Four proto-oncogenes commonly associated with well-differentiated thyroid carcinoma, rearranged during transfection (RET)/papillary thyroid cancer, BRAF, RAS, and PAX8/peroxisome proliferator activated receptor-gamma, may carry diagnostic and prognostic significance. These oncogenes can be used to improve the diagnosis and management of well-differentiated thyroid carcinoma. Limited therapeutic options are available for patients with metastatic well-differentiated thyroid cancer, necessitating the development of novel therapies. Vascular endothelial growth factor (VEGF)- and RET-directed therapies such as sorafenib, motesanib, and sunitinib have been shown to be the most effective at inducing clinical responses and stabilizing the disease process. Further clinical trials of these therapeutic agents may soon change the management of thyroid cancer.
Diagnosis ; Humans ; Oncogenes ; Proto-Oncogenes ; Thyroid Neoplasms* ; Transfection ; Vascular Endothelial Growth Factor A

There are a lots of evidences that colorectal cancer arise as a result of multiple alterations of genes. Many attempts were made to understand the role of oncogenes and suppressor genes as a prognostic indicator, recently. Although histopathologic staging of tumor is the most important prognostic factor up to now, it is not enough to be used with full confidence. Apoptosis or programmed cell death represents a deletion of damaged or natural cell mechanism. The bel-2 proto-oncogene is known as a inhibitor of apoptosis that may allow accumulation and propagation of cells containing genetic alterations. Overexpression of bcl-2 probably plays a role in colorectal carcinogenesis. The aim of this study was to determine bcl-2 and p53 expression in colorectal carcinoma in correlation with apoptosis, clinical parameters, and histopathology, and to test their prognostic significance in patient with colorectal carcinoma. The bel-2 and p53 protein were identified by immunohistochemical staining using monoclonal and polyclonal antibody. The apoptotic index was detetermined by microscopic examination of hematoxyln and rosin-stained sections at x400. The materials subiected to this study were 54 paraffin-embedded colorectal carcinomas, which were collected randomly from January of 1992 to December of 1994 at Department of Surgery, Chosun University Hospital. Of 54 cases, 21 (38.9%) and 22(40.7%) showed positive expression of bel-2 and p53 protein respectively. Mean apoptotic index(AI) was 2.99% in colorectal carcinoma. Bcl-2 expression did not correlated with p53 expression or apoptotic index. Positive expression of p53 or AI was not correlate with any other clinical and pathologic parameters. An inverse correlation was found between bel-2 expression and increased tumor stage or Iymph node metastasis (P<0.05). In conclusion, these results suggest that bcl-2 expression is significant associated with early stage in colorectal carcinoma. But bcl-2 p53 and AI can`t be a independent prognostic factor in colorectal carcinoma. Further investigations to clarity its possible role in controlling the tumor decelopment and growth of colorectal carcinoma are needed.
Apoptosis ; Carcinogenesis ; Cell Death ; Colorectal Neoplasms* ; Genes, Suppressor ; Humans ; Neoplasm Metastasis ; Oncogenes ; Proto-Oncogenes

A large number of studies for genes involved in oncogenesis have been done during last decade. Over 20 oncogenes have been isolated characterized, and the oncogene expressions in human tumors have been examined. The proto-oncogenes of c-Myc, c-Fos and c-Jun, which modulate the transcription factors, have overexpressed in a variety of human cancers. Immunohistochemical method was used in this study to examine c-Myc, c-Fos and c-Jun oncoprotein expression in 31 patients with human pheochromocytoma 28(90.0%) were benign and 3(10.0%) malignant. C-Myc oncoprotein immunoreactivity was found in 24 cases(77.4%), c-Fos in 29(93.5%), and c-Jun in 25(80.6%). Twenty-one(67.7%) showed positive immunoreactivity for all these oncoproteins, six(19.4%) for 2 oncoproteins, 3 for one oncoprotein. Only 1 case showed negative immunoreactivity for all 3 oncoproteins. The oncoprotein immunoreactivity did not correlate with the amount of 24 hour urinary catecholamine excretion. Although the number of malignant pheochromocytomsa was not so many, most of them showed that the immunoreactivity for oncoprotein was more than 30 percent of tumor cells.The expression of c-Myc, c-Fos and c-Jun oncoprotein were frequently found in human pheochromocytoma. These results suggest that the oncoprotein expression may play an important role in tumorogenesis and proliferation of human pheochromocytoma.
Carcinogenesis ; Humans ; Methods ; Oncogene Proteins ; Oncogenes ; Pheochromocytoma ; Proto-Oncogenes ; Transcription Factors

