Journal of Pathology and Translational Medicine

Original Articles

Difference of Genome-Wide Copy Number Alterations between High-Grade Squamous Intraepithelial Lesions and Squamous Cell Carcinomas of the Uterine Cervix: Bum Hee Lee, Sangyoung Roh, Yu Im Kim, Ahwon Lee, Su Young Kim; Korean J Pathol. 2012;46(2):123-130. Published online April 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.2.123

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Background

About 10% of high-grade squamous intraepithelial lesions (HSILs) progress to invasive carcinomas within 2-10 years. By delineating the events that occur in the early stage of the invasion, the pathogenesis of cervical cancer could be better understood. This will also propose the possible methods for inhibiting the tumor invasion and improving the survival of patients.

Methods

We compared the genomic profiles between the HSIL and the invasive squamous cell carcinoma (SCC) using an array comparative genomic hybridization. Using recurrently altered genes, we performed a principal component analysis to see variation of samples in both groups. To find possibly affected pathways by altered genes, we analyzed genomic profiles with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and GOEAST software.

Results

We found 11q12.3 and 2p24.1 regions have recurrent copy number gains in both groups. 16p12-13 and 20q11-13 regions showed an increased copy number only in cases of HSIL. 1q25.3 and 3q23-29 regions showed copy number gains only in cases of SCC. Altered genes in the SCC group were related to the mitogen-activated protein kinase signaling pathway and the RNA transport. Altered genes in the HSIL group were related to the ubiquitin mediated proteolysis and cell adhesion molecules.

Conclusions

Our results showed not only that gains in 11q12.3 and 2p24.1 were early events occurring in the premalignant lesions and then maintained in cases of SCC but also that gains in 1q25.3 and 3q23-29 were late events occurring after invasion in those of SCC.

Citations

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Cytokeratin and protein expression patterns in squamous cell carcinoma of the oral cavity provide evidence for two distinct pathogenetic pathways
GESCHE FROHWITTER, HORST BUERGER, PAUL J. VAN DIEST, EBERHARD KORSCHING, JOHANNES KLEINHEINZ, THOMAS FILLIES
Oncology Letters.2016; 12(1): 107. CrossRef
'Drawing' a Molecular Portrait of CIN and Cervical Cancer: a Review of Genome-Wide Molecular Profiling Data
Olga V Kurmyshkina, Pavel I Kovchur, Tatyana O Volkova
Asian Pacific Journal of Cancer Prevention.2015; 16(11): 4477. CrossRef

Copy Number Alterations of BCAS1 in Squamous Cell Carcinomas.: Yu Im Kim, Ahwon Lee, Jennifer Kim, Bum Hee Lee, Sung Hak Lee, Suk Woo Nam, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo, Jung Young Lee, Sang Ho Kim, Su Young Kim; Korean J Pathol. 2011;45(3):271-275.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.3.271

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Abstract PDF

BACKGROUND
Breast carcinoma amplified sequence 1 (BCAS1), located in 20q13, is amplified and overexpressed in breast cancers. Even though BCAS1 is expected to be an oncogene candidate, its contribution to tumorigenesis and copy number status in other malignancies is not reported. To elucidate the role of BCAS1 in squamous cell carcinomas, we investigated the copy number status and expression level of BCAS1 in several squamous cell carcinoma cell lines, normal keratinocytes and primary tumors.
METHODS
We quantitated BCAS1 gene by real-time polymerase chain reaction (PCR). Expression level of BCAS1 was measured by real-time reverse transcription-PCR and immunoblot.
RESULTS
Seven (88%) of 8 squamous cell carcinoma cell lines showed copy number gain of BCAS1 with various degrees. BCAS1 gene in primary tumors (73%) also showed copy number gain. However, expression level did not show a linear correlation with copy number changes.
CONCLUSIONS
We identified copy number gain of BCAS1 in squamous cell carcinomas. Due to lack of linear correlation between copy numbers of BCAS1 and its expression level, we could not confirm that the overexpression of BCAS1 is a common finding in squamous cell carcinoma cell lines. However, this study shows that the copy number gain of BCAS1 is a common finding in squamous cell carcinomas.

