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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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Potential association of eEF1A dimethylation at lysine 55 in the basal area of Helicobacter pylori-eradicated gastric mucosa with the risk of gastric cancer: a retrospective observational study. BMC Gastroenterol 2022; 22:490. [PMID: 36437464 PMCID: PMC9703661 DOI: 10.1186/s12876-022-02521-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 09/29/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Although eradication therapy for chronic Helicobacter pylori (H. pylori) reduces the risk of gastric cancer (GC), its effectiveness is not complete. Therefore, it is also critically important to identifying those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status, efficacy of eradication therapy, and GC risk in H. pylori-eradicated mucosa, and to reveal the potential downstream molecules of eEF1A dimethylation. METHODS Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9 mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2. RESULTS The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with the negative mucosa (surface, p = 0.0031; basal, p = 0.0036, respectively). The eEF1A dimethyl-levels in the surface area were significantly reduced by eradication therapy (p = 0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio = 3.6611, 95% confidence interval = 1.0350-12.949, p = 0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors, Oct4 and Nanog, by immunohistochemistry and in vitro genome editing experiments. CONCLUSIONS The results indicated that H. pylori infection induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori eradicated-gastric mucosa.
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Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming Towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner. Microorganisms 2020; 8:microorganisms8101519. [PMID: 33023180 PMCID: PMC7599721 DOI: 10.3390/microorganisms8101519] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR−/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMT−RGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMT−RGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm.
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Al-Sadik H, Sugathan S, Saseedharan P, Sulaiman S, Beegam S, Nemmar A, Attoub S, Karam SM. Effects of Diesel Exhaust Particles on Mouse Gastric Stem Cells. Life (Basel) 2020; 10:life10080149. [PMID: 32806566 PMCID: PMC7460091 DOI: 10.3390/life10080149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/31/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023] Open
Abstract
Stem cells have attracted many scientists because of their unique properties and therapeutic applications. However, very little is known on the environmental toxins that could affect their biological features. This study focuses on the consequences of the exposure of a cell line representative of the mouse gastric stem/progenitor (mGS) cells to diesel exhaust particles (DEPs). These immortal cells were cultured using routine protocols. The DEPs were added to the culture media at 1, 10, and 100 µg/mL for 1 to 72 h. The cells were assayed for their viability, migration, oxidative stress, and the expression of genes specific for cell proliferation, pluripotency, and death. DEPs induced a reduction in the metabolic activity of mGS cells, only at a high concentration of 100 µg/mL. However, no significant effects were detected on cell migration, oxidative stress markers (glutathione and thiobarbituric acid reactive substances), and cell death related proteins/genes. Interestingly, these findings were associated with down-regulation of Notch 2 and 3 and Bmi-1 proteins and activation of STAT3 involved in the regulation of the fate of stem cells. In conclusion, this study demonstrates that mGS cells have some resistance to oxidative stress and apoptosis when exposed to DEPs at the expense of their stemness.
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Affiliation(s)
- Heba Al-Sadik
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (H.A.-S); (S.S.); (P.S.)
| | - Subi Sugathan
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (H.A.-S); (S.S.); (P.S.)
| | - Prashanth Saseedharan
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (H.A.-S); (S.S.); (P.S.)
| | - Shahrazad Sulaiman
- Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (S.S.); (S.A.)
| | - Sumaya Beegam
- Department of Physiology, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (S.B.); (A.N.)
| | - Abderrahim Nemmar
- Department of Physiology, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (S.B.); (A.N.)
- Zayed Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE
| | - Samir Attoub
- Department of Pharmacology and Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (S.S.); (S.A.)
- Zayed Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE
| | - Sherif M. Karam
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, UAE; (H.A.-S); (S.S.); (P.S.)
- Zayed Center for Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE
- Correspondence: ; Tel.: +971-3-713-7493
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El-Guindy DM, Wasfy RE, Abdel Ghafar MT, Ali DA, Elkady AM. Oct4 expression in gastric carcinoma: association with tumor proliferation, angiogenesis and survival. J Egypt Natl Canc Inst 2019; 31:3. [PMID: 32372156 DOI: 10.1186/s43046-019-0005-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 09/20/2019] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Octamer-binding transcription factor 4 (Oct4) is a transcription factor that has an important role in stem cell differentiation and self-renewal. Oct4 has also been implicated in tumorigenicity of different cancers. This study aimed to analyze Oct4 expression in gastric carcinoma (GC) and to evaluate the relation between Oct4 expression and clinicopathologic parameters, tumor proliferation, and angiogenesis in addition to patient survival. RESULTS Oct4 mRNA was detected by quantitative reverse transcription PCR (qRT-PCR) in 45 GC specimens and adjacent non-cancerous tissues. We found a significant difference in Oct4 mRNA relative expression levels in GC tissue compared with adjacent non-cancerous tissues (p < 0.001). Furthermore, immunohistochemistry (IHC) was performed to study the Oct4 expression in GC cases. High Oct4 immunostaining was detected in 62.2% of GC specimens. High Oct4 expression both by mRNA relative quantitation and IHC were significantly related to poorly differentiated tumors, nodal metastasis, and stage III tumors. Moreover, high Oct4 IHC expression was also associated with cases positive for Ki-67 and VEGF expressions (p < 0.001 and 0.021, respectively). Oct4 expression identified by both mRNA relative quantitation and IHC was significantly related (p < 0.001). As regards patient survival, high Oct4 expression was significantly related to poor overall survival (OS) and disease-free survival (DFS) (p = 0.029 and 0.031, respectively). CONCLUSION Oct4 plays a valuable role in the progression and prognosis of GC. High Oct4 expression is associated with high tumor grade, nodal metastasis, stage III tumors, and poor OS and DFS. High Oct4 is also significantly associated with Ki-67 and VGEF expression, thus enhancing tumor proliferation and angiogenesis.
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Affiliation(s)
- Dina M El-Guindy
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Rania E Wasfy
- Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Dina A Ali
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Asmaa M Elkady
- Clinical Oncology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Czerwińska P, Mazurek S, Wiznerowicz M. Application of induced pluripotency in cancer studies. Rep Pract Oncol Radiother 2018; 23:207-214. [PMID: 29760595 DOI: 10.1016/j.rpor.2018.04.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 02/20/2018] [Accepted: 04/08/2018] [Indexed: 12/13/2022] Open
Abstract
As soon as induced pluripotent stem cells (iPSCs) reprogramming of somatic cells were developed, the discovery attracted the attention of scientists, offering new perspectives for personalized medicine and providing a powerful platform for drug testing. The technology was almost immediately applied to cancer studies. As presented in this review, direct reprogramming of cancer cells with enforced expression of pluripotency factors have several basic purposes, all of which aim to explain the complex nature of cancer development and progression, therapy-resistance and relapse, and ultimately lead to the development of novel anti-cancer therapies. Here, we briefly present recent advances in reprogramming methodologies as well as commonalities between cell reprogramming and carcinogenesis and discuss recent outcomes from the implementation of induced pluripotency into cancer research.