The protein encoded by the Bcl-2 proto-oncogene has been shown to prolong cell su-rvival by preventing cell death(Apoptosis) induced by many insults including cancer therap-eutic drugs. Recently many researches have elucidated the bcl-2 expression in several hu-man solid cancers. However, there is still a few avaiable data to determine the role of Bcl-2 expression in the ovarian carcinogenesis and its prognostic significance in ovarian can-cers. Hence, we examined the expression of Bcl-2 in 68 ovarian epithelial cancers using immunohistochemistry and determined whether Bcl-2 expression has prognostic significance in the ovarian epithelial cancers. We found Bcl-2 expression(>5% positive cell) in 31 patients(40%). Bcl-2 expression were exclusively negative in the mucinous type of the ovarian epithelial cancer. Bcl-2 exp- ression was not correlated with tumor stage(stage I & II vs III & IV, p=0.63). The patients with Bcl-2 positivity had lower recurrence rate than the patients with negativity at the se- cond look operation(p<0.01). Although there was a trend that the patients with Bcl-2 posi- tivity had better acturial survival than the patient with negativity, the stastical significance was not present(3 years acturial survival;+vs-;63%, 29%;p>0.05). These results sug- gest the Bcl-2 expression appears an early event in the ovarian carcinogenesis and has an inhibiting role in progression of ovarian tumor.
Carcinogenesis ; Humans ; Immunohistochemistry ; Mucins ; Ovarian Neoplasms* ; Proto-Oncogenes ; Recurrence

OBJECTIVETo investigate the correlation between the expression of key proto-oncogenes playing major roles in tumorigenic process and abnormal sarring.

METHODSImmunohistochemical technique was performed to detect the expressions of c-myc, c-fos and ras p21 proteins on hypertrophic scars, keloids and normal skin. Image analysis was used to compare their quantitative difference of expression.

RESULTSC-myc and c-fos expressions on the nucleus of fibroblasts of hypertrophic and keloid scars were significantly higher than normal skin controls, and there was no difference between the two lesions. Ras p21 expression was not detected on the fibroblasts of hypertrophic and keloid scars.

CONCLUSION1. c-myc and c-fos oncogenes are activated on hypertrophic and keloid scars, which may contribute to proliferation and differentiation of fibroblasts, synthesis and degradation of collagen and regulation of cytokines and induce abnormal scarring, the mechanisms of their effects remain to be further studied. 2. Ras gene may not mutate or its mutations may not play a major role in the process of abnormal scarring. 3. Only part of proto-oncogenes moderately expressed on abnormal scars. The expression of multiple oncogenes does not coexist in abnormal scars may be the cause of their less chances to induce malignant transformation.

Cicatrix, Hypertrophic ; metabolism ; Humans ; Immunohistochemistry ; Proto-Oncogene Proteins c-fos ; analysis ; Proto-Oncogene Proteins c-myc ; analysis ; Proto-Oncogene Proteins p21(ras) ; analysis ; Proto-Oncogenes

OBJECTIVETo define the frequency and spectrum of c-kit gene mutations in gastrointestinal stromal tumors (GIST).

METHODSFifty two cases of GIST and 28 cases of other tumors were examined for mutations in exon 11, 9 and 13 of c-kit gene using PCR amplification and DNA sequencing.

