Two rice varieties, Xiushui 110 with high cadmium (Cd) tolerance and Xiushui 11 with low Cd tolerance were used to study the effects of Cd stress on seed germination, seedling growth and amylase activities. The low ca...Two rice varieties, Xiushui 110 with high cadmium (Cd) tolerance and Xiushui 11 with low Cd tolerance were used to study the effects of Cd stress on seed germination, seedling growth and amylase activities. The low cadmium concentration had little effect on seed germination rate. However, cadmium stress could significantly inhibit plumule and radicle growth, especially for radicle growth. Germination index, vigour index, radicle length and amylase activities of Xiushui 11 decreased more significantly with the increasing cadmium level compared with Xiushui 110. The cadmium content in seedlings of Xiushui 11 was higher than that in Xiushui 110 when the cadmium concentration exceeded 5 μmol/L, which caused lower mitotic index in root tips and amylase activities, and more serious cadmium toxicity in Xiushui 11.展开更多
Background: A number of meningeal neoplastic lesions may radiologically and clinically simulate meningioma, include hemangiopericytomas, solitary fibrous tumors, schwannomas, hematolymphoid lesions, metastases, and ot...Background: A number of meningeal neoplastic lesions may radiologically and clinically simulate meningioma, include hemangiopericytomas, solitary fibrous tumors, schwannomas, hematolymphoid lesions, metastases, and others very rarely, also may clinically mimic meningiomas. Case Description: We present the case of A 28-year-old male patient, with no notable medical history, who presented with worsening headaches for 3 months, imbalance, and visual deficits, An initial MRI revealed extra-axial lesion involving the right Parieto-occipital, The tumor was hypointense on T1-weighted MR images, hyperintense signals on T2-weightedMR images, and heterogeneously enhanced suggestive of a meningioma, total resection was achieved, and the histopathological analysis confirmed the diagnosis of an angioblastic meningioma. However, 15 months later, the patient presented with the same initial visual complaints. A subsequent MRI showed lesion recurrence, leading to a second surgical intervention. The histopathological analysis confirmed the diagnosis of an anaplastic xanthoastrocytoma. Conclusion: This represents an unusual location for an anaplastic pleomorphic xanthoastrocytoma, which should broaden the differential diagnosis of extra-axial lesions.展开更多
In this study on the mutagenic effects of different concentrations of chromium trioxide (CrO3) on Vicia faba root tip, micronucleus assay and chromosome aberration assay were used to determine the mitotic indexes, mic...In this study on the mutagenic effects of different concentrations of chromium trioxide (CrO3) on Vicia faba root tip, micronucleus assay and chromosome aberration assay were used to determine the mitotic indexes, micronucleus rate and chromosome aberration rate of Vicia faba root tip cells. The results showed that the effects of CrO3 concentration on the mitotic indexes were complicated. CrO3 increases the micronucleus rate of Vicia faba root tip cells. It was found that within certain range of CrO3 concentration the micronucleus rate increased systematically with increased concentration of CrO3, but that the micronucleus rate decreased at higher level of CrO3 and that CrO3 also caused various types of chromosome aberration at a rate which increased systematically with increased concentration of CrO3. We concluded that CrO3 has significant mutagenic effect on Vicia faba root tip cells.展开更多
In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. ...In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in benign pre-neoplasia to substantiate this idea, which appears to be linked to the wound-healing process of injured tissue. Rarer association between a wound healing process and a cancer occurrence has long been known. The wound healing multi-program-system involved a phase of tetraploidy that showed diplochromosomes. The hypothesis is that the inflammatory phase may not always be sufficient in getting rid of dead and damaged cells (by apoptosis and autophagy), such that cells with genomic damage (DNA breakage) may survive by genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of these cells to be an orderly, mechanistic two-step, meiotic-like system, resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example, physical, toxic environment or from a disease as in Barrett’s esophagus (BE) with acid reflux into the esophagus. For this condition, it is acknowledged that damage of the esophagus lining is a pre-condition to hyperplastic lesions of pre-neoplasia. These initial lesions were from “diploid” propagating cells and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1, which with S-phase entry would lead to asymmetric tetraploid mitoses, characteristic for dysplastic lesions. This change in hyperplasia to dysplasia is the root-essential condition for a potential progression of pre-neoplasia to cancer. In BE the hyperplastic lesion showed increasing gains of cells with inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb) protein-control over S-phase 展开更多
