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Ma N, Zhao S, Yang W, Wang Y. B-cell-specific Moloney murine leukemia virus integration site 1 knockdown impairs adriamycin resistance of gastric cancer cells. Arab J Gastroenterol 2023; 24:168-174. [PMID: 36878814 DOI: 10.1016/j.ajg.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 01/13/2023] [Accepted: 02/23/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND AND STUDY AIMS The B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is associated with the progression of gastric cancer (GC). However, its role in drug resistance of gastric cancer stem cell (GCSC) remains unclear. This study aimed to explore the biological function of BMI-1 in GC cells and its role in drug resistance of GCSCs. PATIENTS AND METHODS We assessed BMI-1 expression in the GEPIA database and in our collected samples from patients with GC. We silenced BMI-1 using siRNA to study the cell proliferation and migration of GC cells. We also used Hoechst 33342 staining to verify the effect of adriamycin (ADR) on side population (SP) cells, and measured the effects of BMI-1 on the expression of N-cadherin, E-cadherin, and drug-resistance-related proteins (multidrug resistance mutation 1 and lung resistance-related protein). Finally, we analyzed BMI-1-related proteins uing the STRING and GEPIA databases. RESULTS BMI-1 mRNA was upregulated in GC tissues and cell lines, especially in MKN-45 and HGC-27 cells. Silencing BMI-1 reduced the proliferation and migration of GC cells. Knocking down BMI-1 significantly decreased epithelial-mesenchymal transition progression, expression levels of drug-resistant proteins, and the number of SP cells in ADR-treated GC cells. Bioinformatics analysis showed that EZH2, CBX8, CBX4, and SUZ12 were positively correlated with BMI-1 in GC tissues. CONCLUSION Our study demonstrates that BMI-1 affects the cellular activity, proliferation, migration, and invasion of GC cells. Silencing the BMI-1 gene significantly reduces the number of SP cells and the expression of drug-resistant proteins in ADR-treated GC cells. We speculate that inhibition of BMI-1 increases the drug resistance of GC cells by affecting GCSCs, and that EZH2, CBX8, CBX4, and SUZ12 may participate in BMI-1-induced enhancement of GCSC-like phenotype and viability.
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Affiliation(s)
- Ning Ma
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China.
| | - Sihui Zhao
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Wei Yang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
| | - Yongfang Wang
- Department of General Surgery Ⅱ, the First People's Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
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Glucose and Cell Context-Dependent Impact of BMI-1 Inhibitor PTC-209 on AKT Pathway in Endometrial Cancer Cells. Cancers (Basel) 2022; 14:cancers14235947. [PMID: 36497428 PMCID: PMC9739103 DOI: 10.3390/cancers14235947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/04/2022] Open
Abstract
PURPOSE In our study, the glucose and cell context-dependent impact of the BMI-1 inhibitor PTC-209 on the AKT pathway in endometrial cancer cells was determined. METHODS The expression of BMI-1 was inhibited by PTC-209 in endometrial cancer cells HEC-1A and Ishikawa stimulated with insulin and grown in different glucose concentrations. The migration, invasion, viability, and proliferative potential after PTC-209 treatment was assessed using wound-healing, Transwell assay, Matrigel-coated inserts, and MTT tests. Chromatin immunoprecipitation was used to determine the localization of BMI-1 protein at promoter sites of the genes tested. RESULTS BMI-1 inhibition caused an increase in PHLPP1/2 expression and a decrease in phospho-AKT level in both cell lines. The glucose concentration and insulin stimulation differentially impact the AKT pathway through BMI-1 in cells differing in PTEN statuses. The expression of BMI-1 is dependent on the glucose concentration and insulin stimulation mostly in PTEN positive HEC-1A cells. In high glucose concentrations, BMI-1 affects AKT activity through PHLPPs and in hypoglycemia mostly through PTEN. BMI-1 inhibition impacts on genes involved in SNAIL, SLUG, and CDH1 and reduces endometrial cancer cells' migratory and invasive potential. CONCLUSIONS Our results indicate that the relationship between BMI-1 and phosphatases involved in AKT regulation depends on the glucose concentration and insulin stimulation.
