Tanshinone ⅡA improves Alzheimer’s disease via RNA nuclearenriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has shown potential neuroprotective effects;however,the mechanisms underlying such a function remain unclear.AIM To investigate potential Tan-ⅡA neuroprotective effects in AD and to elucidate their underlying mechanisms.METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology.To assess changes in oxidative stress and neuroinflammation,we performed enzyme-linked immunosorbent assay and western blotting.Additionally,the effect of Tan-ⅡA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Genetic changes related to the long non-coding RNA(lncRNA)nuclear-enriched abundant transcript 1(NEAT1)/microRNA(miRNA,miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.RESULTS In vivo,Tan-ⅡA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice.In vitro experiments showed that Tan-ⅡA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability,apoptosis,oxidative stress,and neuroinflammation.In this process,the lncRNA NEAT1-a potential therapeutic target-is highly expressed in AD mice and downregulated via Tan-ⅡA treatment.Mechanistically,NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p,which activates nuclear factor kappa-B(NF-κB)signaling,leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein,which exacerbates AD.Tan-ⅡA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.CONCLUSION This study demonstrates that Tan-ⅡA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway,serving as a foundation for the development of innovative approaches for AD therapy.

The role of tazarotene-induced gene 1 in carcinogenesis:is it a tumor suppressor gene or an oncogene?

Tazarotene-induced gene 1(TIG1)is induced by a derivative of vitamin A and is known to regulate many important biological processes and control the development of cancer.TIG1 is widely expressed in various tissues;yet in many cancer tissues,it is not expressed because of the methylation of its promoter.Additionally,the expression of TIG1 in cancer cells inhibits their growth and invasion,suggesting that TIG1 acts as a tumor suppressor gene.However,in some cancers,poor prognosis is associated with TIG1 expression,indicating its protumor growth characteristics,especially in promoting the invasion of inflammatory breast cancer cells.This review comprehensively summarizes the roles of the TIG1 gene in cancer development and details the mechanisms through which TIG1 regulates cancer development,with the aim of understanding its various roles in cancer development.

Concomitant epidermal growth factor receptor mutation/c-ros oncogene 1 rearrangement in non-small cell lung cancer: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.

TCGA-based analysis of oncogenic signaling pathways underlying oral squamous cell carcinoma

Background:Oral squamous cell carcinoma(OSCC)represents a prevalent malignancy in the oral and maxillofacial area,having a considerable negative impact on both the quality of life and overall survival of affected individuals.Our research endeavors to leverage bioinformatic approaches to elucidate oncogenic signaling pathways,with the ultimate goal of gaining deeper insights into the molecular underpinnings of OSCC pathogenesis,and thus laying the groundwork for the development of more effective therapeutic and preventive strategies.Methods:Differential expression analysis was performed on mRNA data from tumor and normal tissue groups to identify genes associated with OSCC,using The Cancer Genome Atlas database.Predictions of oncogenic signaling pathways linked to differentially expressedmRNAs were made,and these results were presented visually using R software,using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichments.Results:GO and KEGG analyses of 2938 differentially expressed genes in OSCC highlighted their significant involvement in various biological processes.Notably,these processes were related to the extracellular matrix,structural organization,connective tissue development,and cell cycle regulation.Conclusions:The comprehensive exploration of gene expression patterns provides valuable insights into potential oncogenic mechanisms in OSCC.

Expressions of oncogenes c-fos and c-myc in skin lesion of cutaneous squamous cell carcinoma

Objective:To explore the expressions of c-fos and c-myc in skin lesion of cutaneous squamous cell carcinoma(CSCC).Methods:Using retrospective analysis.73 cases of CSCC were selected from Department of Dermatology,the Second Affiliated Hospital of Xi'an Jiaotong University.which were removed between January 2000 and January 2012.It was considered as experimental group.Meanwhile.11 cases of normal skin specimens of non tumor patients were selected as control group.The expression level of c-fos and c-myc was compared in the two groups.Results:The expressions of c-fos[72.60%(53/73)]and c-myc[83.56%(61/73)]in experimental group were statistically significant(P≤0.05)compared with control group(0%).Expression of c-myc protein was negatively related to differentiation of CSCC.The difference was statistically significant(X^2=7.26.P=0.001<0.05).While expression of c-fos protein was positively related to differentiation of CSCC.which was statistically significant(X^2=7.47,P=0.0012<0.025).Conclusions:The expression level of c-fos and c-myc can be used as an importan indicator of CSCC differentiation,and it has closely connection with the differentiated degree,which can guide clinical prognosis.