Triple-negative breast cancer(TNBC)is characterized by fast growth,high metastasis,high invasion,and a lack of therapeutic targets.Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC ma...Triple-negative breast cancer(TNBC)is characterized by fast growth,high metastasis,high invasion,and a lack of therapeutic targets.Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression.It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors,but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown.In this study,we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1(PLK1)activation and participating in mitosis of TNBC cells.We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization(ISH),northern blot,fluorescent in situ hybridization(FISH)and cell nucleus/cytoplasm RNA fraction isolation.High AFAP1-AS1 expression was negatively correlated with overall survival(OS),disease-free survival(DFS),metastasis-free survival(MFS)and recurrence-free survival(RFS)in TNBC patients.We explored the function of AFAP1-AS1 by transwell,apoptosis,immunofluorescence(IF)and patient-derived xenograft(PDX)models in vitro and in vivo.We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth,migration and invasion.Mechanistically,AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein.Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression,such as CDC25C,CDK1,BUB1 and TTK.More importantly,AFAP1-AS1 increased lung metastases in a mouse metastasis model.Taken together,AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway.AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.展开更多
The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model...The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.展开更多
Objective To investigate the effect of lidamycin （LDM） on telomerase activity in human hepatoma BEL-7402 cells under the condition of LDM inducing mitotic cell death and senescence. Methods Chromatin condensation wa...Objective To investigate the effect of lidamycin （LDM） on telomerase activity in human hepatoma BEL-7402 cells under the condition of LDM inducing mitotic cell death and senescence. Methods Chromatin condensation was detected by co-staining with Hoechst 33342 and PI. Cell multinucleation was observed by Giemsa staining and genomic DNA was separated by agarose gel electrophoresis. Fluorescent intensity of Rho123 was determined for mitochondrial membrane potential. MTT assay and SA-13-gal staining were employed to analyze the senescence-like phenotype. The expression of proteins was analyzed by Western blot. Telomerase activity was assayed by telomerase PCR-ELISA. Results Mitotic cell death occurred in LDM-treated cells characterized by unique and atypical chromatin condensation, multinucleation and increased mitochondrial membrane potential. However, no apoptotic bodies or DNA ladders were found. In addition, apoptosis-related proteins remained nearly unaltered. Senescence-like phenotype was identified by increased and elongated size of cells, growth retardation, enhanced SA-13-gal activity and the changes of senescence-related protein expression. Telomerase activity markedly decreased （P〈0.01） in LDM-treated hepatoma BEL-7402 cells. Conclusion Mitotic cell death and senescence could be triggered simultaneously or sequentially after exposure of hepatoma BEL-7402 cells to LDM. The decrease in telomerase activity may play a key role in the defective mitosis and aging morphology. Further investigation of detailed mechanism is needed.展开更多
IN the late 1970s, biochemical analysis and electron microscopy of isolated, histone-depleted mitotic chromosomes demonstrated the existence of a central scaffold consisting mainly of nonhistone proteins (NHPs) in met...IN the late 1970s, biochemical analysis and electron microscopy of isolated, histone-depleted mitotic chromosomes demonstrated the existence of a central scaffold consisting mainly of nonhistone proteins (NHPs) in metaphase chromosomes. Subsequently, by using silver impregnation techniques and light microscopy, Howell et al. showed the presence of an axial chromatid core in relatively intact chromosomes of mammals; this core is believed to be展开更多