Citations

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Electrochemical Approaches for Preparation of Tailor-Made Amino Acids
Nana Wang, Jingcheng Xu, Haibo Mei, Hiroki Moriwaki, Kunisuke Izawa, Vadim A. Soloshonok, Jianlin Han
Chinese Journal of Organic Chemistry.2021; 41(8): 3034. CrossRef

The Role of gadd and p53 Genes in Apoptosis and Cell Cycle Delay by Genotoxic Agents.: Jung Young Lee, Jung Duk Lee, Seung Myung Dong, Eun Young Na, Min Sun Shin, Su Young Kim, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo; Korean J Pathol. 1998;32(4):239-247.

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Abstract PDF: The aim of this study was to investigate the relationships between the gadd genes expression and an apoptosis induction in two different growing cell types after treatments with cisplatin and methylmethan sulfonate (MMS). We have examined the kinetics and specificity of gadd45 and gadd153 expression following cisplatin and MMS treatments to HL-60 cells and primary cultured human kidney (HKN) cells. We have also determined an induction time of apoptosis by DNA fragmentation analysis and the presence of the cell cycle arrest by a flow cytometric measurement. The results were as follows. In non-adherent HL-60 cells, a typical ladder pattern was observed within 4 hours after treatments of 20 micrometer of cisplatin and 100 microgram/ml of MMS. At the same time while adherent HKN cells failed to exhibit a ladder pattern at even higher doses of genotoxic agents. Since HL-60 cells do not have p53 gene, these findings suggest the presence of a p53-independent apoptotic pathway. The increasing patterns of the mRNA levels of gadd45 and gadd153 varied with the type of genotoxic agents. In the case of MMS treatment, the induction was rapid and transient, regardless of the cell types. The mRNA level peaked at 4 hours after MMS treatment and markedly decreased after 12 hours. On the other hand, cisplatin-induced transcriptions of gadd45 and gadd153 continued to increase for at least 24 hours and reached a peak level at 48 hours after cisplatin treatment, regardless of the cell types. HL-60 cells revealed G2 arrest following 24 hours after cisplatin and MMS treatments. These findings suggest that the regulation mechanism of apoptosis between adherent and non-adherent cells, might be different and that gadd45 and gadd153 might have an important role in DNA repair rather than apoptosis. Also, the findings suggest that an expression pattern of gadd45 and gadd153 might be different according to the type of genotoxic agents.

Identification of Differentially Expressed Genes Using RNA Fingerprinting in Cell after DNA Damage.: Jung Young Lee, Min Sun Shin, Seung Myung Dong, Eun Young Na, Su Young Kim, Sug Hyung Lee, Won Sang Park, Nam Jin Yoo; Korean J Pathol. 1998;32(5):321-327.

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Abstract: RNA fingerprinting using on arbitrary primed polymerase chain reaction (RAP-PCR) was carried out to identify differentially expressed genes in HL-60 cell after treatment of methylmethane sulfonate (MMS). Twenty differentially expressed PCR products were cloned and analyzed. We have successfully obtained eight partial cDNA sequences by TA cloning method. Among these, six cDNAs were up-regulated and two cDNAs were down-regulated after the MMS treatment. Of these six up-regulated cDNAs, 3 cDNAs were equivalent to known genes in the GenBank/EMBL databases with 98~100% homology searched by BLAST program: genomic DNA fragment containing CpGg island (clone 26h8), Human Rev interacting protein-1 (RIP-1), and human zinc finger protein-4 (HZF4). The sequences of the three remaining cDNA were entirely new genes, but we didn't try to identify a full cDNA sequence. Two clones called KIAA0060 and KIAA0065, were down-regulated in HL-60 cells after the MMS treatment. These findings suggest that the RNA fingerprinting method using RAP-PCR is an effective method which can identify and separate the differentially expressed cDNAs and that the isolated cDNAs might involve in regulation mechanism of apoptosis and/or cell cycle delay, especially a p53-independent pathway, in the cells after DNA damage. But the nature of cDNAs that we have isolated remains to be elucidated.