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Al-Nadaf S, Peacott-Ricardos KS, Dickinson PJ, Rebhun RB, York D. Expression and therapeutic targeting of BMI1 in canine gliomas. Vet Comp Oncol 2022; 20:871-880. [PMID: 35833892 DOI: 10.1111/vco.12852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/01/2022]
Abstract
The BMI1 proto-oncogene, polycomb ring finger protein (BMI1) is a key component of the epigenetic polycomb repressor complex 1, and has been associated with aggressive behavior and chemotherapeutic resistance in various malignances including human gliomas. Similar to humans, spontaneous canine gliomas carry a poor prognosis with limited therapeutic options. BMI1 expression and the effects of BMI1 inhibition have not been evaluated in canine gliomas. Here, we demonstrate that BMI1 is highly expressed in canine gliomas. Although increased BMI1 protein expression correlated with higher glioma grade in western blot assays, this correlation was not observed in a larger sample set using immunohistochemical analysis. The BMI1 inhibitor, PTC-209, suppressed BMI1 expression in established canine glioma cell lines and resulted in antiproliferative activity when used alone and in combination with chemotherapeutic agents. PTC-209 targeting of BMI1 activated the RB pathway through downregulation of total and phosphorylated RB, independent of INK4A/ARF signaling, likely through BMI1-inhibition mediated upregulation of p21. These data support the rationale for targeting of BMI1 signaling and the use of canine glioma as a translational therapeutic model for human disease. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Sami Al-Nadaf
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Kyle S Peacott-Ricardos
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Peter J Dickinson
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Robert B Rebhun
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Daniel York
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
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Olesiński T, Lutkowska A, Balcerek A, Sowińska A, Piotrowski P, Trzeciak T, Maj T, Hevelke P, Jagodziński PP. Long noncoding RNA CCAT1 rs67085638 SNP contribution to the progression of gastric cancer in a Polish population. Sci Rep 2021; 11:15369. [PMID: 34321511 PMCID: PMC8319342 DOI: 10.1038/s41598-021-94576-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 07/07/2021] [Indexed: 01/17/2023] Open
Abstract
The role of the long noncoding RNA CCAT1 NC_000008.10:g.128220661C > T (rs67085638) in the development of colon cancer has been reported. Therefore, we assessed the prevalence of rs67085638 in patients with gastric cancer (GC). We also evaluated the effect of rs67085638 on B-cell-specific Moloney leukaemia virus insertion site 1 (BMI1) transcripts in primary GC and counterpart histopathologically confirmed disease-free margin tissue. Using high-resolution melting analysis, we evaluated rs67085638 frequency in patients with the GC genotype (n = 214) and controls (n = 502) in a Polish Caucasian population. qRT-PCR was used to determine BMI1 transcripts. We observed the trend of rs67085638 association in all patients with GC (ptrend = 0.028), a strong risk of the GC genotype in male (ptrend = 0.035) but not female (ptrend = 0.747) patients, and the association with non-cardia GC (ptrend = 0.041), tumour stages T3 (ptrend = 0.014) and T4 (ptrend = 0.032), differentiation grading G3 (ptrend = 0.009), lymph node metastasis stage N3 (ptrend = 0.0005) and metastasis stage M0 (ptrend = 0.027). We found that significantly increased BMI1 transcripts were associated with the primary GC genotype classified as grade G3 (p = 0.011) and as lymph node metastasis N3 (p = 0.010) and counterpart marginal tissues (p = 0.026, p = 0.040, respectively) from carriers of the T/T versus C/C genotypes. rs67085638 may contribute to increased BMI1 transcripts and the progression and rapid growth of GC.
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Affiliation(s)
- Tomasz Olesiński
- Department of Oncological Gastroenterology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Anna Lutkowska
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego St., 60-781, Poznan, Poland
| | - Adam Balcerek
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego St., 60-781, Poznan, Poland
| | - Anna Sowińska
- Department of Computer Science and Statistics, Poznań University of Medical Sciences, Poznan, Poland
| | - P Piotrowski
- Molecular Biology Department, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Tomasz Trzeciak
- Department of Orthopedics and Traumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Tomasz Maj
- Department of Oncological Gastroenterology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Piotr Hevelke
- Department of Oncological Gastroenterology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Pawel P Jagodziński
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego St., 60-781, Poznan, Poland.