Study of differential polymerase chain reaction of C-erbB-2 oncogene amplification in gastric cancer

AIM To study the significance of C-erbB-2 oncogene amplification in gastric cancer.METHODS C-erbB-2 oncogene amplification was examined by using differential polymerase chain reaction (dPCR) in surgical and endoscopic specimens of 83 cases of gastric cancer and 101 metastatic lymph nodes.RESULTS C-erbB-2 amplification was found in 28.9% (24/ 83) surgical specimens and 20.5% (17/ 83) endoscopic ones of gastric cancer patients. The amplification was significant in both types of specimens of advanced cancer cases (P＜0.05) and surgical specimens with lymph node metastasis (P＜0.01). The incidence of C-erbB-2 amplification in lymph nodes with metastasis was higher than in primary sites (surgical specimens, P＜0.05). The patients with amplification tumors had poorer 5-year survival rates than those with unamplification ones in the early cancers and well to moderately differentiated adenocarcinomas (P＜0.05). The same surgical samples were tested again by Southern blot hybridization to ascertain C-erbB-2 amplification, and the positive rate of C-erbB-2 amplification (15.7%) was lower than that of dPCR (28.9%, P＜0.05).CONCLUSION Examining C-erbB-2 amplification by dPCR is a quick, simple, reliable and independent method, and is helpful in predicting prognosis and metastatic potential of gastric cancer.

Dual fluorescence in situ hybridization in detection of HER-2 oncogene amplification in primary hepatocellular carcinoma

BACKGROUND: Molecular cytogenetics of oncogene HER-2 amplification in primary hepatocellular carcinoma (HCC) is still unknown. The aim of this study was to in vestigate the frequency of HER-2 oncogene amplification in primary HCC and its relations to clinicopathological pa rameters and prognosis. METHODS: Forty-two surgical samples from patients with primary HCC were detected for their HER-2 oncogene am plification. The number of chromosome 17 and their ratio were tested by dual fluorescence in situ hybridization (FISH) technique, and then the correlations between HER-2 amplification, clinicopathological characteristics and prog nosis were analyzed statistically. RESULTS: HER-2 oncogene amplification was detected in 9 (21.4%) of the 42 primary HCCs, including 4 patient with high copy (HC) (9.5%) and 5 patients with low copy (LC) (11.9%). HER-2 amplification was associated signifi cantly with tumor size and postoperative survival time o HCC patients (P<0.05), and the presence of HER-2 gene amplification was correlated with postoperative relapse (P— 0.257), but not related to sex, age, AFP level, HBV infec tion, histopathological grading and clinical staging of HCC patients (P>0.05). The HER-2 oncogene copy was exa mined in 31 (73.8%) of the 42 primary HCCs, consisting of 9 patients with HER-2 amplification (21.4%) and 22 pa tients with aneuploidy (52.4%). No significant relation were observed between the HER-2 oncogene copy, patien sex, tumor size, histopathological grading, clinical stag ing, postoperative relapse and survival time (P >0.05); bu the HER-2 oncogene copy was correlated significantly to age, AFP level and HBV infection (P <0.05). CONCLUSIONS: There are a lower frequency of HER-2 oncogene amplification and a higher frequency of chromo- some 17 aneuploidy in primary HCC. HER-2 oncogene amplification may be involved in the development and pro- gression of large HCC in some patients, and seems to be a valuably independent prognostic factor predicting the re- currence and poor survival in patients with large HCC.

Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma

AIM: To identify the downstream regulated genes of GAEC1 oncogene in esophageal squamous cell carcinoma and their clinicopathological significance. METHODS: The anti-proliferative effect of knocking down the expression of GAEC1 oncogene was stud-ied by using the RNA interference (RNAi) approach through transfecting the GAEC1 -overexpressed esophageal carcinoma cell line KYSE150 with the pSilencer vector cloned with a GAEC1 -targeted sequence, followed by MTS cell proliferation assay and cell cycle analysis using flow cytometry. RNA was then extracted from the parental, pSilencer-GAEC1 -targeted sequence transfected and pSilencer negative control vector transfected KYSE150 cells for further analysis of different patterns in gene expression. Genes differentially expressed with suppressed GAEC1 expression were then determined using Human Genome U133 Plus 2.0 cDNA microarray analysis by comparing with the parental cells and normalized with the pSilencer negative control vector transfected cells. The most prominently regulated genes were then studied by immunohistochemical staining using tissue microarrays to determine their clinicopathological correlations in esophageal squamous cell carcinoma by statistical analyses. RESULTS: The RNAi approach of knocking down gene expression showed the effective suppression of GAEC1 expression in esophageal squamous cell carcinoma cell line KYSE150 that resulted in the inhibition of cell proliferation and increase of apoptotic population. cDNA microarray analysis for identifying differentially expressed genes detected the greatest levels of downregulation of calpain 10 (CAPN10 ) and upregulation of trinucleotide repeat containing 6C (TNRC6C ) transcripts when GAEC1 expression was suppressed. At the tissue level, the high level expression of calpain 10 protein was significantly associated with longer patient survival (month) of esophageal squamous cell carcinoma compared to the patients with low level of calpain 10 expression (37.73 ± 16.33 vs 12.62 ± 12.44, P = 0.032). No significant correction was observed among the TNRC6C protein expression level and the clinocopathologcial features of esophageal squamous cell carcinoma. CONCLUSION: GAEC1 regulates the expression of CAPN10 and TNRC6C downstream. Calpain 10 expression is a potential prognostic marker in patients with esophageal squamous cell carcinoma.

Studies on Hepatocyte Apoptosis, Proliferation and Oncogene c-fos Expression in Carbon Tetrachloride-induced Cirrhotic Rat Liver

Summary: To investigate the significance of hepatocyte apoptosis, proliferation and oncogene c fos expression in carbon tetrachloride (CCl 4) induced cirrhotic rat liver. Rat cirrhosis was induced by subcutaneous injection of 50 % (v∶v 1∶1) CCl 4. Hepatocyte apoptosis, proliferation and oncogene c fos expression were examined with TUNEL, PCNA and c fos immunohistochemical methods in control group and treatment group 72 h, 5, 7, 11 and 15 weeks after CCl 4 induction. Hepatocyte apoptosis was rarely seen in control rat liver. The hepatocyte apoptosis was obviously increased 72 h after treatment. Fifteen weeks after treatment, the apoptosis was still more obvious in treatment group than that in controls. PCNA was constantly expressed in CCl 4 group, with highest level at middle phase. C fos was positive 7 and 11 weeks after CCl 4 treatment. The results suggest that: 1) apoptosis is involved in rat liver damage at the early phase in CCl 4 induced injury, and the process can alleviate nodule reconstruction or eradicate potentially mutational hepatocytes at the later phase; 2) hepatocytes constantly proliferate in CCl 4 induced rat liver cirrhosis, especially at the middle phase; 3) c fos might modulate hepatocyte proliferation in CCl 4 induced rat liver cirrhosis.

