the same samples, a significant correlation was observed between mRNA expression of HIWI and the stage of tumor cells (P=0.034). These results documented the important role of HIWI and DPPA2 in tumorigenesis and also in lymph node metastasis of tumor cells. Further evaluation is required to uncover the detailed role of HIWI and DPPA2 and their interactions in tumorigenesis of CRC.
Porphyrias are rare metabolic hereditary diseases originating from defects in specific enzymes in... more Porphyrias are rare metabolic hereditary diseases originating from defects in specific enzymes involved in the heme biosynthesis pathway. Congenital erythropoietic porphyria (CEP) is the rarest autosomal recessive porphyria resulting from a deficiency of uroporphyrinogen III cosynthase (UROS), the fourth enzyme in heme biosynthesis. CEP leads to an excessive production and accumulation of type I porphyrins in bone marrow, skin and several other tissues. Clinical manifestations are presented in childhood with severe cutaneous photosensitivity, blistering, scarring and deformation of the hands and the loss of eyebrows and eyelashes. Less than 200 cases of CEP have been reported to date. Four CEP patients and their family members were studied for the first time in Iran. A missense mutation in the UROS gene was identified in this family. A, T to C change at nucleotide 34313, leading to a substitution of Leucine by Proline at codon 237, was observed in the homozygous state in these 4 patients and heterozygous state in their parents. Our data from the Iranian population emphasizes the importance of codon 237 alone, given the rarity of this disease. This fact can be taken into consideration in the mutational analysis of UROS. This work emphasizes the advantages of molecular genetic techniques as diagnostic tools for the detection of clinically asymptomatic heterozygous mutation carriers as well as CEP within families.
Background: Human cancer cells resemble stem cells in expression signatures leading them to share... more Background: Human cancer cells resemble stem cells in expression signatures leading them to share some features, most notably, self-renewal. A complex network of transcription factors and signaling molecules are required for continuance of this trait. SALL4 is a zinc finger transcriptional activator crucial for maintenance of self-renewal in stem cells; however, its expression level has not yet been elucidated in colorectal tumor cells. To determine this level and probable clinicopathological consequences, its expression was analyzed.
Background Colorectal cancer (CRC) remains the third most common cancer in the world. Approximate... more Background Colorectal cancer (CRC) remains the third most common cancer in the world. Approximately in 50 percent of patients, metastatic disease is a major cause of death. Therefore, early diagnosis of CRC is crucial for a successful outcome. For the detection of circulating cancer cells, this study applied a sensitive method that employed specific tumor markers for early detection. Methods A total of 80 blood samples from 40 CRC patients and 40 age-matched healthy controls were collected for the study. The circulating mRNA levels of two CRC tumor markers, tumor endothelial marker 8 (TEM-8) and carcinoembryogenic antigen (CEA) were evaluated using an absolute quantitative real-time PCR assay in a Stratagene Mx-3000P real-time PCR system. GAPDH was used as the endogenous control.
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Papers by Meysam Moghbeli