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Yu J, Chen L, Bao Z, Liu Y, Liu G, Li F, Li L. BMI‑1 promotes invasion and metastasis in endometrial adenocarcinoma and is a poor prognostic factor. Oncol Rep 2020; 43:1630-1640. [PMID: 32323819 PMCID: PMC7108087 DOI: 10.3892/or.2020.7539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/12/2020] [Indexed: 12/31/2022] Open
Abstract
Endometrial adenocarcinoma is one of the most common types of gynecological malignancies and its incidence and mortality rates are increasing. Due to tumor recurrence and metastasis, the overall five-year survival rate of patients with endometrial adenocarcinoma is shortened. The aim of the present was to investigate the role of the polycomb group protein B-lymphoma Mo-MLV insertion region 1 (BMI-1) in the invasion, metastasis and the epithelial-mesenchymal transition (EMT) of endometrial adenocarcinoma cells, as well its effects on the prognosis of patients with endometrial adenocarcinoma. Immunohistochemistry was used to examine the expression profile of BMI-1 in normal and endometrial adenocarcinoma tissues. Western blotting was used to examine the expression levels of BMI-1 and EMT markers. Kaplan-Meier plots and a Cox proportional hazards model were used to assess the overall survival. MTT cell viability assays were used to detect the proliferation of endometrial cancer cells. Transwell assays were used to examine cell migration and invasion. Small interfering RNA was used to downregulate BMI-1 expression levels, to study its effect on EMT. Immunohistochemical and clinicopathological analyses showed that BMI-1 expression was increased in endometrial adenocarcinoma tissue compared with the normal endometrial tissue (P<0.05). The increased expression levels of BMI-1 were closely associated with stage, myometrial invasion and lymph node metastasis (P<0.05). Kaplan-Meier plots and a Cox proportional hazards model showed that increased BMI-1 expression was associated with a less favorable prognosis [P=0.040, hazards ratio (HR)=1.596] and was associated with late-stage adenocarcinoma (P=0.006, HR=1.670). Myometrial invasion (P=0.006, HR=1.509) and lymph node metastasis (P=0.004, HR=1.703) were determined to predict a less favorable prognosis. Downregulation of BMI-1 reduced migration and invasion in endometrial cancer cells in vivo. It was also found that downregulation of BMI-1 increased the expression levels of the epithelial markers E-cadherin and keratin, and decreased the expression levels of the mesenchymal markers N-cadherin, vimentin and the downstream transcription factor, Slug. In conclusion, BMI-1 expression was correlated with tumor invasion and metastasis, contributing to deep myometrial invasion and lymph node metastasis, and was a poor prognostic factor for endometrial adenocarcinoma.
