• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.965-970
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• 2015

Colorectal cancer is one of the most severe subtypes of cancer, and has the highest propensity to manifest as metastatic disease. Because of the lack of knowledge of events that correlate with tumor cell migration and invasion, few therapeutic options are available. The current study aimed to explore the mechanism of colorectal cancer in hope of identifying the ideal target for future treatment. We first discovered the pro-tumor effect of a controversial cell cycle regulator, cylin-dependent kinase inhibitor 3 (CDKN3), which is highly expressed in colorectal cancer, and the possible related signaling pathways, by bioinformatics tools. We found that CDKN3 had remarkable effects in suppressing colorectal cancer cell proliferation and migration, inducing cell cycle arrest and apoptosis in a colorectal cancer cell line, SW480 cells. Our study, for the first time, provided consistent evidence showing overexpression of cell cycle regulator CDKN3, in colorectal cancer. The in vitro studies in SW480 cells revealed a unique role of CDKN3 in regulating cellular behavior of colorectal cancer cells, and implied the possibility of targeting CDKN3 as a novel treatment for colorectal cancer.

• Journal of Yeungnam Medical Science
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• v.22 no.2
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• pp.166-182
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• 2005

Background: Cyclin-dependent kinase (CDK) inhibitors are family of molecules that regulate the cell cycle. The CDKN2, a CDK4 inhibitor, also called p16, has been implicated in human tumorigenesis. The CDKN2 inhibits the cyclin/CDK complexes which regulate the transition from G1 to S phase of cell cycle. There is a previous report that homozygous deletion of CDKN2 region on chromosome 9p21 was detected frequently in astrocytoma, glioma and osteosarcoma, less frequently in lung cancer, leukemia and ovarian cancer, but not detected in colon cancer and neuroblastoma. However, little is known about the relationship between CDKN2 and laryngeal cancer. Therefore this study was initiated to investigate the role of CDKN2 in human laryngeal squamous cell carcinoma development.1) Materials and methods: We used 5 human laryngeal carcinoma cell lines whether they have deletions or losses of CDKN2 gene expression by DNA-PCR or RT-PCR, respectively. We examined 8 fresh frozen human laryngeal cancer tissues to detect the loss of heterozygosity (LOH) of CDKN2. PCR was performed by using microsatellite markers of short arm of human chromosome 9 (D9S126, D9S144, D9S156, D9S161, D9S162, D9S166, D9S171, D9S200 and D9SIFNA). For informative cases, allelic loss was scored if the signal of one allele was significantly decreased in tumor DNA when compared to the same allele in normal DNA. Results: The CDKN2 DNA deletion was observed in 3 cell lines. The CDKN2 mRNA expression was observed in only one cell line, which was very weak. LOH was detected in 7 cases (87.5%). Conclusion: These results suggest that CDKN2 plays a role in the carcinogenesis of human laryngeal squamous cell carcinoma.

• Korean Journal of Radiology
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• v.24 no.2
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• pp.133-144
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• 2023