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Affiliation(s)
- Patrycja Czerwińska
- Laboratory of Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
| | - Sylwia Mazurek
- Laboratory of Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Wiznerowicz
- Laboratory of Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland
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You L, Guo X, Huang Y. Correlation of Cancer Stem-Cell Markers OCT4, SOX2, and NANOG with Clinicopathological Features and Prognosis in Operative Patients with Rectal Cancer. Yonsei Med J 2018; 59:35-42. [PMID: 29214774 PMCID: PMC5725361 DOI: 10.3349/ymj.2018.59.1.35] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/08/2017] [Accepted: 10/03/2017] [Indexed: 02/07/2023] Open
Abstract
PURPOSE To investigate the association of cancer stem-cell markers [octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2), and Nanog homebox (NANOG)] expression with clinicopathological properties and overall survival (OS) in operative rectal cancer (RC) patients receiving adjuvant therapy. MATERIALS AND METHODS 153 patients with primary RC receiving surgery were enrolled. Tumor tissue and paired adjacent normal tissue sample were collected, and OCT4, SOX2, and NANOG expressions were assessed by immunofluorescent staining. The median follow-up duration was 5.2 years, and the last follow-up date was August 2016. RESULTS Tumor tissue OCT4 (p<0.001), SOX2 (p=0.003), and NANOG (p<0.001) expressions were higher than those in adjacent tissue. OCT4 expression was positively correlated with pathological grade (R=0.185, p=0.022), tumor size (R=0.224, p=0.005), and N stage (R=0.170, p=0.036). NANOG expression was positively associated with tumor size (R=0.169, p=0.036). Kaplan-Meier suggested that OCT4⁺ was associated with worse OS compared with OCT4? (p<0.001), while no association of SOX2 (p=0.121) and NANOG expressions (p=0.195) with OS was uncovered. Compared with one or no positive marker, at least two positive markers were associated with shorter OS (p<0.001), while all three positive markers were correlated with worse OS compared with two or less positive markers (p<0.001). Multivariate Cox's analysis revealed that OCT4⁺ (p<0.001) and N stage (p=0.046) were independent factors for shorter OS. CONCLUSION Tumor tissue OCT4 expression was correlated with poor differentiation, tumor size, and N stage, and it can serve as an independent prognostic biomarker in operative patients with RC receiving adjuvant therapy.
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Affiliation(s)
- Liuping You
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin Guo
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yuenan Huang
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
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Javanbakht M, Akhavanmoghadam J, Talaei AJ, Aghyani M, Mozafari M, Khedmat L, Mohebbi M. Differential expression of two genes Oct-4 and MUC5AC associates with poor outcome in patients with gastric cancer. Clin Exp Pharmacol Physiol 2017; 44:1099-1105. [PMID: 28762513 DOI: 10.1111/1440-1681.12840] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 07/10/2017] [Accepted: 07/25/2017] [Indexed: 12/22/2022]
Abstract
Gastric cancer (GC) is the most frequent leading cause of cancer-associated mortality worldwide that is linked to poor prognosis due to the lack of appropriate biomarkers. Our aim was to evaluate the MUC5AC and Oct-4 expression levels in GC and to assess their association with clinical factors. Immunohistochemical analysis (IHC) and qRT-PCR were performed in GC patients to examine the MUC5AC and Oct-4 expression levels. The mRNA level of MUC5AC was significantly decreased in tumour tissues compared with non-cancerous tissues (1.11 ± 0.69 vs 3.7 ± 0.71; P = .024). On the other hand, Oct-4 mRNA level was upregulated in tumour tissues as compared to normal tissues (2. 86 ± 0.78 vs 0.87 ± 0.54; P = .0015). Decreased expression of MUC5AC was detected in 27 patients (67.5%), while high to moderate expression levels were observed in 13 cases (32.5%), but in normal tissues the expression levels of MUC5AC were increased (P = .001). The decreased expression of MUC5AC was associated with aggressive tumour characteristics, such as TNM stage (P = .023), histologic type (P = .012) and lymph node metastasis (P = .001). High expression of Oct-4 was detected in 24 tumour tissues (60%), while 16 cases (40%) showed low expression level. Increased Oct-4 expression was correlated with clinicopathological characteristics such TNM stage (P = .002), histologic type (P = .008) and lymph node metastasis (P = .001). Our results showed that high Oct-4 expression and the reduction of MUC5AC expression may be involved in the progression and an unfavorable prognosis of GC.
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Affiliation(s)
- Milad Javanbakht
- School of Medicine Science, Islamic Azad University, Sarab, Iran
| | - Jamal Akhavanmoghadam
- Trauma Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR, Iran
| | - Amir Jouya Talaei
- Department of Genetics, Faculty of Life Science, Azad University of Tehran Medical Sciences Branch, Tehran, Iran
| | - Maryam Aghyani
- General practitioner (GP), Doctor of Medicine (MD), Tehran and Tabriz, Iran
| | - Mohamad Mozafari
- General practitioner (GP), Doctor of Medicine (MD), Tehran and Tabriz, Iran.,Graduated from Tabriz University of Medical Science, Tabriz, Iran
| | - Leila Khedmat
- Department of Social Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Mohebbi
- General practitioner (GP), Doctor of Medicine (MD), Tehran and Tabriz, Iran
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Chen Z, Zhang L, Zhu Q, Wang X, Wu J, Wang X. Clinical value of octamer-binding transcription factor 4 as a prognostic marker in patients with digestive system cancers: A systematic review and meta-analysis. J Gastroenterol Hepatol 2017; 32:567-576. [PMID: 28320060 DOI: 10.1111/jgh.13624] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Revised: 09/10/2016] [Accepted: 09/27/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM The role of octamer-binding transcription factor 4 (Oct4) has been implicated in the clinical prognosis of various kinds of digestive system cancers, but the results remain controversial. The purpose of this meta-analysis is to assess the potential role of Oct4 as a prognostic marker in digestive system tumors. METHODS Relevant articles were retrieved from Pubmed, Web of Science, and Cochrane Library up to July 2016. The software Stata 12.0 was used to analyze the outcomes, including overall survival (OS), disease-free survival, recurrence-free survival, and clinicopathological characteristics. RESULTS A total of 13 eligible studies with 1538 patients were included. Elevated Oct4 expression was significantly associated with poor OS (pooled hazard ratio [HR] = 2.183, 95% confidence interval [CI]: 1.824-2.612), disease-free survival (pooled HR = 1.973, 95% CI: 1.538-2.532), and recurrence-free survival (pooled HR = 2.209, 95% CI: 1.461-3.338) of digestive system malignancies. Subgroup analyses showed that cancer type, sample size, study quality, and laboratory detection method did not alter the significant prognostic value of Oct4. Additionally, Oct4 expression was found to be an independent predictive factor for OS (HR = 2.068, 95% CI: 1.633-2.619). No significant association was found between Oct4 and clinicopathological features of digestive system malignancies. CONCLUSION This study provided evidence of Oct4 and/or its closely related homolog protein as a predictive factor for patients with digestive system cancers. More large-scale clinical studies on the prognostic value of Oct4 are warranted.
