Biomedical subjects

Yeul Hong Kim

Publications and source records attributed to Yeul Hong Kim.

At least 19 recordsLinked to original sources

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2006

Comparative genomic hybridization array analysis and real time PCR reveals genomic alterations in squamous cell carcinomas of the lung.

Genomic alterations have been identified in lung cancer tissues and reported in numerous studies. To analyze genomic aberrations in lung cancer patients, we used array comparative genomic hybridization (array CGH) in 14 squamous cell lung carcinoma (SqC) tissues. Copy number gain and loss in chromosomal regions were detected, and the corresponding genes were confirmed by real time PCR. Several frequently altered loci, including gain of 3q (36% of samples), were found. The most frequently identified losses were found at 14q32.33 (21% of samples). The relative degree of chromosomal change was analyzed using log2 ratios. High-level DNA amplifications (>0.8 log2 ratio) were detected at 20 regions in 1p, 2q, 3q, 4q, 6q, 7p, 8q, 9p, 10q, 12q, 14q and 19p. We found that the fold change levels were highest at EVI1 (3q26.2), LPP (3q27-28) and FHF-1 (3q28) gene loci. Our results show that array CGH is a useful tool for identification of gene alteration in lung cancer, and that the above-mentioned genes might represent potential candidate genes for pathogenesis and diagnosis of lung cancer.

Aged↗

PubMed2006

Comparative genomic hybridization array analysis and real-time PCR reveals genomic copy number alteration for lung adenocarcinomas.

Genomic alterations in lung cancer tissues have been observed in various studies. To analyze the aberrations in the genome of lung cancer patients, we used array comparative genomic hybridization (array CGH) in 15 lung adenocarcinoma (AdC) tissues. Copy number gains and losses in chromosomal regions were detected and corresponding genes were confirmed by real-time polymerase chain reaction (PCR). As for the results, several frequently altered loci, including gain of 16p (46% of samples), were found, and the most common losses were found in 14q32.33 (26% of samples). High-level DNA amplifications (> 0.8 log(2) ratio) were detected at 1p, 5p, 7p, 9p, 11p, 11q, 12q, 14q, 16p, 17q, 19q, 20p, 21q, and 22q. A subset of genes, gained or lost, was checked for over- or underrepresentation by means of real-time PCR. The degree of fold change was highest in ECGF1 (22q13.33), HOXA9 (7p15.2), MAFG (17q25.3), TSC2 (16p13.3), and ICAM1 (19p13.2) genes and the 16p chromosome terminal region (16p13.3pter). Taken together, these results show that array CGH could be used as a powerful tool for identification of genomic alteration for lung cancer, and the above-mentioned genes may represent potential candidate genes in the study of lung cancer pathogenesis and diagnosis.

Adenocarcinoma↗

PubMed2006

Phase II study of a gemcitabine and cisplatin combination regimen in taxane resistant metastatic breast cancer.

PURPOSE: To determine the safety and efficacy of gemcitabine and cisplatin in patients with taxane resistant metastatic breast cancer. PATIENTS AND METHODS: Thirty-three taxane resistant metastatic breast cancer patients were treated with gemcitabine 1,250 mg/m2 IV infusion over 30 min on days 1 and 8, and with cisplatin 75 mg/m2 by IV infusion over 1 h on day 1 in 21 day cycles. RESULTS: Of the 30 evaluable patients, there were 9 (30%) partial responses and no complete response, an overall objective response rate of 30%. Median time to progression and median survival duration for all study subjects were 7 (95% CI 5.1-8.9 months) and 15 months (95% CI 10.5-19.5 months), respectively. Toxicities included grade 3 and 4 leucopenia in 10 (30%), thrombocytopenia in 6 (18%), anemia in 2 (6%) and oral mucositis in 2 (6%). No grade 3 or 4 peripheral neuropathy, renal dysfunction, hepatic dysfunction, or nausea/vomiting was observed, and no treatment-related deaths occurred. CONCLUSION: The described gemcitabine plus cisplatin combination was found to be an active and tolerable salvage regimen in patients with taxane resistant metastatic breast cancer.

Adult↗

PubMed2006

Randomized phase II study of gemcitabine plus cisplatin versus etoposide plus cisplatin for the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience.