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Affiliation(s)
- Jing Yu
- Department of Pathology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Ling Chen
- Department of Obstetrics and Gynecology, First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang 832001, P.R. China
| | - Zhenhua Bao
- Department of Oncology, People's Hospital of Haiyang, Haiyang, Shandong 265100, P.R. China
| | - Ying Liu
- Department of Physical Examination, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Guohong Liu
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Fengling Li
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
| | - Lianqin Li
- Department of Obstetrics and Gynecology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
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Zaczek A, Jóźwiak P, Ciesielski P, Forma E, Wójcik-Krowiranda K, Cwonda Ł, Bieńkiewicz A, Bryś M, Krześlak A. Relationship between polycomb-group protein BMI-1 and phosphatases regulating AKT phosphorylation level in endometrial cancer. J Cell Mol Med 2019; 24:1300-1310. [PMID: 31863623 PMCID: PMC6991679 DOI: 10.1111/jcmm.14782] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 08/24/2019] [Accepted: 08/29/2019] [Indexed: 12/25/2022] Open
Abstract
The PI3K/AKT pathway is frequently activated in endometrial carcinoma. BMI‐1 (B‐lymphoma Mo‐MLV insertion region 1) protein affects expression of PTEN (phosphatase and tensin homolog) in some cancers, but its significance for endometrial tumorigenesis is not known. The objective of this study was to determine the relationship between BMI‐1 and expression of factors affecting AKT (protein kinase B) phosphorylation level in endometrial cancer. The expression of proteins and mRNAs was investigated in endometrial cancer specimens and samples of non‐neoplastic endometrial tissue by Western blot and RT‐PCR, respectively. The impact of BMI‐1 down‐regulation on AKT phosphorylation and expression of genes coding for several phosphatases were studied in HEC1A cells. The results showed that BMI‐1 depletion caused increase in PHLPP1 and PHLPP2 (PH domain and leucine‐rich repeat protein phosphatases 1/2) expression and decrease in phospho‐AKT (pAKT) level. In more advanced tumours with higher metastatic potential, the expression of BMI‐1 was lower compared to tumours less advanced and without lymph node metastasis. There were significant inverse correlations between BMI‐1 and PHLPPs, especially PHLPP1 in normal endometrial samples. The inverse correlation between BMI‐1 and PHLPP1/PHLPP2 expression was observed in PTEN positive but not PTEN negative cancers. Low PHLPP2 expression in tumours predicted poorer overall survival. BMI‐1 impacts on AKT phosphorylation level in endometrial cells by regulation of PHLPP expression.
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Affiliation(s)
- Agnieszka Zaczek
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Paweł Jóźwiak
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Piotr Ciesielski
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Ewa Forma
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | | | - Łukasz Cwonda
- Clinical Division of Gynecological Oncology, Medical University of Lodz, Lodz, Poland
| | - Andrzej Bieńkiewicz
- Clinical Division of Gynecological Oncology, Medical University of Lodz, Lodz, Poland
| | - Magdalena Bryś
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Anna Krześlak
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
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dos Santos HT, de Souza do Nascimento J, Meireles F, Scarini JF, Egal ES, Montalli VA, Fonseca FP, Mariano FV, Altemani A. Evaluation of the expression of Bmi-1 stem cell marker in sinonasal melanomas and its correlation with the expression of cell cycle proteins. SURGICAL AND EXPERIMENTAL PATHOLOGY 2019. [DOI: 10.1186/s42047-019-0034-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Sinonasal melanomas (SNM) are aggressive neoplasms, which present distinct clinicopathological and molecular aspects when compared to cutaneous melanomas (CM). B-cell-specific moloney murine leukemia virus integration site-1 (Bmi-1) is a stem cell marker involved in the regulation of the cell cycle and has been found to be expressed in 70% of CM and 100% of benign nevi. Regarding the cell cycle, Bmi-1 is known to be an upstream repressor of p16, which is a tumor suppressor encoded by the INK4a/Arf locus. Considering this, the aim of this study is to evaluate the immunohistochemical expression of Bmi-1 in a series of SNM and its correlation with the expression of cell cycle proteins (p16 and Ki-67, a nuclear antigen of proliferating cells).
Methods
In 16 cases of SNM, nuclear expression of Bmi-1 and nuclear and cytoplasmic of p16 was classified as: absent, low (> 5 to < 50% of cells) and high (≥50%). Ki-67 proliferation index was represented by the ratio positive cells/ total cells.
Results
Histologically, all cases presented varying amount of necrosis and 75% contained undifferentiated cells. Bmi-1 was detected in 6 cases (37.5%) with high level of expression in 2; p16 expression was seen in 10 cases (62.5%) with high level in 7. The frequency of p16 expression did not differ significantly between tumors with or without Bmi-1 expression. Ki-67 index ranged from 8 to 22%. Neither Bmi-1 nor p16 expression showed correlation with Ki-67 index. Bmi-1 negative tumors presented more extensive necrosis (71.4%); no association between Bmi-1 expression and undifferentiated phenotype was observed.