Objective: Cyclin-dependent kinase inhibitor (CDKN)2A/B homozygous deletion is a key molecular marker of isocitrate dehydrogenase (IDH)-mutant astrocytomas in the 2021 World Health Organization. We aimed to investigate whether qualitative and quantitative MRI parameters can predict CDKN2A/B homozygous deletion status in IDH-mutant astrocytomas. Materials and Methods: Preoperative MRI data of 88 patients (mean age ± standard deviation, 42.0 ± 11.9 years; 40 females and 48 males) with IDH-mutant astrocytomas (76 without and 12 with CDKN2A/B homozygous deletion) from two institutions were included. A qualitative imaging assessment was performed. Mean apparent diffusion coefficient (ADC), 5th percentile of ADC, mean normalized cerebral blood volume (nCBV), and 95th percentile of nCBV were assessed via automatic tumor segmentation. Logistic regression was performed to determine the factors associated with CDKN2A/B homozygous deletion in all 88 patients and a subgroup of 47 patients with histological grades 3 and 4. The discrimination performance of the logistic regression models was evaluated using the area under the receiver operating characteristic curve (AUC). Results: In multivariable analysis of all patients, infiltrative pattern (odds ratio [OR] = 4.25, p = 0.034), maximal diameter (OR = 1.07, p = 0.013), and 95th percentile of nCBV (OR = 1.34, p = 0.049) were independent predictors of CDKN2A/B homozygous deletion. The AUC, accuracy, sensitivity, and specificity of the corresponding model were 0.83 (95% confidence interval [CI], 0.72-0.91), 90.4%, 83.3%, and 75.0%, respectively. On multivariable analysis of the subgroup with histological grades 3 and 4, infiltrative pattern (OR = 10.39, p = 0.012) and 95th percentile of nCBV (OR = 1.24, p = 0.047) were independent predictors of CDKN2A/B homozygous deletion, with an AUC accuracy, sensitivity, and specificity of the corresponding model of 0.76 (95% CI, 0.60-0.88), 87.8%, 80.0%, and 58.1%, respectively. Conclusion: The presence of an infiltrative pattern, larger maximal diameter, and higher 95th percentile of the nCBV may be useful MRI biomarkers for CDKN2A/B homozygous deletion in IDH-mutant astrocytomas.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2629-2633
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• 2012

Background: Raw betel nut (RBN) chewing is an important contributing factor for esophageal squamous cell carcinoma (ESCC), although associated genomic changes remain unclear. One difficulty in assessing the effects of exclusively RBN induced genetic alterations has been that earlier studies were performed with samples of patients commonly using tobacco and alcohol, in addition to betel-quid. Both CDKN2A (at 9p21) and Rb1 gene (at 13q14.2) are regarded as tumor suppressors involved in the development of ESCC. Therefore, the present study aimed to verify the RBN's ability to induce ESCC and assess the involvement of CDKN2A and Rb1 genes. Methods: A panel of dinucelotide polymorphic markers were chosen for loss of heterozygosity studies in 93 samples of which 34 were collected from patients with only RBN-chewing habit. Promoter hypermethylation was also investigated. Results: Loss in microsatellite markers D9S1748 and D9S1749, located close to exon $1{\beta}$ of CDKN2A/ARF gene at 9p21, was noted in 40% ESCC samples with the habit of RBN-chewing alone. Involvement of a novel site in the 9p23 region was also observed. Promoter hypermethylation of CDKN2A gene in the samples with the habit of only RBN-chewing alone was significantly higher (p=0.01) than Rb1 gene, also from the samples having the habit of use both RBN and tobacco (p=0.047). Conclusions: The data indicate that the disruption of 9p21 where CDKN2A gene resides, is the most frequent critical genetic event in RBN-associated carcinogenesis. The involvement of 9p23 as well as 13q14.2 could be required in later stages in RBN-mediated carcinogenesis.

• Tuberculosis and Respiratory Diseases
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• v.64 no.4
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• pp.285-292
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• 2008