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Affiliation(s)
- Zhiqiang Chen
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Long Zhang
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qin Zhu
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaowei Wang
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jindao Wu
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xuehao Wang
- Key Laboratory on Living Donor Liver Transplantation of Ministry of Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Hashimoto I, Nagata T, Sekine S, Moriyama M, Shibuya K, Hojo S, Matsui K, Yoshioka I, Okumura T, Hori T, Shimada Y, Tsukada K. Prognostic significance of KLF4 expression in gastric cancer. Oncol Lett 2016; 13:819-826. [PMID: 28356964 DOI: 10.3892/ol.2016.5499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 11/07/2016] [Indexed: 12/21/2022] Open
Abstract
To understand the roles of pluripotent stem cell-inducing genes in gastric cancer, the expression of Krüppel-like factor 4 (KLF4), Nanog, octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc) and sex-determining region Y-box 2 (SOX2) was examined using the newly developed gastric carcinoma tissue microarray. The associations between the immunohistochemical expression levels of the pluripotency-inducing factors and the clinicopathological data of 108 patients with gastric cancer were analyzed. No associations were identified between the expression levels of the five pluripotency-inducing factors and the tumor-node-metastasis (TNM) classification or clinicopathological characteristics of the patients. In addition, multivariate analysis revealed no association of Nanog, Oct4, SOX2 or c-Myc with the prognosis of the gastric cancer patients; however, low expression of KLF4 was determined to be an independent negative prognostic factor (P=0.0331), particularly in patients who underwent R0 resection (TNM stages 2 and 3; P=0.0048). In summary, low KLF4 expression was found to be negatively associated with overall survival, and may therefore be a useful prognostic marker in gastric cancer patients.
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Affiliation(s)
- Isaya Hashimoto
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Takuya Nagata
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Shinichi Sekine
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Makoto Moriyama
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Kazuto Shibuya
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Shozo Hojo
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Koshi Matsui
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Isaku Yoshioka
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Tomoyuki Okumura
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
| | - Takashi Hori
- Department of Pathology, Graduate School of Research into Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Yutaka Shimada
- Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8304, Japan
| | - Kazuhiro Tsukada
- Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama 930-0194, Japan
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Tan X, Wu X, Ren S, Wang H, Li Z, Alshenawy W, Li W, Cui J, Luo G, Siegel RS, Fu SW, Lu Y. A Point Mutation in DNA Polymerase β (POLB) Gene Is Associated with Increased Progesterone Receptor (PR) Expression and Intraperitoneal Metastasis in Gastric Cancer. J Cancer 2016; 7:1472-80. [PMID: 27471563 PMCID: PMC4964131 DOI: 10.7150/jca.14844] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/15/2016] [Indexed: 12/29/2022] Open
Abstract
Increased expression of progesterone receptor (PR) has been reported in gastric cancer (GC). We have previously identified a functional T889C point mutation in DNA polymerase beta (POLB), a DNA repair gene in GC. To provide a detailed analysis of molecular changes associated with the mutation, human cDNA microarrays focusing on 18 signal transduction pathways were used to analyze differential gene expression profiles between GC tissues with T889C mutant in POLB gene and those with wild type. Among the differentially expressed genes, notably, PR was one of the significantly up-regulated genes in T889C mutant POLB tissues, which were subsequently confirmed in POLB gene transfected AGS cell line. Interestingly, patients with T889C mutation and PR positivity were associated with higher incidence of intraperitoneal metastasis (IM). In vitro studies indicate that PR expression was upregulated in AGS cell line when transfected with T889C mutant expression vector. Cotransfection of T889C mutant allele and PR gene induced cell migration in the cell line. These data demonstrated that T889C mutation-associated PR overexpression results in increased IM. Therefore, T889C mutation-associated PR overexpression may serve as a biomarker for an adverse prognosis for human GC.
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Affiliation(s)
- Xiaohui Tan
- 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China;; 6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA
| | - Xiaoling Wu
- 2. Department of Gastroenterology, The Chengdu Military General Hospital, Chengdu, China;; 6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA
| | - Shuyang Ren
- 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
| | - Hongyi Wang
- 3. Department of Sugary, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
| | - Zhongwu Li
- 4. Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
| | - Weaam Alshenawy
- 6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA
| | - Wenmei Li
- 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
| | - Jiantao Cui
- 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
| | - Guangbin Luo
- 5. Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Robert S Siegel
- 6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA
| | - Sidney W Fu
- 6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA
| | - Youyong Lu
- 1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China
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12
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Chirco KR, Tucker BA, Stone EM, Mullins RF. Selective accumulation of the complement membrane attack complex in aging choriocapillaris. Exp Eye Res 2016; 146:393-397. [PMID: 26368849 PMCID: PMC4788569 DOI: 10.1016/j.exer.2015.09.003] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 08/14/2015] [Accepted: 09/09/2015] [Indexed: 12/22/2022]
Abstract
The complement membrane attack complex (MAC) shows increased abundance in the choriocapillaris during normal aging and is especially prevalent in age-related macular degeneration (AMD). While perivascular MAC accumulation occurs in the choroid, it is not well understood whether similar deposition occurs in other aging tissues. In this study we examined the abundance of MAC across multiple human tissues. For studies on fixed tissues, paraffin sections were obtained from six human donor eyes and a commercially available tissue array containing 19 different tissues. Immunohistochemical labeling was performed using antibodies directed against the MAC and intercellular adhesion molecule-1 (ICAM-1), as well as the lectin Ulex europaeus agglutinin-I (UEA-I). The choriocapillaris was the only tissue with high levels of the MAC, which was not detected in any of the 38 additional samples from 19 tissues. ICAM-1 was abundantly expressed in the majority of tissues evaluated, and UEA-I labeled the vasculature in all tissues. A second experiment was performed using unfixed frozen sections of RPE-choroid and 7 extraocular tissues, which confirmed the relatively limited localization of the MAC to the choriocapillaris. In comparison to other tissues assessed, the restricted accumulation of MAC in the choriocapillaris may, in part, explain the specificity of AMD to the neural retina, RPE and choroid, and the relative absence of systemic pathology in this disease.