Conclusions
In our SNM series, low immunohistochemical expression of Bmi-1 was a common phenomenon favoring the hypothesis that mucosal melanoma possibly presents molecular pathways different from the cutaneous counterpart. In SNM, Bmi-1 and p16 expression levels did not correlate with each other or with the cell proliferative index.
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Wu Y, Tian S, Chen Y, Ji M, Qu Y, Hou P. miR-218 inhibits gastric tumorigenesis through regulating Bmi-1/Akt signaling pathway. Pathol Res Pract 2018; 215:243-250. [PMID: 30420101 DOI: 10.1016/j.prp.2018.10.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 10/14/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Previous studies indicated that miR-218 was deregulated in gastric cancer patients and correlated with tumor invasion and prognosis. The aim of this study was to clarify the effect of miR-218 on the malignant behavior of gastric cancer and its role in regulating Bmi-1/Akt signaling pathway. MATERIALS AND METHODS We used miR-218 mimic to transfect gastric cancer cell lines AGS and SGC-7901, and the overexpression efficiency was validated using qRT-PCR assay. MTT assay and Transwell chamber system were performed to detect the effect of miR-218 on cell proliferation, invasion and migration on gastric cancer. Western blot and qRT-PCR assay was used to test the role of miR-218 in regulating Bmi-1/Akt signaling pathway. RESULTS As shown in our research, ectopic expression of miR-218 in gastric cancer cells inhibits the proliferation, invasion and migration of gastric cancer cells. In addition, miR-218 re-expression inhibits the expression of Bmi-1 and its downstream target p-Akt473, as well as MMPs and EMT process. CONCLUSIONS miR-218 inhibits the proliferation, invasion and migration of gastric cancer cells through modulating EMT process and the expression of MMPs via Bmi-1/Akt signaling pathway.
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Affiliation(s)
- Yongxing Wu
- Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Sijia Tian
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yijun Chen
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Meiju Ji
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yiping Qu
- Department of Radio-Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
| | - Peng Hou
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Zhang W, Zhou P, Meng A, Zhang R, Zhou Y. Down-regulating Myoferlin inhibits the vasculogenic mimicry of melanoma via decreasing MMP-2 and inducing mesenchymal-to-epithelial transition. J Cell Mol Med 2017; 22:1743-1754. [PMID: 29164766 PMCID: PMC5824422 DOI: 10.1111/jcmm.13455] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/14/2017] [Indexed: 12/14/2022] Open
Abstract
Vasculogenic mimicry (VM) constitutes a novel approach for tumour blood supply and contributes to tumour metastasis and poor prognosis in patients with melanoma. Myoferlin (MYOF), a type II membrane protein involved in membrane regeneration and repair, is elevated in several malignant tumours, especially in advanced melanomas. This study aims to investigate the role and mechanism of MYOF in the regulation of VM. VM structures were found in 14 of 52 tested melanoma samples, and high MYOF expression correlated with VM structures. According to Kaplan–Meier survival curves, VM channels and elevated MYOF expression both correlated with poor prognosis in melanoma patients. Down‐regulation of MYOF by siRNA severely impaired the capability of A375 cells to form VM structures in vitro. Further studies demonstrated MYOF knockdown inhibited cell migration and invasion, which is required for VM formation, via decreasing MMP‐2 expression as evidenced by Western blotting, RT‐RCP and ELISA results. SB‐3CT, a specific inhibitor of MMP‐2, showed similar inhibiting effects with siMYOF, further supporting that MYOF down‐regulation inhibits MMP‐2 expression to affect VM formation. Moreover, MYOF knockdown suppress VM formation by A375 cells by inducing mesenchymal‐to‐epithelial transition (MET). After down‐regulating MYOF, focal adhesions were enlarged and A375 cells developed into a clear epithelial morphology. Such cells acquired the expression of E‐cadherin at adherens junctions along with a loss of mesenchymal markers, such as Vimentin and Twist1. In conclusion, MYOF plays an important role in VM and knockdown of MYOF suppresses VM formation via decreasing MMP‐2 and inducing MET in A375 melanoma cells.