Human polo-like kinases （PLK1-PLK4） have been implicated in mitotic regulation and carcinogenesis. PLK1 phosphorylates early mitotic inhibitor 1 （Emil） to ensure mitosis entry, whereas Emi2 plays a key role during...Human polo-like kinases （PLK1-PLK4） have been implicated in mitotic regulation and carcinogenesis. PLK1 phosphorylates early mitotic inhibitor 1 （Emil） to ensure mitosis entry, whereas Emi2 plays a key role during the meiotic cell cycle. Transcription factor E2F is primarily considered to regulate the G1/S transition of the cell cycle but its involvement in the regulation of mitosis has also been recently suggested. A gap still exists between the molecular basis of E2F and mitotic regulation. The present study was designed to characterize the transcriptional regulation of human PLK and Emi genes. Adenoviral overexpression of E2F1 increased PLK1 and PLK3 mRNA levels in A549 cells. A reporter gene assay revealed that the putative promoter regions of PLK1, PLK3, and PLK4 genes were responsive to activators E2F, E2F1-E2F3. We further characterized the putative promoter regions of Emil and Emi2 genes, and these could be regulated by activators E2F and E2F1-E2F4, respectively. Finally, PLK1-PLK4, Emil, and Emi2 mRNA expression levels in human adult, fetal tissues, and several cell lines indicated that each gene has a unique expression pattern but is uniquely expressed in common tissues and cells such as the testes and thymus. Collectively, these results indicate that E2F can integrate G1/S and G2/M to oscillate the cell cycle by regulating mitotic genes PLK and Emi, leading to determination of the cell fate.展开更多
In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a ca...In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a cancerous pathway. Colorectal and other preneoplasia are known with the pathogenic, histological phases of hyperplasia to arrested adenoma/nevi that can give rise to dysplasia with high risk for cancer development. The present theme is to find solutions to tumorigenic unsolved, biological problems (queries), explainable from the tetraploid 4n-system, which would support its operation in the cancerous pathway. Presently admitted, the mutational sequencing of the cancer genome (cancer chemistry) cannot discover so-called “dark matter”, which herein is considered to be the queries. The solutions from the 4n-system were largely supported by mutated APC-induced same type of tetraploidy from the mitotic slippage process. But importantly, these behaviors and consequences could be linked to the beginning of hyperplastic lesions and their development to the arrest-phase of preneoplasia (polyps/nevi). Function of HFSMs is mostly unknown, but for Barrett’s esophagus, HFSMs (p53, p16ink4a) caused inactivation of the Rb gene, leading to dysplasia with 4n, aneuploid, abnormal cell cycles. In vitro models of the 4n-system from normal human cells recapitulated preneoplasia-like histopathological changes. It was speculated that the “cancer-crucial” step to dysplasia could be therapy-vulnerable to CRISPR-caspase editing, and perhaps antibody treatment. Additionally, the 4n-system with spontaneous cell-behaviors together with preneoplasia molecular data promises construction of a more truthful cancer-paradigm than from sequencing data alone.展开更多
The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile...The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile sites, some 100 distributed over the genome. These latter studies had shown that chemical induced replication-stress led to un-replicated lesions in these fragile sites, which from inaccurate repair processes caused genomic instability. In the chain of events of the ontogeny process to the special tetraploidy, it was proposed that primary damaged human cells could undergo replication stress from repair-process present during cell replication, a suggestion verified by X-ray damaged cells producing the unstable fragile sites (see text). The cancer-importance for therapy is recognition of cell cycle change for the 4n derivative fitness-gained, diploid progeny cells. An open question is whether RB controlling G1 to S-period is mutated at this suggested tumorigenesis initiating phase, and if so, with what consequences for therapy. The fragile site studies further showed that repair of repetitive DNAs could produce two types of genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally located on “borders” to repairing satellite lesions. This genomic placement was found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC), favoring a bad luck location for their cancer “mutational nature”. The CNVs in cancers, are here seen as molecular expressions of long-known cytogenetic HSRs and DMs also with demonstrated origin from amplifications of single genes. Over-expression of oncogenes was hinted of being from duplications, but Drosophila genetics demonstrated the opposite, gene inactivation. The reduced eye-size from dominant, BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the genetic system for eye-size. The finding of CNVs showing “evasion” of the immune system suggests, inactivation of immune-determining genetics. Since 展开更多
Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms.In complex organisms such as mammals,it represents an evolutionary rudiment which persisted as one of th...Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms.In complex organisms such as mammals,it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms,and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover.This event is familiar as loss of heterozygosity,which is one of the key mechanisms responsible for the development and progression of almost all cancers.We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma.The hypothesis could be tested by in vitro inhibition of Rad51 protein,orthotopic grafting of human colon cancer tissue into the gut of mice,and treatment with potential inhibitors.After these procedures,the frequency of mitotic crossover would be estimated.The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma,as well as many other neoplastic events.Loss of heterozygosity is an event responsible for carcinogenesis,its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention,as well as on growth reduction and a cessation in the progression of earlier developed tumors.展开更多
Decades of investigation on DNA methylation have led to deeper insights into its metabolic mechanisms and biological functions.This understanding was fueled by the recent development of genome editing tools and our im...Decades of investigation on DNA methylation have led to deeper insights into its metabolic mechanisms and biological functions.This understanding was fueled by the recent development of genome editing tools and our improved capacity for analyzing the global DNA methylome in mammalian cells.This review focuses on the maintenance of DNA methylation patterns during mitotic cell division.We discuss the latest discoveries of the mechanisms for the inheritance of DNA methylation as a stable epigenetic memory.We also highlight recent evidence showing the rapid turnover of DNA methylation as a dynamic gene regulatory mechanism.A body of work has shown that altered DNA methylomes are common features in aging and disease.We discuss the potential links between methylation maintenance mechanisms and diseaseassociated methylation changes.展开更多
Discs大同源相关蛋白5(Discs large homologous affinity protein 5,DLGAP5)是泛素-蛋白酶体途径调控的有丝分裂磷酸化蛋白,在细胞癌变过程中为细胞周期调节因子。DLGAP5的过表达不仅导致异常的细胞周期调控而且引起细胞有丝分裂过程的...Discs大同源相关蛋白5(Discs large homologous affinity protein 5,DLGAP5)是泛素-蛋白酶体途径调控的有丝分裂磷酸化蛋白,在细胞癌变过程中为细胞周期调节因子。DLGAP5的过表达不仅导致异常的细胞周期调控而且引起细胞有丝分裂过程的病理改变。本文综述DLGAP5的致病机制及其在NSCLC中的临床应用价值。展开更多
In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its co...In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.展开更多
基金supported by the Project of National Key Basic Research and Development, China (Grant No. 2002CB410804)the Natural Science Foundation of Guizhou Province, China (Grant No. 20072058)the Foundation for Young Scholars Scientists of Guizhou University (Grant No. X060036), China.
文摘Two rice varieties, Xiushui 110 with high cadmium (Cd) tolerance and Xiushui 11 with low Cd tolerance were used to study the effects of Cd stress on seed germination, seedling growth and amylase activities. The low cadmium concentration had little effect on seed germination rate. However, cadmium stress could significantly inhibit plumule and radicle growth, especially for radicle growth. Germination index, vigour index, radicle length and amylase activities of Xiushui 11 decreased more significantly with the increasing cadmium level compared with Xiushui 110. The cadmium content in seedlings of Xiushui 11 was higher than that in Xiushui 110 when the cadmium concentration exceeded 5 μmol/L, which caused lower mitotic index in root tips and amylase activities, and more serious cadmium toxicity in Xiushui 11.
