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.

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.

THE EXPRESSIONS OF HBV X GENE AND ets-2, IGF-Ⅰ, c-myc AND N-ras ONCOGENES IN HUMAN HEPATOCELLULAR CARCINOMA AND TUMOR-ADJACENT TISSUES

The expressions of HBV X gene and ets-2, IGF-I, c-myc and N-ras were studied in 7 pairs of human primary hepatocellular carcinoma (PHC) and tumor-adjacent tissues, using RNA hybridization and im-munoblot methods. The results showed that specific 17 and 28 kD HBV X gene products (HBxAg) were existed in a portion of PHC and tumor-adjacent tissues. The 17 kD HBxAg was detected in the sera of 3 patients who also had 17 kD HBxAg in their liver tissues. Multiple expressions of oncogenes such as ets-2, c-myc and N-ras were observed in PHC and tumor-adjacent tissues that had HBxAg expressed, indicating HBxAg might function as a transactivator in the course of intracellular proto-oncogene activation. It is also observed that in some tumor-adjacnet tissues the expressions of ets-2, c-myc and N-ras were higher than those in corresponding PHC. The relationship of HBxAg to the expression of est-2, IGF-Ⅱ, c-myc and their possible roles in the carcinogenesis of PHC are discussed.

EXPRESSION OF CELLULAR ONCOGENES IN HUMAN PRIMARY HEPATOCELLULAR CARCINOMA

With DNA-mRNA hybridization in situ technique, the expression of five oncogenes, c-N-ras, c-Ki-ras. c-Ha-ras, c-myc and c-fos, was observed in two cases of human hepatocellular carcinoma. The expression of c-N-ras & c-fos was greatly enhanced in tumor tissues of the two cases, and about 25% -50% of the tumor cells showed positive expression. The other three oncogenes namely c-Ki-ras, c-Ha-ras & c-myc, were not detected in these two carcinomas or in the non-cancerous liver tissues adjacent to the carcinomas. It is surmised that c-N-ras and c-fos may play coordinative role in maintaining the malignant phenotype of human primary hepatocellular carcinoma.

Special Reports and Review ONCOGENES AND CELL IMMUNOGENITY：v－H－ras SUPPRESSING MHC CLASS I EXPRESSION IN MOUSE FIBROBLAST

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THE ROLE OF ONCOGENES AND ONCO-SUPPRESSOR GENES IN CARCINOGENESIS

Carcinogenesis is a multi-stage process.This process may involve both genetic and epi-genetic events. Analyses of the involvement ofgenetic events (mutations in the global sensewhich include point mutations, deletions, trans-locations and rearrangements of genetic mate-rial) in carcinogenesis have implicated twomajor classes of genes, oncogenes and onco-suppressor genes. Oncogenes, a term first usedby Huebner and Todaro, are derived by muta-tion of normal cellular genes, protooncogenes.More than 40 oncogenes have now been isolatedand found to encode proteins with diverse bio-chemical functions.

Proto-oncogenes expression in the process of asthma airway remodeling

Objective: To observe the expression of proto-oncogenes in the process of airway remodeling in asthma. Methods: Guinea pig was used as an asthma model challenged by ovoglobulin. Dot-blot, Northern-blot molecular hybridization and immunohistochemistry techniques were used to detect the expression of c-fos, c-myc, c-jun and c-sis. Results: Expression of c-fos and c-myc mRNA could not be detected or detected at very low level in the control group. There were greatly increased expression of c-fos and c-myc mRNA after guinea pigs were challenged by ovoglobulin. Thirty minutes after the challenge, the expression of c-fos and c-myc mRNA reached to the peak and returned to normal level 4 h after the challenge. Immunohistochemistry studies showed that Fos, Myc, Jun and Sis expressed at low level in control group and increased after ovoglobulin stimulation. Immunohistochemically positive cells laid in the plasma of airway epithelium, in cell nucleus of bronchial epithelium and in the inflammatory cells. Pathologic studies showed there were smooth muscle thicken around bronchia and lymphocytes infiltration under mucosa or around bronchia smooth muscle. Conclusion: Proto-oncogenes expressed in airway of asthma in a guinea pig model, proto-oncogenes may have roles in the process of airway remodeling.