Identification of Differentially Expressed Genes from Serum Deprived p388D1 Cells.: Su Young Kim, Sang Ho Kim, Sug Hyung Lee, Nam Jin Yoo, Jung Young Lee, Choo Soung Kim; Korean J Pathol. 1998;32(7):488-493.

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Abstract: This experiment is designed to find differentially expressed genes in p388D1 cells that are specific for the serum deprived state. Serum starvation induces cells to enter the quiscent state in the cell cycle and is used to arrest cell growth or synchronize the cell cycle. Differential display and ribonuclease protection assay were used to identify quantitative change in gene expression. Nineteen genes that showed a differential expression in the differential display were cloned and 7 clones were verified by a ribonuclease protection assay. Among the 7 clones clone-16 showed same expression pattern in comparison with the differential display. Deduced amino acid sequences of clone-16 had N-glycosylation motif and seems to be a secretory protein. Getting a full sequence of clone-16 is critical for the characterization of it.

Identification of Zinc Finger Genes that are Differentially Expressed upon Apoptosis of Ramos B Cells.: Min Sun Shin, Su Young Kim, Seung Myung Dong, Eun Young Na, Sug Hyung Lee, Won Sang Park, Jung Young Lee, Nam Jin Yoo; Korean J Pathol. 1998;32(12):1043-1048.

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Abstract: Typical programmed cell death requires de novo macromolecular synthesis and shares common morphological changes referred to as apoptosis. To elucidate the molecular mechanism of apoptosis, we isolated 13 cDNA clones of zinc finger genes that are differentially expressed in calcium ionophore-induced apoptosis of Ramos human B cell by 'targeted RNA fingerprinting' protocol (Stone & Wharton, 1993). According to DNA sequence analysis of the 13 cDNA clones, three clones are identical with ZNF7, ZNF143 and MTB-Zf, respectively, and 8 out of the other 10 clones showed partial homology to known zinc finger genes. Differential expression was confirmed in the three known zinc finger genes by ribonuclease protection assay. ZNF7 and ZNF143 are up-regulated after induction of apoptosis, and, in contrast, MTB-Zf is down-regulated. According to the previous reports on these three genes, all of the three genes have been suspected to be tumor suppressor genes, but their functions have not been identified yet. Taken together, our results suggest that many of the novel and known zinc finger genes might play important roles in regulation of apoptosis and that these findings also provide clues as to the functions of the three putative tumor suppressor genes, ZNF7, ZNF143 and MTB-Zf in terms of apoptosis. In addition, the isolation of zinc finger genes by targeted RNA fingerprinting could be a straightforward approach for the identification of novel candidate genes associated with apoptosis.

Loss of Heterozygosity at VHL, FHIT, and p16 Loci in Nonpapillary Renal Cell Carcinoma.: Won Sang Park, Seung Myung Dong, Yong Hyun Cho, Tae Gon Hwang, Su Young Kim, Min Sun Shin, Jae Ho Pi, Suk Hyung Lee, Nam Jin Yoo, Jung Young Lee; Korean J Pathol. 1999;33(1):8-14.

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Abstract PDF: The objectives of this study were to characterize the alterations of 3p and 9p in sporadic renal cell carcinomas (RCC) and to assess the relationship between the clinical stages or tumor size and the alteration of these chromosomes. Thirty eight archival, paraffin embedded tissue sections from 38 patients with RCC were analyzed for loss of heterozygosity (LOH) at 3p and 9p with 11 microsatellite markers. LOH was detected in 81.6% (31/38) and 37.8% (14/37) at 3p and 9p, respectively. The frequencies of LOH at VHL and FHIT locus were 75.6% and 72.2%, respectively. Twelve cases out of 38 showed LOH at both 9p21 and 3p. The loss of 3p in the samples tested was not related to clinical stages and tumor size, but that of 9p21 was significantly associated with advanced stage and larger tumor size. These results support that 3p deletion, including VHL and FHIT gene, play a critical role in the tumorigenesis of sporadic RCC, especially at early stage, and that 9p21 may contribute to the progression of sporadic RCC.