RESULTSFourteen out of 25 malignant GIST (56%), while 2 of 27 benign and borderline GIST (7.4%) revealed mutations in exon 11 of c-kit gene (P < 0.01). Most of the mutations consisted of in-frame deletion or replication from 3 to 48 bp in heterozygous and homozygous fashions, but none of the mutations disrupted the downstream reading frame of the gene. Point mutation and deletion concentrated at 550 - 570 codons but replication clustered within 570 - 585 codons. The mutation pattern in recurrence tissues was the same as the primary ones. Normal tissues adjacent to GIST with or without c-kit gene mutations showed wild type c-kit gene sequence. No mutation was found in exon 9 and 13. Neither c-kit gene expression nor gene mutations was found in 3 leiomyomas, 8 leiomyosarcomas, 2 schwannomas, 2 intra-abdomenal fibromitoses and 8 adenocarcinomas.

CONCLUSIONThe mutations in exon 11 of c-kit gene might partially represent one of the molecular mechanisms of GIST. It can be used as a marker for distinguishing benignancy and malignancy of GIST. The mutations did not involve the reading frame. Except for long frame deletion, most mutations also did not affect protein expression. Mutation of c-kit gene in GIST provides a new genotypic marker to distinguish GIST from authentic leiomyomas, leiomyosarcomas, schwannomas and etc.

Base Sequence ; Gastrointestinal Neoplasms ; genetics ; Humans ; Molecular Sequence Data ; Mutation ; Proto-Oncogene Proteins c-kit ; analysis ; genetics ; Proto-Oncogenes

This article reviews the specific expression of many proto-oncogenes during male germ cell development. The normal expression of proto-oncogenes plays an important role in the regulation of spermatogonial mitosis, spermatocyte meiosis as well as spermiogenesis and sperm maturation.
Animals ; Gene Expression Regulation ; Male ; Mice ; Proto-Oncogene Proteins ; biosynthesis ; genetics ; Proto-Oncogenes ; genetics ; Spermatocytes ; metabolism ; Transcription, Genetic

The development of next generation sequencing (NGS) has led to marked advancement of our understanding of genetic events mediating the initiation and progression of thyroid cancers. The NGS studies have confirmed the previously reported high frequency of mutually-exclusive oncogenic alterations affecting BRAF and RAS proto-oncogenes in all stages of thyroid cancer. Initially identified by traditional sequencing approaches, the NGS studies also confirmed the acquisition of alterations that inactivate tumor protein p53 (TP53) and activate phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in advanced thyroid cancers. Novel alterations, such as those in telomerase reverse transcriptase (TERT) promoter and mating-type switching/sucrose non-fermenting (SWI/SNF) complex, are also likely to promote progression of the BRAF(V600E)-driven thyroid cancers. A number of genetically engineered mouse models (GEMM) of BRAF(V600E)-driven thyroid cancer have been developed to investigate thyroid tumorigenesis mediated by oncogenic BRAF and to explore the role of genetic alterations identified in the genomic analyses of advanced thyroid cancer to promote tumor progression. This review will discuss the various GEMMs that have been developed to investigate oncogenic BRAF(V600E)-driven thyroid cancers.
Animals ; Carcinogenesis ; Catalytic Domain ; Mice ; Mice, Transgenic ; Negotiating ; Proto-Oncogene Proteins B-raf ; Proto-Oncogenes ; Telomerase ; Thyroid Gland ; Thyroid Neoplasms