Bioinformatics Analysis Revealed Potential Tumor Suppressors (KLF4/CGN), Oncogenes (SHH/LIF) and Biomarkers of Asian Stomach Adenocarcinoma

Stomach adenocarcinoma (STAD) is the fifth most prevalent cancer and the third leading cause of cancer-related death in the world and is more common in Asia than in most Western countries. There is an urgent need to identify potential novel oncogenes and tumor suppressor genes, and biomarkers for STAD. 6652 differentially expressed genes were identified between STAD and normal samples based on the transcriptome data analysis of the TCGA and GEO databases. 13 key modules were identified in STAD by WGCNA analysis. 293 potential STAD associated genes were identified from intersection by Venn Diagram. The 293 intersected genes were enriched in cell cortex and infection by GO and KEGG analysis. 10 hub genes were identified from PPI and Cytoscape analyses of the intersected genes. KLF4/CGN low and SHH/LIF high expression were associated with short overall survival of Asian STAD patients. Bioinformatics analysis revealed potential novel tumor suppressors (KLF4/CGN), oncogenes (SHH/LIF) and biomarkers for diagnosis, therapy and prognosis of STAD, specifically for Asian patients.

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.

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.

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.

Relationship between the high-risk HPV infection and the expression of oncogenes, anti-oncogenes in cervical dysplasia

Objective:To study the relationship between the infection of high-risk HPV in cervical precancerous lesion and the expression of oncogene, anti-oncogene.Methods:218 cases ofcervical intraepithelial neoplasia patients in our hospital during May 2014–May 2016 were chosed and divided into high-risk HPV group (n=107), low-risk HPV group (n=111) according to cervical tissue HPV test;another 100 cases of patients received cervical biopsy and confirmed as benign lesions were enrolled in the control group. RT-PCR method was used to detect the mRNA expression of proto-oncogene and anti-oncogene in three groups, Western-blot method was used to detect the protein expression of Sox-2 and Wnt/β-catenin signal pathway.Results: mRNA expression of oncogene DEK, Bmi-1, c-fos, K-ras, Prdx4 in high-risk HPV group were higher than low-risk HPV group and control group (P<0.05);mRNA expression of anti-oncogene P27, P16, DAPK, PTEN, eIF4E3 in high-risk HPV group were lower than low-risk HPV group and control group (P<0.05);expression of Sox-2 and Wnt/β-catenin signaling pathway protein Sox-2,β-catenin, wnt-1, wnt-3a in high-risk HPV group were higher than low-risk HPV group and control group (P<0.05).Conclusions:High-risk HPV infection can increase the expression of oncogenes and reduce the expression of anti-oncogenes in cervical dysplasia tissues on Sox-2- and Wnt/β-catenin signaling pathway manners.

THE EXPRESSION OF C-MYC AND N-RAS ONCOGENES IN HUMAN HEPATOCELLULAR CARCINOMA-AN IN SITU HYBRIDIZATION STUDY ON PARAFFIN EMBEDDED TISSUE SECTIONS

In this research, we investigated the expression of C myc and N-ras mRNAs on 21 cases paraffin- embedded tissue sections of hepatocellular carcinoma(HCC) using insitu hybridization technique with biotinylated labelled cDNA probes. Of 21 cases of hepatoma , C-myc mRNA was positive-expressed in 9 cases(42. 9 % ) and N-ras positive in 4 cases ( 19% ) in hepatoma cells, and C-myc and N-ras positive in 4 and 1 cases respectively in peritumor hepatocytes. C- myc mRNAs were localized within cytoplasms of both hepatoma cells and peritumor hepatocytes. However , the positive intensities of C-myc and N-ros mRNAs in hepatoma cells were much greater than those in peritumor hepatocytes. The results indicated that Cmyc and N-ras oncogenes were overexpressed in HCC, and may play an important role in coordinatively maintaince of the malignant phenotypes in HCC.