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Affiliation(s)
- Wenxue Zhang
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Ping Zhou
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Ai Meng
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Rongxin Zhang
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
| | - Yan Zhou
- Tianjin Medical University General Hospital, Tianjin Medical University Cancer Institute and Hospital, School of Basic Medical Sciences, School and Hospital of Stomatology, Tianjin Medical University, Tianjin, China
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Ye K, Chen QW, Sun YF, Lin JA, Xu JH. Loss of BMI-1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD-2/MyD88-mediated NF-κB signaling. J Cell Biochem 2017; 119:1922-1930. [PMID: 28815730 DOI: 10.1002/jcb.26353] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 08/11/2017] [Indexed: 01/04/2023]
Abstract
Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment created by immune cells facilitates tumor migration. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in an inflammatory microenvironment. B-lymphoma Moloney murine leukemia virus insertion region 1 (BMI-1) acts as an oncogene in various tumors. Ectopic expression of Bmi-1 have an effect on EMT and invasiveness. The purpose of this study was to investigate the efficacy of BMI-1 on inflammation-induced tumor migration and EMT and the underlying mechanism. We observed that the expression of BMI-1, TNF-α, and IL-1β was significantly increased in HT29 and HCT116 cells after THP-1 Conditioned-Medium (THP-1-CM) stimulation. Additionally, inhibition of BMI-1 impeded cell invasion induced by THP-1-CM-stimulation in both HT29 and HCT116 cells. BMI-1 knockdown remarkably repressed THP-1-CM-induced EMT by regulating the expression of EMT biomarkers with an increase in E-cadherin accompanied by decrease in N-cadherin and vimentin. Furthermore, downregulation of BMI-1 dramatically impeded THP-1-CM-triggered Toll-like receptor 4(TLR4)/myeloid differentiation protein 2(MD-2)/myeloid differentiation factor 88(MyD88) activity by repressing the expression of the TLR4/MD-2 complex and MyD88. Further data demonstrated that knockout of BMI-1 also dampened NF-κB THP-1-CM-triggered activity. Taken all data together, our findings established that BMI-1 modulated TLR4/MD-2/MyD88 complex-mediated NF-κB signaling involved in inflammation-induced cancer cells invasion and EMT, and therefore, could be a potential chemopreventive agent against inflammation-associated colorectal cancer. HIGHLIGHTS Establishment of an inflammatory microenvironment. Suppression of BMI-1 reverses THP-1-CM-induced inflammatory cytokine production in CRC. Loss of BMI-1 suppressed TLR4/MD-2/MyD88 complex-mediated NF-κB signaling.
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Affiliation(s)
- Kai Ye
- Department of Oncology Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China
| | - Qi-Wei Chen
- Department of Oncology Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China
| | - Ya-Feng Sun
- Department of Oncology Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China
| | - Jian-An Lin
- Department of Oncology Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China
| | - Jian-Hua Xu
- Department of Oncology Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, PR China
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Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity. Trends Genet 2017; 33:943-959. [PMID: 28919019 DOI: 10.1016/j.tig.2017.08.004] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 06/20/2017] [Accepted: 08/10/2017] [Indexed: 12/11/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their junctions and polarity to gain a motile mesenchymal phenotype. EMT is essential during embryogenesis and adult physiological processes like wound healing, but is aberrantly activated in pathological conditions like fibrosis and cancer. A series of transcription factors (EMT-inducing transcription factor; EMT-TF) regulate the induction of EMT by repressing the transcription of epithelial genes while activating mesenchymal genes through mechanisms still debated. The nuclear interaction of EMT-TFs with larger protein complexes involved in epigenetic genome modulation has attracted recent attention to explain functions of EMT-TFs during reprogramming and cellular differentiation. In this review, we discuss recent advances in understanding the interplay between epigenetic regulators and EMT transcription factors and how these findings could be used to establish new therapeutic approaches to tackle EMT-related diseases.
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Affiliation(s)
- Nicolas Skrypek
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; These authors contributed equally
| | - Steven Goossens
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium; These authors contributed equally
| | - Eva De Smedt
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Niels Vandamme
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Inflammation Research Center (IRC), VIB, Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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