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Affiliation(s)
- Kathleen R Chirco
- The Stephen A. Wynn Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Budd A Tucker
- The Stephen A. Wynn Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Edwin M Stone
- The Stephen A. Wynn Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA
| | - Robert F Mullins
- The Stephen A. Wynn Institute for Vision Research and the Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, USA.
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13
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Müller M, Hermann PC, Liebau S, Weidgang C, Seufferlein T, Kleger A, Perkhofer L. The role of pluripotency factors to drive stemness in gastrointestinal cancer. Stem Cell Res 2016; 16:349-57. [PMID: 26896855 DOI: 10.1016/j.scr.2016.02.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 01/19/2016] [Accepted: 02/01/2016] [Indexed: 12/28/2022] Open
Abstract
A better molecular understanding of gastrointestinal cancers arising either from the stomach, the pancreas, the intestine, or the liver has led to the identification of a variety of potential new molecular therapeutic targets. However, in most cases surgery remains the only curative option. The intratumoral cellular heterogeneity of cancer stem cells, bulk tumor cells, and stromal cells further limits straightforward targeting approaches. Accumulating evidence reveals an intimate link between embryonic development, stem cells, and cancer formation. In line, a growing number of oncofetal proteins are found to play common roles within these processes. Cancer stem cells share features with true stem cells by having the capacity to self-renew in a de-differentiated state, to generate heterogeneous types of differentiated progeny, and to give rise to the bulk tumor. Further, various studies identified genes in cancer stem cells, which were previously shown to regulate the pluripotency circuitry, particularly the so-called "Yamanaka-Factors" (OCT4, KLF4, SOX2, and c-MYC). However, the true stemness potential of cancer stem cells and the role and expression pattern of such pluripotency genes in various tumor cell types remain to be explored. Here, we summarize recent findings and discuss the potential mechanisms involved, and link them to clinical significance with a particular focus on gastrointestinal cancers.
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Affiliation(s)
- Martin Müller
- Department of Internal Medicine I, Ulm University, Ulm, Germany
| | | | - Stefan Liebau
- Institute of Neuroanatomy, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Clair Weidgang
- Department of Anesthesiology, Ulm University Hospital, Ulm, Germany
| | | | - Alexander Kleger
- Department of Internal Medicine I, Ulm University, Ulm, Germany.
| | - Lukas Perkhofer
- Department of Internal Medicine I, Ulm University, Ulm, Germany
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14
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Inagaki-Ohara K, Okamoto S, Takagi K, Saito K, Arita S, Tang L, Hori T, Kataoka H, Matsumoto S, Minokoshi Y. Leptin receptor signaling is required for high-fat diet-induced atrophic gastritis in mice. Nutr Metab (Lond) 2016; 13:7. [PMID: 26839577 PMCID: PMC4736478 DOI: 10.1186/s12986-016-0066-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 01/26/2016] [Indexed: 12/25/2022] Open
Abstract
Background Obesity increases the risk for malignancies in various tissues including the stomach. Atrophic gastritis with precancerous lesions is an obesity-associated disease; however, the mechanisms that underlie the development of obesity-associated atrophic gastritis are unknown. Leptin is a hormone derived from stomach as well as adipose tissue and gastric leptin is involved in the development of gastric cancer. The aim of the current study is to investigate the involvement of leptin receptor signaling in the development of atrophic gastritis during diet-induced obesity. Methods Male C57BL/6, ob/ob and db/db mice were fed a high-fat diet (HFD) or a control diet (CD) from 1 week to 5 months. Pathological changes of the gastric mucosa and the expression of molecules associated with atrophic gastritis were evaluated in these mice. Results HFD feeding induced gastric mucosal hyperplasia with increased gastric leptin expression. Mucosal hyperplasia was accompanied by a higher frequency of Ki67-positive proliferating cells and atrophy of the gastric glands in the presence of inflammation, which increased following HFD feeding. Activation of ObR signaling-associated molecules such as ObR, STAT3, Akt, and ERK was detected in the gastric mucosa of mice fed the HFD for 1 week. The morphological alterations associated with gastric mucosal atrophy and the expression of Muc2 and Cdx2 resemble those associated with human intestinal metaplasia. In contrast to wild-type mice, leptin-deficient ob/ob mice and leptin receptor-mutated db/db mice did not show increased Cdx2 expression in response to HFD feeding. Conclusion Together, these results suggest that activation of the leptin signaling pathway in the stomach is required to develop obesity-associated atrophic gastritis. Electronic supplementary material The online version of this article (doi:10.1186/s12986-016-0066-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Kyoko Inagaki-Ohara
- Research Institute, National Center for Global Health and Medicine (NCGM), 1-21-1, Toyama Shinjuku, Tokyo, 162-0052 Japan ; Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan ; Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara, Hiroshima 727-0023 Japan
| | - Shiki Okamoto
- Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan
| | - Kazuyo Takagi
- Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan
| | - Kumiko Saito
- Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan
| | - Seiya Arita
- Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara, Hiroshima 727-0023 Japan
| | - Lijun Tang
- Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan
| | - Tetsuji Hori
- Yakult Central Institute for Microbiological Research, 5-11 Izumi, Kunitachi, Tokyo, 186-8650 Japan
| | - Hiroaki Kataoka
- Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692 Japan
| | - Satoshi Matsumoto
- Yakult Central Institute for Microbiological Research, 5-11 Izumi, Kunitachi, Tokyo, 186-8650 Japan
| | - Yasuhiko Minokoshi
- Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan
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15
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Jiang WL, Zhang PF, Li GF, Dong JH, Wang XS, Wang YY. Oct-4 is associated with gastric cancer progression and prognosis. Onco Targets Ther 2016; 9:517-22. [PMID: 26869797 PMCID: PMC4734804 DOI: 10.2147/ott.s90031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Aim To investigate the clinical significance of Oct-4 in the development and progression of gastric cancer. Methods Immunohistochemistry was used to analyze Oct-4 expression in 412 gastric cancer cases. Oct-4 protein levels were upregulated in gastric cancer tissues compared with adjacent noncancerous tissues. Results Positive expression of Oct-4 correlated with age, depth of invasion, Lauren classification, lymph node metastasis, distant metastasis, and TNM stage. In stages I, II, and III, the 5-year survival rate of patients with high expression of Oct-4 was significantly lower than that in patients with low expression of Oct-4. In stage IV, Oct-4 expression did not correlate with the 5-year survival rate. Furthermore, multivariate analysis suggested that the depth of invasion, lymph node metastasis, distant metastasis, TNM stage, and upregulation of Oct-4 were independent prognostic factors of gastric cancer. Conclusion Oct-4 protein is a useful marker in predicting tumor progression and prognosis.