文摘Background: A number of meningeal neoplastic lesions may radiologically and clinically simulate meningioma, include hemangiopericytomas, solitary fibrous tumors, schwannomas, hematolymphoid lesions, metastases, and others very rarely, also may clinically mimic meningiomas. Case Description: We present the case of A 28-year-old male patient, with no notable medical history, who presented with worsening headaches for 3 months, imbalance, and visual deficits, An initial MRI revealed extra-axial lesion involving the right Parieto-occipital, The tumor was hypointense on T1-weighted MR images, hyperintense signals on T2-weightedMR images, and heterogeneously enhanced suggestive of a meningioma, total resection was achieved, and the histopathological analysis confirmed the diagnosis of an angioblastic meningioma. However, 15 months later, the patient presented with the same initial visual complaints. A subsequent MRI showed lesion recurrence, leading to a second surgical intervention. The histopathological analysis confirmed the diagnosis of an anaplastic xanthoastrocytoma. Conclusion: This represents an unusual location for an anaplastic pleomorphic xanthoastrocytoma, which should broaden the differential diagnosis of extra-axial lesions.
文摘In this study on the mutagenic effects of different concentrations of chromium trioxide (CrO3) on Vicia faba root tip, micronucleus assay and chromosome aberration assay were used to determine the mitotic indexes, micronucleus rate and chromosome aberration rate of Vicia faba root tip cells. The results showed that the effects of CrO3 concentration on the mitotic indexes were complicated. CrO3 increases the micronucleus rate of Vicia faba root tip cells. It was found that within certain range of CrO3 concentration the micronucleus rate increased systematically with increased concentration of CrO3, but that the micronucleus rate decreased at higher level of CrO3 and that CrO3 also caused various types of chromosome aberration at a rate which increased systematically with increased concentration of CrO3. We concluded that CrO3 has significant mutagenic effect on Vicia faba root tip cells.
文摘In a series of publications, the hypothesis of a special-type of endo-polyploidy, marked by 4-chromatid chromosomes (diplochromosomes), in the initiation of tumorigenesis has been presented from in vitro experiments. This review uses cellular happenings in benign pre-neoplasia to substantiate this idea, which appears to be linked to the wound-healing process of injured tissue. Rarer association between a wound healing process and a cancer occurrence has long been known. The wound healing multi-program-system involved a phase of tetraploidy that showed diplochromosomes. The hypothesis is that the inflammatory phase may not always be sufficient in getting rid of dead and damaged cells (by apoptosis and autophagy), such that cells with genomic damage (DNA breakage) may survive by genomic repair associated with change to diplochromosomal tetraploidy. In vitro data have shown division of these cells to be an orderly, mechanistic two-step, meiotic-like system, resulting in only two types of progeny cells: 4n/4C/G1 and 2n/2C/G1 pseudo-diploid cells with hyperplastic-like growth-morphology. In vivo damage to tissues can be from many sources for example, physical, toxic environment or from a disease as in Barrett’s esophagus (BE) with acid reflux into the esophagus. For this condition, it is acknowledged that damage of the esophagus lining is a pre-condition to hyperplastic lesions of pre-neoplasia. These initial lesions were from “diploid” propagating cells and, 4n cells with G2 genomic content (no mitosis) accumulated in these lesions before a change to dysplasia. Cell cycle kinetics put these 4n cells in G1, which with S-phase entry would lead to asymmetric tetraploid mitoses, characteristic for dysplastic lesions. This change in hyperplasia to dysplasia is the root-essential condition for a potential progression of pre-neoplasia to cancer. In BE the hyperplastic lesion showed increasing gains of cells with inactivated p53 and p16[ink4a] genes, which destroyed the retinoblastoma (Rb) protein-control over S-phase
基金supported by the Natural Science Foundation of China(Nos.82002782,82202657)the Guangdong Basic and Applied Basic Research Foundation(2022A1515012021,2020A1515110930).