A study on the activation of 8 oncogenes and inactivation of 2 oncosuppressor genes in human gastric cancer

The changes of 8 oncogenes and 2 oncosuppressor genes in the specimens of cancer-ous and juxtacancerous tissues of 42 cases of gastric cancer were studied with southern blot hy-bridization and PCR-RFLP method.The probes used were c-Ha-ras,K-ras,N-ras,N-myc,c-myc,hst,EGFR,c-erbB-2,p53 and Rb.Amplification,rearrangement and deletion of c-Ha-ras were detected in 8/33 (24.2%) cases of gastric cancer,amplification or rearrangement ofhst and c-erbB-2 in 11/42 (26.2%) and 12/41 (29.2%) cases respectively,amplification ofEGFR in 9/42 (21.4%) cases,and deletion or rearrangement of p53 and Rb in 9/30 (30.0%)and 2/15 (13.3%) cases respectively.Amplification or rearrangement of N-ras (0/33),K-ras(1/26),N-myc (1/26),and c-myc (1/35)was rarely encountered.These findings suggest thatc-Ha-ras,hst,c-erbB-2,EGFR and p53 may be important genes involved in the pathogenesisof gastric cancer.

EXPRESSION OF ONCOGENES DURING INDUCED DIFFERENTIATION OF HUMAN HEPATOCARCINOMA CELL LINE

There was no detectable expression of c-fos,but a little c-myc,high c-fms and mederate high IGF-ⅡmRNA in the untreated human hepatocarcinoma cell SMMC- 7721.After treatment with 10 μmol/L retinoic acid or 0.5 mmol/L dibutyryl cyclic-3',5'adenosine monophosphate(db-cAMP),the c-fos was transiently expressed within 20- 60mins.If the treatment of RA or db-cAMP prolonged to 1-5 days, the transcriptions of c- myc were increased,reaching the highest level on the 2nd and 4th day.Simultaneously the transcriptions of c- fms and IGF- Ⅱwere gradually decreased.On the 5th day of the treatment,c-fms and IGF-ⅡmRNA were decreased to 32% and 14%respectively of the control (untreated cell) value by RA,and 35% and 22%respectively by db-cAMP.The biological significance of the above mentioned results was discussed.

Amplification of three oncogenes c－myc，N－ras and c－erbB of ovarian tumor tissue

In the present study,using nucleic acid hybridization technique with [α-32P] dATP labelled c-myc,Nras and c-erbB as gene probes fwe carried out dot hybridization in 17 cases of primary ovarian cancer,3 recurrent ovarian cancer,2 malignant germinoma,5 ovarian serous cystadenoma and 4 normal controls and also performed southern blot hybridization in some of these cases. The results showed that there existed various degrees of amplification of the 3 oncogenes in ovarian tumor tissue. c-myc was amplified in 12 cases (54. 5 %),N-ras in 14 (64.1 %) and c-erbB in 7 (31. 8%),which were markedly higher than that in benign ovarian tumors & normal ovarian tissue. Moreover, simultaneous amplification of two or more oncogenes was noted in 40. 9 % of cases. The findings also revealed that c-myc amplification was negatively correlated with cell differentiation (P<0. 05). Higher degree of N-ras amplification was present in phase Ⅲ - Ⅳ ovarian cancer. Though the level of c-erbB amplification was lower than that of myc & ras,the postoperative survival time of 7 patients with amplification was 9 months,which is shorter than that of the patients without amplification.

THE EXPRESSION OF PROTOONCOGENES IN HUMAN GASTRIC CANCER CELL LINES AND PRIMARY GASTRIC CANCERS DEFINED BY IN SITU HYBRIDIZATION

The expression of several protooncogenes was detected in three different differentiated gastric cancer cell lines (MKN28, MKN45, SGC7901) and 5 specimens from 5 human primary gastric cancers at cellular level by in situ hybridization. The data indicated that there were high levels of c-Ha-ras expression in both cell lines and tumor tissues as compared with control samples. But the transcripts of c-myc and c-erbB were rather low. The results suggested that Ha-ras be involved in or associated with the gastric cancer. There were another two interesting findings: (1) The levels of c-Ha-ras was different among the individual cancer cells within a single gastric cnacer. (2) Some inflammatory cells in the tumor tissuse and normal tissues adjacent to the cancer displayed high level of c-Ha-ras expression. Those two phenomena are worthwhile for further study.