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Affiliation(s)
- Wen-Li Jiang
- Department of Surgery, Juxian People's Hospital, Rizhao People's Hospital of Traditional Chinese Medicine, Rizhao, People's Republic of China
| | - Peng-Fei Zhang
- Department of Surgery, Rizhao People's Hospital of Traditional Chinese Medicine, Rizhao, People's Republic of China
| | - Guo-Feng Li
- Department of Surgery, Juxian People's Hospital, Rizhao People's Hospital of Traditional Chinese Medicine, Rizhao, People's Republic of China
| | - Jian-Hua Dong
- Department of Surgery, Juxian People's Hospital, Rizhao People's Hospital of Traditional Chinese Medicine, Rizhao, People's Republic of China
| | - Xue-Song Wang
- Department of Surgery, Juxian People's Hospital, Rizhao People's Hospital of Traditional Chinese Medicine, Rizhao, People's Republic of China
| | - Yuan-Yu Wang
- Department of Gastrointestinal Surgery, Zhejiang Provincial People's Hospital, Hangzhou, People's Republic of China
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16
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Liu C, Zhang D, Shen Y, Tao X, Liu L, Zhong Y, Fang S. DPF2 regulates OCT4 protein level and nuclear distribution. BIOCHIMICA ET BIOPHYSICA ACTA 2015; 1853:3279-3293. [PMID: 26417682 DOI: 10.1016/j.bbamcr.2015.09.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 08/28/2015] [Accepted: 09/21/2015] [Indexed: 02/05/2023]
Abstract
The amount of transcription factor OCT4 is strictly regulated. A tight regulation of OCT4 levels is crucial for mammalian embryonic development and oncogenesis. However, the mechanisms underlying regulation of OCT4 protein expression and nuclear distribution are largely unknown. Here, we report that DPF2, a plant homeodomain (PHD) finger protein, is upregulated during H9 cell differentiation induced by retinoic acid. Endogenous interaction between DPF2 and OCT4 in P19 cells was revealed by an immunoprecipitation assay. GST-pull down assay proved that OCT4 protein in H9 cells and recombinant OCT4 can precipitate with DPF2 in vitro. In vitro ubiquitination assay demonstrated DPF2 might serve as an E3 ligase. Knock down of dpf2 using siRNA increased OCT4 protein level and stability in P19 cells. DPF2 siRNAs also up-regulates OCT4 but not NANOG in H9 cells. However, RA fails to downregulates OCT4 protein level in cells infected by lenitviruses containing DPF2 siRNA. Moreover, overexpression of both DPF2 and OCT4 in 293 cells proved the DPF2-OCT4 interaction. DPF2 but not PHD2 mutant DPF2 enhanced ubiquitination and degradation of OCT4 in 293 cells co-expressed DPF2 and OCT4. Both wild type DPF2 and PHD2 mutant DPF2 redistributes nuclear OCT4 without affecting DPF2-OCT4 interaction. Further analysis indicated that DPF2 decreases monomeric and mono-ubiquitinated OCT4, assembles poly-ubiquitin chains on OCT4 mainly through Ub-K48 linkage. These findings contribute to an understanding of how OCT4 protein level and nuclear distribution is regulated by its associated protein.
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Affiliation(s)
- Chao Liu
- Department of Histology and Embryology, Institute of Stem Cell and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032 China; Center for Biomedical Engineering and Technology (BioMET), University of Maryland, Baltimore, MD 21201 USA.
| | - Dijuan Zhang
- Department of Histology and Embryology, Institute of Stem Cell and Tissue Engineering, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032 China
| | - Yuxian Shen
- School of Basic Medical Sciences, Institute of Biopharmaceuticals, Anhui Medical University, Hefei, Anhui 230032 China
| | - Xiaofang Tao
- School of Basic Medical Sciences, Institute of Biopharmaceuticals, Anhui Medical University, Hefei, Anhui 230032 China
| | - Lihua Liu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui 230032, China
| | - Yongwang Zhong
- Center for Biomedical Engineering and Technology (BioMET), University of Maryland, Baltimore, MD 21201 USA
| | - Shengyun Fang
- Center for Biomedical Engineering and Technology (BioMET), University of Maryland, Baltimore, MD 21201 USA.
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17
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Alfazari AS, Al-Dabbagh B, Al-Dhaheri W, Taha MS, Chebli AA, Fontagnier EM, Koutoubi Z, Kochiyi J, Karam SM, Souid AK. Profiling cellular bioenergetics, glutathione levels, and caspase activities in stomach biopsies of patients with upper gastrointestinal symptoms. World J Gastroenterol 2015. [PMID: 25593494 DOI: 10.3748/wjg.v21.i2.635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To measure biochemical parameters in stomach biopsies and test their suitability as diagnostic biomarkers for gastritis and precancerous lesions. METHODS Biopsies were obtained from the stomachs of two groups of patients (n = 40) undergoing fiber-optic endoscopy due to upper gastrointestinal symptoms. In the first group (n = 17), only the corpus region was examined. Biopsies were processed for microscopic examination and measurement of mitochondrial O2 consumption (cellular respiration), cellular adenosine triphosphate (ATP), glutathione (GSH), and caspase activity. In the second group of patients (n = 23), both corpus and antral regions were studied. Some biopsies were processed for microscopic examination, while the others were used for measurements of cellular respiration and GSH level. RESULTS Microscopic examinations of gastric corpus biopsies from 17 patients revealed normal mucosae in 8 patients, superficial gastritis in 7 patients, and chronic atrophic gastritis in 1 patient. In patients with normal histology, the rate (mean ± SD) of cellular respiration was 0.17 ± 0.02 μmol/L O2 min(-1) mg(-1), ATP content was 487 ± 493 pmol/mg, and GSH was 469 ± 98 pmol/mg. Caspase activity was detected in 3 out of 8 specimens. The values of ATP and caspase activity were highly variable. The presence of superficial gastritis had insignificant effects on the measured biomarkers. In the patient with atrophic gastritis, cellular respiration was high and ATP was relatively low, suggesting uncoupling oxidative phosphorylation. In the second cohort of patients, the examined biopsies showed either normal or superficial gastritis. The rate of cellular respiration (O2. μmol/L min(-1) mg(-1)) was slightly higher in the corpus than the antrum (0.18 ± 0.05 vs 0.15 ± 0.04, P = 0.019). The value of GSH was about the same in both tissues (310 ± 135 vs 322 ± 155, P = 0.692). CONCLUSION The corpus mucosa was metabolically more active than the antrum tissue. The data in this study will help in understanding the pathophysiology of gastric mucosa.