Background: A diagnosis of malignant pleural effusion is clinically important, as the prognosis of lung cancer patients with malignant pleural effusion is poor. The diagnosis will be difficult if a cytological test is negative. This study was performed to investigate whether the detection of hypermethylation of the p16 (CDKN2A) and retinoic acid receptor b2 (RARB2) genes in pleural fluid is useful for a diagnosis of malignant pleural effusion. Methods: Pleural effusion was collected from 43 patients and was investigated for the aberrant promoter methylation of the RARB2 and CDKN2A genes by use of methylation-specific PCR. Results were compared with findings from a pleural biopsy and from pleural fluid cytology. Results: Of 43 cases, 17 cases of pleural effusion were due to benign diseases, and 26 cases were from lung cancer patients with malignant pleural effusion. Hypermethylation of the RARB2 and CDKN2A genes was not detected in the case of benign diseases, independent of whether or not the patients had ever smoked. In 26 cases of malignant pleural effusion, hypermethylation of RARB2, CDKN2A or either of these genes was detected in 14, 5 and 15 cases, respectively. The sensitivities of a pleural biopsy, pleural fluid cytology, hypermethylation of RARB2, hypermethylation of CDKN2A, or hypermethylation of either of the genes were 73.1%, 53.8%, 53.8%, 19.2%, and 57.7%, respectively; negative predictive values were 70.8%, 58.6%, 58.6%, 44.7%, and 60.7%, respectively. If both genes are considered together, the sensitivity and negative predictive value was lower than that for a pleural biopsy, but higher than that for pleural fluid cytology. The sensitivity of hypermethylation of the RARB2 gene for malignant pleural effusion was lower in small cell lung cancers than in non-small cell lung cancers. Conclusion: These results demonstrate that detection of hypermethylation of the RARB2 and CDKN2A genes showed a high specificity, and sensitivity was higher than for pleural fluid cytology. With a better understanding of the pathogenesis of lung cancer according to histological types at the molecular level, and if appropriate genes are selected for hypermethylation testing, more precise results may be obtained.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.46 no.4
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• pp.391-401
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• 2020

Flavonoids are polyphenolic compounds derived from plants metabolites and are known to be capable of controlling various human physiological functions. Among them, fisetin (3,3', 3', 7-tetrahydroxyflavone) is found in various fruits and vegetables, and it has been recently known to restore the function of certain tissues through senolytic activity. In this study, targeting human epidermal keratinocytes, control of skin barrier genes and antioxidant efficacy of fisetin were analyzed. Fisetin increased the activity of telomerase and decreased the expression of CDKN1B. In addition, it increased the expression of KRT1, FLG, IVL, and DSP, which are main genes that make up the skin barrier. The fisetin also increased the expression of CerS3 and CerS4 genes, which are forms of ceramide synthases. These results show that the efficacy of fisetin is not limited as senolytics but is also involved in various physiological regulation of human keratinocytes. Therefore, we consider that fisetin could be used as an active ingredient in cosmetics and pharmaceuticals.

• Molecular & Cellular Toxicology
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• v.2 no.3
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• pp.159-165
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• 2006

To determine the anticancer effect of D-amygdalin (D-mandelinitrole-${\beta}$-D-gentiobioside) in human chronic myeloid leukemia cells K562, we profiled the gene expression between amygdalin treatment and control groups. Through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicity of D-amygdalin was $57.79{\pm}1.83%$ at the concentration of 5 mg/mL for 24 h. We performed cDNA microarray analysis and compared the gene expression profiles between D-amygdalin (5 mg/mL, 24 h) treatment and control groups. Among the genes changed by D-amygdalin, we paid attention to cell cycle-related genes, and particularly cell cycle regulator genes; because arrest of cell cycle processing was ideal tactic in remedy for cancer. In our data, expressions of cyclin-dependent kinase inhibitor 1B (p27, Kip1) (CDKN1B), ataxia telangiectasia mutated (includes complementation groups A, C, and D) (ATM), cyclin-dependent kinase inhibitor 1C (p57, Kip2) (CDKN1C), and CHK1 checkpoint homolog (CHEK1, formally known as CHK1) were increased, while expressions of cyclin-dependent kinase 2 (CDK2), cell division cycle 25A (CDC25A), and cyclin E1 (CCNE1) were decreased. The pattern of these gene expressions were confirmed through RT-PCR. Our results showed that D-amygdalin might control cell cycle regulator genes and arrest S phase of cell cycle in K562 cells as the useful anticancer drug.