Some proto-oncogenes in human malignancies can be primary cause of carcinogenesis and can be correlated to histologic aggressiveness or prognosis. In this study, to define the role of c-myc and c-fos protooncogenes in multistage tumorigenesis of thyroid tumor and to correlate the expression of c-myc protooncogene with the degree of histologic aggressiveness and EORTC prognostic index in patients of thyroid carcinoma, 132 fresh specimens obtained at surgery from 71 cases of thyroid tumor were analysed by slot blot hybridization for the expression of c-myc and c-fos proto-oncogene, and 42 formalin-fixed paraffin-embedded tissues were analysed by immunohistochemical staining with monoclonal c-myc antibody and monoclonal Ki-67 antibody, and in 34 paraffin-embedded malignant tissues, the degree of histologic aggressiveness was determined, and in 42 cases of thyroid cancer, EORTC prognostic index were determined. And each item was compared to c-myc mRNA expression level. The results obtained were as follows: 1. The level of c-myc mRNA was significantly higher in malignant thyroid tissues as compared to normal or benign thyroid tissues(p=0.01). 2. The level of c-fos mRNA was similar in normal, benign and well differentiated thyroid carcinoma 3. There was no difference of c-myc mRNA expression levels between central and peripheral tumor tissues. 4. C-myc expression of normal tissues originated from cancer was higher than those from benign tumor(p=0.01) 5. A high level of c-myc mRNA in differentiated thyroid cancer corresponded to a high degree of histologic aggressiveness, although there was no statistically significant correlation between two. 6. High levels of c-myc mRNA were more frequently found in thyroid carcinoma with unfavourable prognosis, although there was no statistically significant correlation between c-myc mRNA expression and EORTC prognostic index or other prognostic factors such as age, sex, tumor size, tumor extent in thyroid carcinoma. 7. C-myc mRNA expression was statistically significantly correlated to the degree of immunohistochemical staining of monoclonal c-myc antibody(p=0.01). 8. C-myc mRNA expression was statistically significantly correlated to Ki-67 cell proliferative index score(p=0.005). On the basis of results, it can be suggested that overexpression of c-myc protooncogene in thyroid carcinoma is secondary phenotype of growth signal rather than primary cause of thyroid carcinogenesis, and expression of c-fos protooncogene was similar in normal, benign and malignant tumor tissues. C-myc may be useful prognostic indicator because there was some relationship between c-myc mRNA expression and EORTC prognostic index score or histologic aggressiveness score. And because c-myc correaltes significantly to Ki-67 cell proliferative index score, c-myc expression will be important growth signal in follicular cell of thyroid and have a role of progression of thyroid carcinoma.
Carcinogenesis ; Genes, fos ; Humans* ; Phenotype ; Prognosis ; Proto-Oncogenes ; RNA, Messenger ; Thyroid Gland* ; Thyroid Neoplasms

A number of naturally-occurring or synthetic chemicals have been reported to exhibit prostate chemopreventive effects. Synthetic 5alpha-reductase (5-AR) inhibitors, e.g. finasteride and durasteride, gained special interests as possible prostate chemopreventive agents. Indeed, two large-scale epidemiological studies have demonstrated that finasteride or durasteride significantly reduced the incidence of prostate cancer formation in men. However, these studies have raised an unexpected concern; finasteride and durasteride increased the occurrence of aggressive prostate tumor formation. In the present study, we have observed that treatment of finasteride did not affect the growth of androgen-refractory PC-3 prostate cancer cells. Finasteride also failed to induce apoptosis or affect the expression of proto-oncogenes in PC-3 cells. Interestingly, we found that treatment of finasteride induced the expression of Nrf2 and HO-1 proteins in PC-3 cells. In particular, basal level of Nrf2 protein was higher in androgen-refractory prostate cancer cells, e.g. DU-145 and PC-3 cells, compared with androgen-responsive prostate cancer cells, e.g. LNCaP cells. Also, treatment of finasteride resulted in a selective induction of Nrf2 protein in DU-145 and PC-3 cells, but not in LNCaP cells. In view of the fact that upregulation of Nrf2-mediated phase II cytoprotective enzymes contribute to attenuating tumor promotion in normal cells, but, on the other hand, confers a selective advantage for cancer cells to proliferate and survive against chemical carcinogenesis and other forms of toxicity, we propose that finasteride-mediated induction of Nrf2 protein might be responsible, at least in part, for an increased risk of high-grade prostate tumor formation in men.
Apoptosis ; Carcinogenesis ; Chemoprevention ; Finasteride* ; Hand ; Humans ; Incidence ; Male ; Prostate* ; Prostatic Neoplasms ; Proto-Oncogenes ; Up-Regulation