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Affiliation(s)
- Ali S Alfazari
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Bayan Al-Dabbagh
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Wafa Al-Dhaheri
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Mazen S Taha
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Ahmad A Chebli
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Eva M Fontagnier
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Zaher Koutoubi
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Jose Kochiyi
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Sherif M Karam
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
| | - Abdul-Kader Souid
- Ali S Alfazari, Bayan Al-Dabbagh, Department of Medicine, United Arab Emirates University, PO Box 17666, Al Ain, United Arab Emirates
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18
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Alfazari AS, Al-Dabbagh B, Al-Dhaheri W, Taha MS, Chebli AA, Fontagnier EM, Koutoubi Z, Kochiyi J, Karam SM, Souid AK. Profiling cellular bioenergetics, glutathione levels, and caspase activities in stomach biopsies of patients with upper gastrointestinal symptoms. World J Gastroenterol 2015; 21:644-652. [PMID: 25593494 PMCID: PMC4292300 DOI: 10.3748/wjg.v21.i2.644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 06/30/2014] [Accepted: 07/30/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To measure biochemical parameters in stomach biopsies and test their suitability as diagnostic biomarkers for gastritis and precancerous lesions.
METHODS: Biopsies were obtained from the stomachs of two groups of patients (n = 40) undergoing fiber-optic endoscopy due to upper gastrointestinal symptoms. In the first group (n = 17), only the corpus region was examined. Biopsies were processed for microscopic examination and measurement of mitochondrial O2 consumption (cellular respiration), cellular adenosine triphosphate (ATP), glutathione (GSH), and caspase activity. In the second group of patients (n = 23), both corpus and antral regions were studied. Some biopsies were processed for microscopic examination, while the others were used for measurements of cellular respiration and GSH level.
RESULTS: Microscopic examinations of gastric corpus biopsies from 17 patients revealed normal mucosae in 8 patients, superficial gastritis in 7 patients, and chronic atrophic gastritis in 1 patient. In patients with normal histology, the rate (mean ± SD) of cellular respiration was 0.17 ± 0.02 μmol/L O2 min-1 mg-1, ATP content was 487 ± 493 pmol/mg, and GSH was 469 ± 98 pmol/mg. Caspase activity was detected in 3 out of 8 specimens. The values of ATP and caspase activity were highly variable. The presence of superficial gastritis had insignificant effects on the measured biomarkers. In the patient with atrophic gastritis, cellular respiration was high and ATP was relatively low, suggesting uncoupling oxidative phosphorylation. In the second cohort of patients, the examined biopsies showed either normal or superficial gastritis. The rate of cellular respiration (O2.μmol/L min-1 mg-1) was slightly higher in the corpus than the antrum (0.18 ± 0.05 vs 0.15 ± 0.04, P = 0.019). The value of GSH was about the same in both tissues (310 ± 135 vs 322 ± 155, P = 0.692).
CONCLUSION: The corpus mucosa was metabolically more active than the antrum tissue. The data in this study will help in understanding the pathophysiology of gastric mucosa.
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Pulikkot S, Greish YE, Mourad AI, Karam SM. Establishment of a three-dimensional culture system of gastric stem cells supporting mucous cell differentiation using microfibrous polycaprolactone scaffolds. Cell Prolif 2014; 47:553-63. [PMID: 25345659 PMCID: PMC6495834 DOI: 10.1111/cpr.12141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 08/02/2014] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES To generate various polycaprolactone (PCL) scaffolds and test their suitability for growth and differentiation of immortalized mouse gastric stem (mGS) cells. MATERIALS AND METHODS Non-porous, microporous and three-dimensional electrospun microfibrous PCL scaffolds were prepared and characterized for culture of mGS cells. First, growth of mGS cells was compared on these different scaffolds after 3 days culture, using viability assay and microscopy. Secondly, growth pattern of the cells on microfibrous scaffolds was studied after 3, 6, 9 and 12 days culture using DNA PicoGreen assay and scanning electron microscopy. Thirdly, differentiation of the cells grown on microfibrous scaffolds for 3 and 9 days was analysed using lectin/immunohistochemistry. RESULTS The mGS cells grew preferentially on microfibrous scaffolds. From 3 to 6 days, there was increase in cell number, followed by reduction by days 9 and 12. To test whether the reduction in cell number was associated with cell differentiation, cryosections of cell-containing scaffolds cultured for 3 and 9 days were probed with gastric epithelial cell differentiation markers. On day 3, none of the markers examined bound to the cells. However by day 9, approximately, 50% of them bound to N-acetyl-d-glucosamine-specific lectin and anti-trefoil factor 2 antibodies, indicating their differentiation into glandular mucus-secreting cells. CONCLUSIONS Microfibrous PCL scaffolds supported growth and differentiation of mGS cells into mucus-secreting cells. These data will help lay groundwork for future experiments to explore use of gastric stem cells and PCL scaffolds in stomach tissue engineering.