• Genomics & Informatics
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• v.18 no.3
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• pp.27.1-27.12
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• 2020

The prevalence of early-onset type 2 diabetes (EOT2D) is increasing in Asian countries. Genome-wide association studies performed in European and various other populations have identified associations of numerous variants with type 2 diabetes in adults. However, the genetic component of EOT2D which is still unexplored could have similarities with late-onset type 2 diabetes. Here in the present study we aim to identify the association of variants with EOT2D in South Indian population. Twenty-five variants from 18 gene loci were genotyped in 1,188 EOT2D and 1,183 normal glucose tolerant subjects using the MassARRAY technology. We confirm the association of the HHEX variant rs1111875 with EOT2D in this South Indian population and also the association of CDKN2A/2B (rs7020996) and TCF7L2 (rs4506565) with EOT2D. Logistic regression analyses of the TCF7L2 variant rs4506565(A/T), showed that the heterozygous and homozygous carriers for allele 'T' have odds ratios of 1.47 (95% confidence interval [CI], 1.17 to 1.83; p = 0.001) and 1.65 (95% CI, 1.18 to 2.28; p = 0.006) respectively, relative to AA homozygote. For the HHEX variant rs1111875 (T/C), heterozygous and homozygous carriers for allele 'C' have odds ratios of 1.13 (95% CI, 0.91 to 1.42; p = 0.27) and 1.58 (95% CI, 1.17 to 2.12; p = 0.003) respectively, relative to the TT homozygote. For CDKN2A/2B variant rs7020996, the heterozygous and homozygous carriers of allele 'C' were protective with odds ratios of 0.65 (95% CI, 0.51 to 0.83; p = 0.0004) and 0.62 (95% CI, 0.27 to 1.39; p = 0.24) respectively, relative to TT homozygote. This is the first study to report on the association of HHEX variant rs1111875 with EOT2D in this population.

• Journal of Interdisciplinary Genomics
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• v.5 no.2
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• pp.18-23
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• 2023

Conventional evaluation method for identifying the organic cause of short stature has a low detection rate. If an infant who is small for gestational age manifests postnatal growth deterioration, triangular face, relative macrocephaly, and protruding forehead, a genetic testing of IGF2, H19, GRB10, MEST, CDKN1, CUL7, OBSL1, and CCDC9 should be considered to determine the presence of Silver-Russell syndrome and 3-M syndrome. If a short patient with prenatal growth failure also exhibits postnatal growth failure, microcephaly, low IGF-1 levels, sensorineural deafness, or impaired intellectual development, genetic testing of IGF1 and IGFALS should be conducted. Furthermore, genetic testing of GH1, GHRHR, HESX1, SOX3, PROP1, POU1F1, and LHX3 should be considered if patients with isolated growth hormone deficiency have short stature below -3 standard deviation score, barely detectable serum growth hormone concentration, and other deficiencies of anterior pituitary hormone. In short patients with height SDS <-3 and high growth hormone levels, genetic testing should be considered to identify GHR mutations. Lastly, when severe short patients (height z score <-3) exhibit high levels of prolactin and recurrent pulmonary infection, genetic testing should be conducted to identify STAT5B mutations.

• Korean Journal of Clinical Laboratory Science
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• v.55 no.2
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• pp.93-104
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• 2023

This study aimed to identify new markers that cause lung adenocarcinoma by analyzing mutation hotspots for the top five genes with high mutation frequency in lung adenocarcinoma in Koreans by next generation sequencing (NGS) analysis. The association between TP53 mutation types and patterns with smoking, a major cause of lung cancer, was examined. The clinicopathological characteristics of lung adenocarcinoma patients with TP53 P72R SNPs were analyzed. In Korean lung adenocarcinoma cases, regardless of the smoking status, the TP53 P72R SNP was the most frequently occurring mutational hotspot, in which the nucleotide base was transversed from C to G, and the amino acid was substituted from proline to arginine at codon 72 of TP53. An analysis of the clinicopathological characteristics of lung adenocarcinoma cases with TP53 P72R SNP revealed no significant correlation with the patient's age, gender, smoking status, and tumor differentiation, but a significant correlation with low stage (P-value =0.026). This study confirmed an increase in TP53 rather than EGFR, which was reported as the most frequent mutations in lung adenocarcinoma in Koreans through NGS. Among them, TP53 P72R SNP is the most frequent regardless of smoking status.