文摘Triple-negative breast cancer(TNBC)is characterized by fast growth,high metastasis,high invasion,and a lack of therapeutic targets.Mitosis and metastasis of TNBC cells are two important biological behaviors in TNBC malignant progression.It is well known that the long noncoding RNA AFAP1-AS1 plays a crucial role in various tumors,but whether AFAP1-AS1 is involved in the mitosis of TNBC cells remains unknown.In this study,we investigated the functional mechanism of AFAP1-AS1 in targeting Polo-like Kinase 1(PLK1)activation and participating in mitosis of TNBC cells.We detected the expression of AFAP1-AS1 in the TNBC patient cohort and primary cells by in situ hybridization(ISH),northern blot,fluorescent in situ hybridization(FISH)and cell nucleus/cytoplasm RNA fraction isolation.High AFAP1-AS1 expression was negatively correlated with overall survival(OS),disease-free survival(DFS),metastasis-free survival(MFS)and recurrence-free survival(RFS)in TNBC patients.We explored the function of AFAP1-AS1 by transwell,apoptosis,immunofluorescence(IF)and patient-derived xenograft(PDX)models in vitro and in vivo.We found that AFAP1-AS1 promoted TNBC primary cell survival by inhibiting mitotic catastrophe and increased TNBC primary cell growth,migration and invasion.Mechanistically,AFAP1-AS1 activated phosphorylation of the mitosis-associated kinase PLK1 protein.Elevated levels of AFAP1-AS1 in TNBC primary cells increased PLK1 pathway downstream gene expression,such as CDC25C,CDK1,BUB1 and TTK.More importantly,AFAP1-AS1 increased lung metastases in a mouse metastasis model.Taken together,AFAP1-AS1 functions as an oncogene that activates the PLK1 signaling pathway.AFAP1-AS1 could be used as a potential prognostic marker and therapeutic target for TNBC.
文摘The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.
基金This study was supported by the National High Technology Research and Development Program of China (863 Programm Grant No.2006AA02A255)the National Natural Science Foundation of China (Grant No.30472042 30300424).
文摘Objective To investigate the effect of lidamycin （LDM） on telomerase activity in human hepatoma BEL-7402 cells under the condition of LDM inducing mitotic cell death and senescence. Methods Chromatin condensation was detected by co-staining with Hoechst 33342 and PI. Cell multinucleation was observed by Giemsa staining and genomic DNA was separated by agarose gel electrophoresis. Fluorescent intensity of Rho123 was determined for mitochondrial membrane potential. MTT assay and SA-13-gal staining were employed to analyze the senescence-like phenotype. The expression of proteins was analyzed by Western blot. Telomerase activity was assayed by telomerase PCR-ELISA. Results Mitotic cell death occurred in LDM-treated cells characterized by unique and atypical chromatin condensation, multinucleation and increased mitochondrial membrane potential. However, no apoptotic bodies or DNA ladders were found. In addition, apoptosis-related proteins remained nearly unaltered. Senescence-like phenotype was identified by increased and elongated size of cells, growth retardation, enhanced SA-13-gal activity and the changes of senescence-related protein expression. Telomerase activity markedly decreased （P〈0.01） in LDM-treated hepatoma BEL-7402 cells. Conclusion Mitotic cell death and senescence could be triggered simultaneously or sequentially after exposure of hepatoma BEL-7402 cells to LDM. The decrease in telomerase activity may play a key role in the defective mitosis and aging morphology. Further investigation of detailed mechanism is needed.