The relationship between point mutation and abnormal expression of c-fms oncogene in hepatocellular carcinoma

BACKGROUND: Recent research found abnormal expres- sion of the c-fms oncogene, which encodes the macro- phage colony-stimulating factor receptor (CSF-1R), in several human carcinomas including hepatocellular carcino- ma (HCC). But the relationship between the point muta- tion and abnormal expressing of c-fms oncogene in HCC was not clear. This study is to investigate the relationship between point mutation and abnormal expression of c-fms oncogene in hepatocellular carcinoma (HCC) and to clari- fy the mechanism of HCC. METHODS: The expression of c-fms oncogene at different levels of cell, protein and transcription was observed using immune histological ABC, Western blot and Northern blot. PCR-single strand conformation polymorphism and gene sequencing were used to detect the mutation of c-fms in HCC tissues and their surrounding tissues of 30 patients. RESULTS: The expression of c-fms was significantly higher in HCC tissues than in their surrounding tissues (P <0.01). Point mutation of Leu (TTG)—>Ser (TCG) at codon 301 of c-fms amino acids was observed in 21.4% (3/14) HCC tissues. No mutation of c-fms oncogene was detected in the surrounding cancerous tissues. CONCLUSION: Point mutation at codon 301 of c-fms on- cogene is one of the mechanisms of abnormal over-expres- sion in HCC.

MUTATION AND CLINICAL SIGNIFICANCE OF C-FMS ONCOGENE IN HEPATOCELLULAR CARCINOMA

Objective: To study the clinical significance and relationship between c-fms oncogene and hepatocellular carcinogenesis, to further clarify the occurring mechanism of hepatocellular carcinoma (HCC). Methods: PCR-SSCP technique was used to analyse mutation of c-fms oncogene in 30 cases of HCC tissues. Sequencing the PCR products after cloning to prove the mutations, meanwhile the relationship between c-fms mutations and clinical pathology of HCC was investigated. Results: Two abnormal single strands were observed in 10% (3/30) HCC tissues from c-fms DNA corresponding to 301st codon of c-fms amino acids. PCR products of abnormal single strands were sequenced after cloning, it demonstrated that there was transition of T→C at nucleic acid 14855 of c-fms DNA, which corresponded to transition of Leu (TTG)→Ser (TCG) at 301st codon of c-fms amino acids. The mutation was related to malignant degree and type of HCC tissues as well as patient’s age. Conclusion: Mutation of c-fms codon at site 301 implied a molecular mechanism contributing to hepatocellular carcinogenesis.

Expression and distribution of c-fos oncogene within central nervous system of the rat following halothane anesthesia

Objective: To study the distribution of c fos oncogene expression within central nervous system (CNS) of the rat during halothane anesthesia. Methods: c-fos oncogene immunohistochemical technique (ABC method) was employed. Results: When halothane concentration was 0.75%,1.5%or2.0%, most of the Fos-like immunore- active neurons (FLNs) appeared in telencephalon, diencephalon and brain stem, including cerebral cortex, amygaloid nucleus, accumbens nucleus, lateral keptal nucleus. bed nucleus of the stria terminalis, field CA1 of Ammon’s horn, islands of Calleja, paraventricular thalamic nucleus, central medial thalamic nucleus, reuniens thalamic nucleus, rhomboid thalamic nucleus. ventral posterolateral thalamic nucleus, paraventricular hypothalamic nucleus(ventral part). periventricular hypothalamic nucleus, median preoptic nucleus, supraoptic nucleus, suprachiasmatic nucleus. medial and lateral habenular nucleus. midbrain periaqueductal gray and Edinger-Westphal nucleus.In the present stude. we have also found that the number of FLN registered stable increase along with the increaseof the concentration of halothane. Conclusion: It has been indicated that FLNs participate in the process ofhalothane anesthesia. which should necessitate and pave the way for a further study of the patterns of linkage andthe mechanism of interaction between functional nuclei.

EXPRESSION OF CELLULAR ONCOGENES IN PRIMARY CELLS FROM HUMAN LEUKEMIAS

The expression of three protooncogenes (c-myc, c-fos, N-ras) in.the primary cells from 53 cases of leukemia as well as peripheral WBC from 8 normal individuals was studied. Semiquantitative analysis of mRNA levels of the protooncogenes was carried out by Quick-blot. The results showed that (1) c-myc oncogene was slightly expressed and Nras was marginally expressed, whereas the expression of the c-fos was undetectable in the peripheral leucocytes of 8 normal individuals; (2) the c-myc was obviously expressed in almost all leukemic cells irrespective of the cell types, while N-ras and c-fos were variable expressed; (3) the c-fos was expressed in all 4 cases of M4; (4) the c-myc transcript was detected but the N-ras and c-fos were not in 4 chronic leukemic cases; (5) the relationship between protooncogene expression and state of leukemia or after chemotherapy was also analysed.