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Affiliation(s)
- S. Pulikkot
- Department of AnatomyCollege of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
- Department of ChemistryCollege of ScienceUnited Arab Emirates UniversityAl AinUnited Arab Emirates
| | - Y. E. Greish
- Department of ChemistryCollege of ScienceUnited Arab Emirates UniversityAl AinUnited Arab Emirates
| | - A‐H. I. Mourad
- Department of Mechanical EngineeringCollege of EngineeringUnited Arab Emirates UniversityAl AinUnited Arab Emirates
| | - S. M. Karam
- Department of AnatomyCollege of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
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20
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Coexpression of HMGA2 and Oct4 predicts an unfavorable prognosis in human gastric cancer. Med Oncol 2014; 31:130. [PMID: 25037576 DOI: 10.1007/s12032-014-0130-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Accepted: 07/09/2014] [Indexed: 01/05/2023]
Abstract
High mobility group protein A2 (HMGA2) and octamer-binding transcription factor 4 (Oct4) are transcription factors that play major roles in the acquisition of cancer stemness phenotypes and tumorigenicity of malignant neoplasms. The aim of this study was to analyze the association between HMGA2 and Oct4 expression and various clinicopathologic features in gastric cancer patients including invasion, metastasis, and clinical prognosis, in addition to overall survival. Immunohistochemistry was performed to explore the expression of HMGA2 and Oct4 in 158 gastric cancer and surrounding non-tumor tissues. Moreover, HMGA2 and Oct4 mRNA and protein levels were also detected by qRT-PCR and Western blotting, respectively, in 86 clinical tissue specimens and various gastric epithelial cell lines (GES-1, SGC7901, MKN45, and MKN27). Finally, associations between HMGA2 and Oct4 expression and clinicopathological features were analyzed by Pearson correlation coefficient. Survival analysis was performed by univariate and multivariate analyses. Taken together, we found that HMGA2 and Oct4 expression was significantly higher in gastric cancer tissues compared with non-cancerous tissues (P < 0.01), and HMGA2 and Oct4 protein levels were significantly higher in poorly differentiated gastric cancer cell lines (MKN45), moderately differentiated cell lines (SGC7901), and well-differentiated cell lines (MKN28) compared with human immortalized gastric epithelial cell lines (GES-1) (P < 0.01). Elevated HMGA2 and Oct4 levels were significantly associated with poor clinical prognosis (P < 0.05). Further conclusion showed that coexpression of HMGA2 and Oct4 in gastric cancer correlated with tumor invasion, metastasis, and clinical prognosis and predicted an unfavorable clinical outcome. These transcription factors may represent useful biomarkers to identify patients at high risk of postoperative recurrence.
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Lin H, Sun LH, Han W, He TY, Xu XJ, Cheng K, Geng C, Su LD, Wen H, Wang XY, Chen QL. Knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of the AKT pathway. Mol Med Rep 2014; 10:1335-42. [PMID: 25017645 PMCID: PMC4121418 DOI: 10.3892/mmr.2014.2367] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Accepted: 03/11/2014] [Indexed: 01/01/2023] Open
Abstract
Octamer‑binding transcription factor 4 (OCT4) is one of the factors associated with self‑renewal and differentiation in cancer stem cells, and is crucial for the progression of various types of human malignancy. However, the expression and function of OCT4 in human pancreatic cancer has not been fully elucidated. The purpose of the present study was to investigate the function and molecular mechanisms of OCT4 in pancreatic cancer cells. The clinical significance of OCT4 expression was assessed by an immunohistochemical assay using a tissue microarray procedure in pancreatic cancer tissues and cells with different degrees of differentiation. A loss‑of‑function approach was used to examine the effects of a lentivirus‑mediated OCT4 small hairpin RNA vector on biological behaviors, including cell proliferative activity and invasive potential. The results demonstrated that the expression levels of OCT4 protein in cancer tissues were significantly elevated compared with those in adjacent non‑cancerous tissues (65.0 vs. 42.5%; P=0.005), which was correlated with tumor differentiation (P=0.008). The knockdown of OCT4 inhibited the proliferation and invasion of pancreatic cancer cells (Panc‑1) expressing high levels of OCT4, accompanied with decreased expression of AKT, proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase‑2 (MMP‑2). In conclusion, the present study reveals that the increased expression of OCT4 is correlated with the differentiation of pancreatic cancer, while knockdown of OCT4 suppresses the growth and invasion of pancreatic cancer cells through inhibition of AKT pathway‑mediated PCNA and MMP‑2 expression, suggesting that OCT4 might serve as a potential therapeutic target for the treatment of pancreatic cancer.
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Affiliation(s)
- Hai Lin
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Li-Hua Sun
- Liver Disease Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Wei Han
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Tie-Ying He
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Xin-Jian Xu
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Kun Cheng
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Cheng Geng
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Li-Dan Su
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Hao Wen
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Xi-Yan Wang
- Department of Pancreatic Surgery, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Qi-Long Chen
- Department of Pancreatic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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Gao FL, Li WS, Liu CL, Zhao GQ. Silencing Bmi-1 enhances the senescence and decreases the metastasis of human gastric cancer cells. World J Gastroenterol 2013; 19:8764-8769. [PMID: 24379598 PMCID: PMC3870526 DOI: 10.3748/wjg.v19.i46.8764] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/01/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the impact of Bmi-1 on cell senescence and metastasis of human gastric cancer cell line BGC823.
METHODS: Two pairs of complementary small hairpin RNA (shRNA) oligonucleotides targeting the Bmi-1 gene were designed, synthesized, annealed and cloned into the pRNAT-U6.2 vector. After DNA sequencing to verify the correct insertion of the shRNA sequences, the recombinant plasmids were transfected into BGC823 cells. The expression of Bmi-1 mRNA and protein was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The effects of Bmi-1 knockdown on cell senescence and metastasis were determined by the β-Gal activity assay and Boyden chamber assay, respectively.
RESULTS: The double-stranded oligonucleotide fragments of Bmi-1 short interfering RNA (siRNA) cloned into pRNAT-U6.2 vector conformed to the inserted sequence. RT-PCR and Western blotting indicated that the expression levels of Bmi-1 gene mRNA and protein were markedly decreased in transfected BGC823 cells with pRNAT-U6.2-si1104 and pRNAT-U6.2-si1356, especially in transfected BGC823 cells with pRNAT-U6.2-si1104, compared with two control groups (empty vector and blank group). In particular, Bmi-1 protein expression was almost completely abolished in cells transfected with the recombinant vector harboring shRNA targeting the sequence GGAGGAGGTGAATGATAAA (nt1104-1122). Compared with untransfected cells and cells transfected with the empty vector, the mean percentage of senescent cells increased and the number of cells passing through the Matrigel decreased in cells transfected with the recombinant vectors.
CONCLUSION: Silencing Bmi-1 by RNA interference can increase the senescent cell rate and effectively reduce the metastasis of gastric cancer cells.