Ethnic Differences of the p53 Genetic Alteration in Cutaneous Malignant Melanoma.: Won Sang Park, Eun Young Na, Sang Kyu Lee, Sug Hyung Lee, Su Young Kim, Seok Jin Kang, Kye Yong Song, Suk Woo Nam, Nam Jin Yoo, Jung Young Lee; Korean J Pathol. 2001;35(2):158-164.

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Abstract PDF: BACKGROUND
There are significant differences in the clincopathologic pattern including the incidence, favor site, and histopathologic type between cutaneous malignant melanomas arising from whites, asians and blacks. These differences might suggest that there is a racial difference in the molecular tumorigenesis mechanism of malignant melanoma.
METHODS
To determine the ethnic differences in tumorigenesis of malignant melanoma, we performed loss of heterozygosity (LOH) and sequencing analyses of the p53 gene in cutaneous malignant melanomas arising from 22 white American, 30 Korean and 15 black African patients.
RESULTS
The frequency of LOH of the p53 gene is only 12.5% in white American patients, but the frequency is significantly higher in Korean (42.1%) and black African (61.5%) patients. We also detected 17 mutations (nonsense: 1, missense: 16) of the p53 gene in the cutaneous malignant melanomas of Koreans and black Africans, but none in those of white Americans: among the 16 missense mutations, 10 mutations were C:G to T:A transitional mutations. Of these, we also detected one GG (CC) to AA (TT) tandem mutation at the pyrimidine sequence.
CONCLUSION
These results strongly suggest that there might be a racial difference in molecular carcinogenesis mechanisms among the cutaneous malignant melanomas occurring in white American, Korean and black African patients. But the role of the p53 genetic alteration in the genesis of melanomas in Korean and black African patients is subject to further evaluation.

Mutational Analysis of Proapoptotic bcl-2 Family genes in Colon Carcinomas.: Young Hwa Soung, Jong Woo Lee, Su Young Kim, Suk Woo Nam, Won Sang Park, Jung Young Lee, Nam Jin Yoo, Sug Hyung Lee; Korean J Pathol. 2005;39(3):168-171.

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Abstract PDF: BACKGROUND
Several lines of evidence have indicated that the deregulation of apoptosis is involved in the mechanisms of cancer development, and somatic mutations of the apoptosisrelated genes have been reported in human cancers. Members of the bcl-2 family proteins regulate the intrinsic apoptosis pathway mainly in the mitochondria. The aim of this study was to explore whether the somatic mutation of the proapoptotic bcl-2 family genes, one of the mechanisms that prolong the survival of cancer cells, occurred in colorectal carcinomas.
METHODS
In the current study, to detect the somatic mutations in the DNA sequences encoding the bcl-2 homology 3 (BH3) domain of the human bak, bid, bik, bim, PUMA, bcl-rambo, bcl-G, and bmf genes in 98 colon adenocarcinomas, we used polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP), and DNA sequencing.
RESULTS
The SSCP analysis detected no evidence of somatic mutations of the genes in the coding regions of the BH3 domain in the cancers.
CONCLUSIONS
The data presented here indicate that the proapoptotic bcl-2 family genes, bak, bid, bik, bim, PUMA, bcl-rambo, bcl-G and bmf may not be somatically mutated in human colorectal carcinomas, and suggest that the colorectal cancers may not utilize mutational events of these proapoptotic bcl-2 family genes in the mechanisms for evading apoptosis.

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