The significance of proto-oncogene HGF/SF receptor c-Met mRNA expression in nasopharyngeal carcinoma

Objective: To explore the expression of c-Met mRNA in nasopharyngeal carcinomas (NPC) and its relation with clinical biological behavior. Methods: In situ hybridisation was used to detect mRNA expression of c-Met in 15 cases of non-tumor nasopharyngeal (NP), 55 cases of NPC. Results: The positive rates of c-Met mRNA in NP and NPC cells were 13.3% (2/15) and 61.8% (34/55) respectively. The expression of c-Met mRNA was significantly correlated with lymph node metastasis, local invasion (skull base erosion), and clinical stage. In cases with cervical lymph node metastasis, local invasion, and clinical stage III and IV (UICC), the positive rates of expression of c-Met mRNA were significantly higher than that in those without the conditions mentioned above (P < 0.05 or P < 0.01). But it was not significantly correlated with age, gender, histo- logic grade, and cranial nerve palsy (P > 0.05). Conclusion: The abnormal expression of c-Met gene was well correlated with the biological behavior of metastasis and invasion. To detection the expression of c-Met mRNA could serve as an important index to estimate the prognosis of NPC. C-Met may be a new diagnostic/therapeutic target of NPC.

PDRG1 at the interface between intermediary metabolism and oncogenesis

PDRG1 is a small oncogenic protein of 133 residues. In normal human tissues, the p53 and DNA damageregulated gene 1(PDRG1) gene exhibits maximal expression in the testis and minimal levels in the liver. Increased expression has been detected in several tumor cells and in response to genotoxic stress. High-throughput studies identified the PDRG1 protein in a variety of macromolecular complexes involved in processes that are altered in cancer cells. For example, this oncogene has been found as part of the RNA polymerase Ⅱ complex, the splicing machinery and nutrient sensing machinery, although its role in these complexes remains unclear. More recently, the PDRG1 protein was found as an interaction target for the catalytic subunits of methionine adenosyltransferases. These enzymes synthesize S-adenosylmethionine, the methyl donor for, among others, epigenetic methylations that occur on the DNA and histones. In fact, downregulation of S-adenosylmethionine synthesis is the first functional effect directly ascribed to PDRG1. The existence of global DNA hypomethylation, together with increased PDRG1 expression, in many tumor cells highlights the importance of this interaction as one of the putative underlying causes for cell transformation. Here, we will review the accumulated knowledge on this oncogene, emphasizing the numerous aspects that remain to be explored.

Expression of bcl-2 oncogene in gastric precancerous lesions and its correlation with syndromes in traditional Chinese medicine