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Romano G. The role of the dysfunctional akt-related pathway in cancer: establishment and maintenance of a malignant cell phenotype, resistance to therapy, and future strategies for drug development. SCIENTIFICA 2013; 2013:317186. [PMID: 24381788 PMCID: PMC3870877 DOI: 10.1155/2013/317186] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 11/14/2013] [Indexed: 06/01/2023]
Abstract
Akt serine/threonine kinases, or PKB, are key players in the regulation of a wide variety of cellular activities, such as growth, proliferation, protection from apoptotic injuries, control of DNA damage responses and genome stability, metabolism, migration, and angiogenesis. The Akt-related pathway responds to the stimulation mediated by growth factors, cytokines, hormones, and several nutrients. Akt is present in three isoforms: Akt1, Akt2, and Akt3, which may be alternatively named PKB α , PKB β , and PKB γ , respectively. The Akt isoforms are encoded on three diverse chromosomes and their biological functions are predominantly distinct. Deregulations in the Akt-related pathway were observed in many human maladies, including cancer, cardiopathies, neurological diseases, and type-2 diabetes. This review discusses the significance of the abnormal activities of the Akt axis in promoting and sustaining malignancies, along with the development of tumor cell populations that exhibit enhanced resistance to chemo- and/or radiotherapy. This occurrence may be responsible for the relapse of the disease, which is unfortunately very often related to fatal consequences in patients.
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Affiliation(s)
- Gaetano Romano
- Department of Biology, College of Science and Technology, Temple University, Bio Life Science Building, Suite 456, 1900 N. 12th Street, Philadelphia, PA 19122, USA
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Li J, Wen KM, Zeng QL. Role of Oct4 in gastrointestinal tumors. Shijie Huaren Xiaohua Zazhi 2013; 21:2969-2974. [DOI: 10.11569/wcjd.v21.i28.2969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Octamer-binding transcription factor 4 (Oct4), a member of the POU transcription factor family, is one of the most important transcription factors for maintaining pluripotent and self-renewing state of stem cells. Oct4 is expressed not only in embryonic stem cells, germ cells and germ cell tumors but also in a variety of somatic cells of malignant tumors. The expression of Oct4 is closely related to the development and prognosis of malignant tumors. Therefore, detection of Oct4 expression has great significance in the diagnosis and treatment of tumors. This article provides a brief review of the role of Oct4 in gastrointestinal tumors.
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Li XL, Jia LL, Shi MM, Li X, Li ZH, Li HF, Wang EH, Jia XS. Downregulation of KPNA2 in non-small-cell lung cancer is associated with Oct4 expression. J Transl Med 2013; 11:232. [PMID: 24070213 PMCID: PMC3849263 DOI: 10.1186/1479-5876-11-232] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 09/23/2013] [Indexed: 11/10/2022] Open
Abstract
Background Oct4 is a major transcription factor related to stem cell self-renewal and differentiation. To fulfill its functions, it must be able to enter the nucleus and remain there to affect transcription. KPNA2, a member of the karyopherin family, plays a central role in nucleocytoplasmic transport. The objective of the current study was to examine the association between Oct4 and KPNA2 expression levels with regard to both the clinicopathological characteristics and prognoses of patients with non-small-cell lung cancer (NSCLC). Methods Immunohistochemistry was used to detect the expression profile of Oct4 and KPNA2 in NSCLC tissues and adjacent noncancerous lung tissues. Real-time polymerase chain reaction and western blotting were used to detect the mRNA and protein expression profiles of Oct4 and KPNA2 in lung cancer cell lines. Small interfering RNAs were used to deplete Oct4 and KPNA2 expressions. Double immunofluorescence was used to detect Oct4 expression in KPNA2 knockdown cells. Co-immunoprecipitation was used to detect the interaction of Oct4 and KPNA2. Results Oct4 was overexpressed in 29 of 102 (28.4%) human lung cancer samples and correlated with differentiation (P = 0.002) and TNM stage (P = 0.003). KPNA2 was overexpressed in 56 of 102 (54.9%) human lung cancer samples and correlated with histology (P = 0.001) and differentiation (P = 0.045). Importantly, Oct4 and KPNA2 expression levels correlated significantly (P < 0.01). Expression of Oct4 and KPNA2 was associated with short overall survival. In addition, depleting Oct4 and KPNA2 expression using small interfering RNAs inhibited proliferation in lung cancer cell lines. Real-time polymerase chain reaction and western blotting analysis indicated that reduction of KPNA2 expression significantly reduced mRNA and nucleoprotein levels of Oct4. Double immunofluorescence analysis revealed that nuclear Oct4 signals were reduced significantly in KPNA2 knockdown cells. Co-immunoprecipitation experiments revealed that KPNA2 interacts with Oct4 in lung cancer cell lines. Conclusion Oct4 and KPNA2 play an important role in NSCLC progression. Oct4 nuclear localization may be mediated by its interaction with KPNA2.
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Affiliation(s)
- Xiao-Lei Li
- Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang 110001, China.
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Singh SR. Gastric cancer stem cells: a novel therapeutic target. Cancer Lett 2013; 338:110-9. [PMID: 23583679 DOI: 10.1016/j.canlet.2013.03.035] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 03/25/2013] [Accepted: 03/30/2013] [Indexed: 12/14/2022]
Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer.
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Affiliation(s)
- Shree Ram Singh
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
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Zhang J, Sun M, Li R, Liu S, Mao J, Huang Y, Wang B, Hou L, Ibrahim MM, Tang J. Ech1 is a potent suppressor of lymphatic metastasis in hepatocarcinoma. Biomed Pharmacother 2013; 67:557-60. [PMID: 23809371 DOI: 10.1016/j.biopha.2013.03.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 03/10/2013] [Indexed: 01/15/2023] Open
Abstract
We have previously demonstrated that Ech1 is involved in the lymphatic metastasis of tumors in vitro. Here, we gain an insight into the role that Ech1 is playing in Hca-F cell. The expression of Annexin A7, Gelsolin and Clic1 genes, which were also relevant to tumor lymphatic metastasis, had been inhibited due to downregulation Ech1 gene by Western blot analysis. And downregulated of Ech1 inhibits the metastasic capability of Hca-F cells to peripheral lymph nodes in vivo. Our work indicates although the involvement of Ech1 in tumor metastasis development and progression, but the subcellular location of Ech1 has not much contribution to that.
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Affiliation(s)
- Jun Zhang
- Department of Pathology, Dalian Medical University, Key Laboratory of Tumor Metastasis of Liaoning Province University, 9, West Lvshun Southern Road, Dalian, 116044 Liaoning, China
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