Distinct Transforming Activity of ABL Family Tyrosine Kinase Oncogenes Is Induced by Their C-Terminal Domain

The TEL/ARG oncogene is similar in structure to the TEL/ABL fusion found in human leukemia, however, we have demonstrated previously that the expression of TEL/ARG in Ba/F3 cells does not sustain strong activity of proliferation, whereas, that of TEL/ABL appeared to induce immediate cell proliferation. To study the molecular basis of the difference in the transforming activity of TEL/ARG and TEL/ABL, TEL/ARG mutants that swapped the kinase domain or C-terminus of ARG with the corresponding domain in ABL were generated, and each mutant was expressed in Ba/F3 cells. A TEL/ARG mutant containing the ABL kinase domain was similar to TEL/ARG in this study, but replacing the ARG C-terminal domain with that of ABL resulted in accelerated proliferation that was similar to that of TEL/ABL. When expressed in primary mouse bone marrow cells by retroviral transduction, spontaneous colony formation in methylcellulose culture was observed, in a fashion dependent on the C-terminal portion of ABL. These results indicate that distinct bio-phenotypes associated with these oncogenes are likely to be regulated by their C-termini, and the C-terminus of ARG contains a functional subdomain that impairs the growth signal induced by ABL family tyrosine kinase.

Correlation of the ultrasonic elastography strain rate of malignant thyroid nodules with the expression of oncogenes and angiogenesis genes

Objective: To study the correlation of the ultrasonic elastography strain rate of malignant thyroid nodules with the expression of oncogenes and angiogenesis genes. Methods: Patients with thyroid nodules who underwent ultrasonography in this hospital between March 2015 and February 2017 were selected, and the tissue properties were judged according to the results of fine needle aspiration biopsy;ultrasonic elastography was done to measure the strain rate ratio, and the fluorescence quantitative PCR reaction was performed to determine the mRNA expression of oncogenes and angiogenesis genes. Results: The strain rate ratio of malignant thyroid nodules was greatly lower than that of benign thyroid nodules;CCNG and RASSF1A mRNA expression in malignant thyroid nodules were greatly lower than those in benign thyroid nodules whereas FF3, TPX2, WIP1, Ang2, Tie2, VEGF, VEGFR1, c-met and Survivin mRNA expression were greatly higher than those in benign thyroid nodules;CCNG and RASSF1A mRNA expression in malignant thyroid nodules with low strain rate ratio were greatly lower than those in malignant thyroid nodules with high strain rate ratio whereas FF3, TPX2, WIP1, Ang2, Tie2, VEGF, VEGFR1, c-met and Survivin mRNA expression were higher than those in malignant thyroid nodules with high strain rate ratio. Conclusion: The increase in ultrasonic elastography strain rate ratio of malignant thyroid nodules is closely related to the changes in the expression of oncogenes and angiogenesis genes.

Correlation of small hepatocellular carcinoma ultrasonography parameters with the expression of oncogenes and angiogenesis genes

Objective: To investigate the correlation of small hepatocellular carcinoma ultrasonography parameters with the expression of oncogenes and angiogenesis genes. Methods: A total of 61 patients with small hepatocellular carcinoma who were diagnosed in this hospital between July 2015 and May 2017 were selected as small hepatocellular carcinoma group, and 48 patients with hepatolithiasis were selected as hepatolithiasis group. The ultrasonography parameters of the two groups were recorded and the expression levels of oncogenes and angiogenesis genes in the surgical lesion tissues were detected. Pearson test was used to evaluate the correlation of ultrasonography parameters with the expression of oncogenes and angiogenesis genes. Results: IMAX level in small hepatocellular carcinoma group was higher than that in hepatolithiasis group while TTP and mTT levels were lower than those in hepatolithiasis group;oncogenes C-myc, N-ras, PIK3CA, RMP, Bmil and pim-3 mRNA expression in lesion tissues were higher than those of hepatolithiasis group;angiogenesis genes VEGF, Ang-1, Tie-2 and MACC1 mRNA expression in lesion tissues were higher than those of hepatolithiasis group while ARH1 mRNA expression was lower than that of hepatolithiasis group. Pearson test showed that the ultrasonography parameters IMAX, TTP and mTT levels in patients with small hepatocellular carcinoma were directly correlated to the expression of oncogenes and angiogenesis genes in lesions. Conclusion: The ultrasonography parameters of patients with small hepatocellular carcinoma are significantly different from those of patients with benign diseases, and the specific parameter levels are directly correlated with the malignancy of cancer cells.