AIM: To observe the protein and mRNA expression of bcl-2 oncogene in gastric precancerous lesions (GPL) and to analyze its correlation with syndromes in traditional Chinese medicine (TCM). METHODS: Sixty-seven patients with GPL confirmed by gastroscopy and pathology were studied,including 39 cases of moderate gastric mucosal dysplasia,19 cases of severe gastric mucosa dysplasia, 9 cases of incomplete colon metaplasia. In syndrome differentiation of TCM,17 cases belonged to the syndrome of qi and yin deficiency of the spleen and stomach complicated by qi stagnation, 21 cases belonged to the syndrome of qi and yin deficiency of the spleen and stomach complicated by stomach heat, 29 cases belonged to the syndrome of qi and yin deficiency of the spleen and stomach complicated by blood stasis. Protein and mRNA expression of bcl-2 oncogene were detected by labeled streptavidin biotin (LSAB) immunohist-ochemistry and in situ hybridization respectively. RESULTS: Abnormal expression of protein and mRNA on bcl-2 oncogene was found in GPL,which increased gradually with the course of lesions. In moderate and severe gastric mucosal dysplasia and incomplete colon metaplasia,there was no difference in the expression of bcl-2 oncogene (P>0.05).In different accompanying syndromes, the expression of protein and mRNA on bcl-2 oncogene increased gradually in the following order: deficiency of both qi and yin of the spleen and stomach accompanying qi stagnation→stomach heat→blood stasis. In GPL, compared with accompanying blood stasis, there was an obvious difference in the expression of bcl-2 oncogene between the syndrome of qi and yin deficiency of the spleen and stomach and accompanying stomach heat, so did accompanying qi stagnation (the level of protein: X2=8.45, P<0.05;the level of mRNA: X2=7.35, P<0.05). CONCLUSION: Apoptosis-associated bcl-2 oncogene is abnormally expressed in GPL,which correlates with different accompanying syndromes in TCM.

THE EXPRESSION OF C－erbB－1 AND C－erbB－2ONCOGENES IN BASAL CELL CARCINOMA ANDSQUAMOUS CELL CARCINOMA OF SKIN

The expression of c-erbB-1 and c-erbB-2 oncogenes were investigated by immunohistochemistry using monoclonal antibodies to c-erbB-2 and c-erbB-2 protein in 43 cases of basal cell carcinoma (BCC) and 26 cases of squamous cell carcinoma (SCC). We found that the expression of c-erbB-1 oncogene in all BCC increased by different degrees and the expression of c-erbB-2 oncogene in BCC was significantly reduced or lost when compared to that in normal epidermal cells. Furthermore, apparent negative and positive rela-tionships were observed respectively between the tumor differentiation and the expression of cerbB-1 and c-erbB-2 oncogenes in SCC. It is suggested that the abnormal expression of c-erbB-1 and c-erbB-2 oncogenes in BCC and SCC may play a role in the development of skin tumors. The pattern of the c-erbB-1 and c-erbB-2 oncogenes expression in SCC may assist in distinguishing the biological behavior and prognosis of SCC.

Downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival

Sustained expression of the Spi-1/PU.1 and Fli-1 oncoproteins blocks globin gene activation in mouse erythroleukemia cells; however, only Spi-1/PU.1 expression inhibits the inclusion of exon 16 in the mature 4.1R mRNA. This splicing event is crucial for a functional 4.1R protein and, therefore, for red blood cell membrane integrity. This report demonstrates that Spi-1/PU.1 downregulation induces the activation of TRIM10/hematopoietic RING finger 1 （HERF1）, a member of the tripartite motif （TRIM）/RBCC protein family needed for globin gene transcription. Additionally, we demonstrate that TRIM10/HERF1 is required for the regulated splicing of exon 16 during late erythroid differentia- tion. Using inducible overexpression and silencing approaches, we found that： （1） TRIM10/HERF1 knockdown inhibits hemoglobin production and exon splicing and triggers cell apoptosis in dimethylsulfoxide （DMSO）-induced cells; （2） TRIM10/HERF1 upregulation is required but is insufficient on its own to activate exon retention; （3） Fli-1 has no effect on TRIM10/HERFI expression, whereas either DMSO-induced downregulation or shRNA-knockdown of Spi-I/PU.I expression is sufficient to activate TRIM10/HERF1 expression; and （4） Spi-1/PU.1 knockdown triggers both the transcription and the splicing events independently of the chemical induction. Altogether, these data indicate that primary Spi-1/PU.1 downregulation acts on late erythroid differentiation through at least two pathways, one of which requires TRIM10/HERF1 upregulation and parallels the Spi-1/PU.1-induced Fli-1 shutoff regulatory cascade.