文摘IN the late 1970s, biochemical analysis and electron microscopy of isolated, histone-depleted mitotic chromosomes demonstrated the existence of a central scaffold consisting mainly of nonhistone proteins (NHPs) in metaphase chromosomes. Subsequently, by using silver impregnation techniques and light microscopy, Howell et al. showed the presence of an axial chromatid core in relatively intact chromosomes of mammals; this core is believed to be
文摘Human polo-like kinases （PLK1-PLK4） have been implicated in mitotic regulation and carcinogenesis. PLK1 phosphorylates early mitotic inhibitor 1 （Emil） to ensure mitosis entry, whereas Emi2 plays a key role during the meiotic cell cycle. Transcription factor E2F is primarily considered to regulate the G1/S transition of the cell cycle but its involvement in the regulation of mitosis has also been recently suggested. A gap still exists between the molecular basis of E2F and mitotic regulation. The present study was designed to characterize the transcriptional regulation of human PLK and Emi genes. Adenoviral overexpression of E2F1 increased PLK1 and PLK3 mRNA levels in A549 cells. A reporter gene assay revealed that the putative promoter regions of PLK1, PLK3, and PLK4 genes were responsive to activators E2F, E2F1-E2F3. We further characterized the putative promoter regions of Emil and Emi2 genes, and these could be regulated by activators E2F and E2F1-E2F4, respectively. Finally, PLK1-PLK4, Emil, and Emi2 mRNA expression levels in human adult, fetal tissues, and several cell lines indicated that each gene has a unique expression pattern but is uniquely expressed in common tissues and cells such as the testes and thymus. Collectively, these results indicate that E2F can integrate G1/S and G2/M to oscillate the cell cycle by regulating mitotic genes PLK and Emi, leading to determination of the cell fate.
文摘In a series of publications a special, tetraploid diplochromosomal division system to only two types of progeny cells (4n/4C/G1 and 2n/4C para-diploid) has been suggested to initiate preneoplasia that can lead to a cancerous pathway. Colorectal and other preneoplasia are known with the pathogenic, histological phases of hyperplasia to arrested adenoma/nevi that can give rise to dysplasia with high risk for cancer development. The present theme is to find solutions to tumorigenic unsolved, biological problems (queries), explainable from the tetraploid 4n-system, which would support its operation in the cancerous pathway. Presently admitted, the mutational sequencing of the cancer genome (cancer chemistry) cannot discover so-called “dark matter”, which herein is considered to be the queries. The solutions from the 4n-system were largely supported by mutated APC-induced same type of tetraploidy from the mitotic slippage process. But importantly, these behaviors and consequences could be linked to the beginning of hyperplastic lesions and their development to the arrest-phase of preneoplasia (polyps/nevi). Function of HFSMs is mostly unknown, but for Barrett’s esophagus, HFSMs (p53, p16ink4a) caused inactivation of the Rb gene, leading to dysplasia with 4n, aneuploid, abnormal cell cycles. In vitro models of the 4n-system from normal human cells recapitulated preneoplasia-like histopathological changes. It was speculated that the “cancer-crucial” step to dysplasia could be therapy-vulnerable to CRISPR-caspase editing, and perhaps antibody treatment. Additionally, the 4n-system with spontaneous cell-behaviors together with preneoplasia molecular data promises construction of a more truthful cancer-paradigm than from sequencing data alone.