Oncogenes, Oncogenesis, and Oxygen Radicals

The role that free radicals in general and oxygen radicals in particular play in carcinogenesis has attracted considerable attention in recent years. The oxygen radicals are undesirable but inevitable products of aerobic metabolism in the normal living cell. The cellular antioxidant defense system maintains an appropriate balance between necessary oxidative events and those that are excessive. When this critical balance cannot be maintained because of the overloading of the cellularredox system, oxygen radicals can induce cell damage. They can influence carcinogenesis by inducing DN A damage from direct oxidation or indirectly from DNA-binding products of lipid peroxidation. Oxygen radicals can induce conformational changes in the plasma membrane by lipid peroxidation and protein degradation, thus influencing membrane-associated cellular activities. They are capable of affecting membrane-bound protein kinases, growth factors and their receptors, and, therefore, signal transduction and oncogene activation. Thus, the oxygen radicals can have a major influence on oncogenes and oncogenesis. (C)1990 Academic Press.Inc.

Identification of APEX2 as an oncogene in liver cancer

BACKGROUND DNA damage is one of the critical contributors to the occurrence and development of some cancers.APEX1 and APEX2 are the most important molecules in the DNA damage,and APEX1 has been identified as a diagnostic and prognostic biomarker in liver hepatocellular carcinoma(LIHC).However,the expression of APEX2 and its functional mechanisms in LIHC are still unclear.AIM To examine the expression of APEX2 and the potential mechanism network in LIHC.METHODS We conducted a pan-cancer analysis of the expression of APEX1 and APEX2 using the interactive TIMER tool.GEO datasets,including GSE14520,GSE22058,and GSE64041,were used to compare the APEX2 expression level in tumor tissues and adjacent non-tumor tissues.Then,we calculated the 5-year survival rate according to the web-based Kaplan-Meier analysis.We included the TCGA liver cancer database in GSEA analysis based on the high and low APEX2 expression,showing the potential mechanisms of APEX2 in LIHC.After that,we conducted Pearson correlation analysis using GEPIA2.Next,we performed quantitative polymerase chain reaction(qPCR)assay to examine the APEX2 levels in normal liver cell line LO2 and several liver cancer cell lines,including HepG2,Huh7,SMMC7721,and HCCLM3.APEX2 in HCCLM3 cells was knocked down using small interfering RNA.The role of APEX2 in cell viability was confirmed using CCK-8.Dualluciferase reporter assay was performed to examine the promoter activity of CCNB1 and MYC.RESULTS APEX1 and APEX2 are both highly expressed in the tumor tissues of BLCA,BRCA,CHOL,COAD,ESCA,HNSC,LIHC,LUAD,LUSC,READ,and STAD.APEX2 overexpression in LIHC was validated using GSE14520,GSE22058,and GSE64041 datasets.The survival analysis showed that LIHC patients with high expression of APEX2 had a lower overall survival rate,even in the AJCC T1 patients.High level of APEX2 could indicate a lower overall survival rate in patients with or without viral hepatitis.The GSEA analysis identified that kinetochore and spindle microtubules are the two main cellular components of APEX2 in GO Ontology.APEX2 was also positively associated with molecular function regulation of chromosome segregation and DNA replication.The results of KEGG analysis indicated that APEX2 expression was positively correlated with cell cycle pathway and pro-oncogenic MYC signaling.Pearson correlation analysis showed that APEX2 had a significant positive correlation with CCNB1 and MYC.APEX2 level was higher in liver cancer cell lines than in normal liver LO2 cells.Small interfering RNA could knock down the APEX2 expression in HCCLM3 cells.Knockdown of APEX2 resulted in a decrease in the viability of HCCLM3 cells as well as the expression and promoter activity of CCNB1 and MYC.CONCLUSION APEX2 is overexpressed in LIHC,and the higher APEX2 level is associated with a worse prognosis in overall survival.APEX2 is closely involved in the biological processes of chromosome segregation and DNA replication.APEX2 expression is positively correlated with the pro-oncogenic pathways.Knockdown of APEX2 could inhibit the cell viability and CCNB1 and MYC pathways,suggesting that APEX2 is an oncogene in LIHC,which could be a potential pharmaceutic target in the anti-tumor therapy.