文摘The objective herein was to connect the ontogeny process of diplochromosomal, amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in satellite, repetitive DNAs, especially in the chromosomal fragile sites, some 100 distributed over the genome. These latter studies had shown that chemical induced replication-stress led to un-replicated lesions in these fragile sites, which from inaccurate repair processes caused genomic instability. In the chain of events of the ontogeny process to the special tetraploidy, it was proposed that primary damaged human cells could undergo replication stress from repair-process present during cell replication, a suggestion verified by X-ray damaged cells producing the unstable fragile sites (see text). The cancer-importance for therapy is recognition of cell cycle change for the 4n derivative fitness-gained, diploid progeny cells. An open question is whether RB controlling G1 to S-period is mutated at this suggested tumorigenesis initiating phase, and if so, with what consequences for therapy. The fragile site studies further showed that repair of repetitive DNAs could produce two types of genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally located on “borders” to repairing satellite lesions. This genomic placement was found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC), favoring a bad luck location for their cancer “mutational nature”. The CNVs in cancers, are here seen as molecular expressions of long-known cytogenetic HSRs and DMs also with demonstrated origin from amplifications of single genes. Over-expression of oncogenes was hinted of being from duplications, but Drosophila genetics demonstrated the opposite, gene inactivation. The reduced eye-size from dominant, BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the genetic system for eye-size. The finding of CNVs showing “evasion” of the immune system suggests, inactivation of immune-determining genetics. Since
基金Supported by The Ministry of Science and Education(partially),Republic of Serbia,No.175091
文摘Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms.In complex organisms such as mammals,it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms,and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover.This event is familiar as loss of heterozygosity,which is one of the key mechanisms responsible for the development and progression of almost all cancers.We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma.The hypothesis could be tested by in vitro inhibition of Rad51 protein,orthotopic grafting of human colon cancer tissue into the gut of mice,and treatment with potential inhibitors.After these procedures,the frequency of mitotic crossover would be estimated.The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma,as well as many other neoplastic events.Loss of heterozygosity is an event responsible for carcinogenesis,its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention,as well as on growth reduction and a cessation in the progression of earlier developed tumors.
基金supported by the Chinese Ministry of Science and Technology (2019YFA0801401 to B.Z.)the Chinese Academy of Sciences (XDB39000000 and QYZDY-SSW-SMC031 to B.Z.+1 种基金2019 Special Research Assistant Funding to Y.L.)the National Natural Science Foundation of China (32000559 to Y.L.)。
文摘Decades of investigation on DNA methylation have led to deeper insights into its metabolic mechanisms and biological functions.This understanding was fueled by the recent development of genome editing tools and our improved capacity for analyzing the global DNA methylome in mammalian cells.This review focuses on the maintenance of DNA methylation patterns during mitotic cell division.We discuss the latest discoveries of the mechanisms for the inheritance of DNA methylation as a stable epigenetic memory.We also highlight recent evidence showing the rapid turnover of DNA methylation as a dynamic gene regulatory mechanism.A body of work has shown that altered DNA methylomes are common features in aging and disease.We discuss the potential links between methylation maintenance mechanisms and diseaseassociated methylation changes.
文摘Discs大同源相关蛋白5(Discs large homologous affinity protein 5,DLGAP5)是泛素-蛋白酶体途径调控的有丝分裂磷酸化蛋白,在细胞癌变过程中为细胞周期调节因子。DLGAP5的过表达不仅导致异常的细胞周期调控而且引起细胞有丝分裂过程的病理改变。本文综述DLGAP5的致病机制及其在NSCLC中的临床应用价值。
文摘In this study, freeze-dried water extract from the leaves of Myristica fragrans （Houtt.） was tested for mutagenic and antimutagenic potentials using the Allium cepa assay. Freeze-dried water extract alone and its combination with cyclophosphamide （CP） （50 mg/kg） were separately dissolved in tap water at 500, 1000, 2000, and 4000 mg/kg. Onions （A. cepa） were suspended in the solutions and controls for 48 h in the dark. Root tips were prepared for microscopic evaluation. 2,2-Diphenyl-l-picrylhydrazyl （DPPH） free radicals＇ scavenging power of the extract was tested using butylated hydroxyanisole （BHA） and butylated hydroxytoluene （BHT） as standards. Water extract of Myristica fragrans scavenged free radicals better than BHA, but worse than BHT. The extract alone, as well as in combination with CP suppressed cell division, and induced chromosomal aberrations that were insignificantly different from the negative control （P≤0.05）. However, cytotoxic and mutagenic actions of CP were considerably suppressed. The observed effects on cell division and chromosomes of A. cepa may be principally connected to the antioxidant properties of the extract. The obtained results suggest mitodepressive and antimutagenic potentials of water extract of the leaves of M. fragrans as desirable properties of a promising anticancer agent.