BACKGROUND: Several randomized trials have demonstrated superior response rates and survivals for new agent platinum doublets than for older platinum doublets in advanced non-small cell lung cancer (NSCLC), however, few trials have been performed in Asian populations. Thus, we conducted a randomized study to compare gemcitabine-cisplatin (GP) with etoposide-cisplatin (EP) in Korean patients with advanced NSCLC. METHODS: Patients with histologically confirmed, locally advanced or metastatic NSCLC were randomized to receive either gemcitabine 1250 mg/m2 on days 1 and 8 plus cisplatin 75 mg/m2 on day 1, or etoposide 100 mg/m2 on days 1-3 plus cisplatin 75 mg/m2 on day 1. Treatment was repeated every 21 days in both groups. The primary endpoint was response rate. RESULTS: Between May 2000 and December 2001, 83 patients at 9 Korean centers were enrolled in this study. The GP arm showed a significantly higher response rate (52.6% versus 19.4%; P = 0.002), a longer time to progression (4.3 months in both arms; P = 0.018) and a marginally significant prolongation of overall survival (18.3 months versus 10.9 months; P = 0.059) than the EP arm. Grades 3 and 4 thrombocytopenia (18% versus 0%) was more common in the GP arm whereas grades 3 and 4 neutropenia was more common in EP arm (48.7% versus 71.8%). Other toxicities were comparable in both arms. CONCLUSION: GP provided a significantly higher response rate and a longer time to progression than EP and should be considered a standard treatment in advanced NSCLC in Korean population.

Adenocarcinoma↗

PubMed2006

Single nucleotide polymorphisms of the TGFB1 gene and lung cancer risk in a Korean population.

The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the transforming growth factor-beta 1 (TGFB1) gene and susceptibility to lung cancer and the clinical effect of the SNPs on lung cancer progression in a Korean population. Two polymorphisms in the promoter region of the TGFB1 (T-1572C, C-509T), and one SNP in codon 10 (T+869C) were determined using a SNaPshot primer extension assay in 194 Korean lung cancer patients and 283 normal controls. The polymorphic allele frequencies of A-1572G, C-509T, and T+869C were similar among lung cancer patients (0.52, 0.47, and 0.47, respectively) and controls (0.54, 0.46, and 0.44, respectively). When the data was stratified for smoking history, patients who smoked heavily and had heterozygous C-509T and T+869C genotypes showed an increased lung cancer risk (odds ratio OR = 3.77, confidence interval 95% CI = 1.25-11.30, P = 0.017; OR = 3.61, 95% CI = 1.21-10.74, P = 0.021 for each), after adjustment for age and sex. When heterozygous and homozygous variants for each SNPs were analyzed together, patients who were smokers and had variant genotypes also showed increased risk compared to the reference group. Further analyses to test the effect of the SNPs on the clinical parameters did not reveal an association of each polymorphic allele to the tumor stage or response to treatment. In addition, DNA fragments containing polymorphic genotype of the promoter region (-509T) showed increased transcriptional activity in luciferase assays using non-small cell lung cancer cell lines. In conclusion, this study suggests that heavy smokers in this Korean population who have specific polymorphic variants, which have been associated with increased transcriptional activity of TGFB1, might be more vulnerable to lung cancer.

Base Sequence↗

PubMed2006

uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line.

Urokinase plasminogen activator receptor (uPAR) plays a major role in cancer invasion and metastasis and uPAR expression is correlated with a poor prognosis in various cancer types. Moreover, the expression of uPAR is increased under hypoxic conditions. Nitric oxide (NO) and its metabolites produced by inducible nitric oxide synthase (iNOS) are important products of hypoxic stress, and NO may activate or modulate extracellular signal regulated kinase (ERK). Here, we evaluated uPA, uPAR, and activated ERK levels under hypoxic conditions, and the modulatory effects of iNOS and NO in the MDA-MB-231 human breast cancer cell line. Cells were incubated in a hypoxic or normoxic incubator and treated with PD98059 (a MEK 1/2 inhibitor, which abrogates ERK phosphorylation) and aminoguanidine (a selective iNOS inhibitor). uPAR expression, ERK phosphorylation, and uPA activity were found to be increased under hypoxic conditions. Moreover, when cells were treated with PD98059 under hypoxic conditions, uPAR was downregulated, whereas aminoguanidine markedly increased ERK phosphorylation in a dose dependent manner. Furthermore, aminoguanidine increased uPAR expression and prevented the inhibition of uPAR expression by PD98059. These results demonstrated that uPAR is induced by hypoxia and that increased uPAR expression is mediated by ERK phosphorylation, which in turn is modulated by iNOS/NO in MDA-MB-231 cells. We conclude that iNOS/NO downregulates the expression of uPAR under hypoxic conditions via ERK pathway modulation.

Breast Neoplasms↗

PubMed2006

Neural network-based analysis of thiol proteomics data in identifying potential selenium targets.

Generation of a monomethylated selenium metabolite is critical for the anticancer activity of selenium. Because of its strong nucleophilicity, the metabolite can react directly with protein thiols to cause redox modification. Here, we report a neural network-based analysis to identify potential selenium targets. A reactive thiol specific reagent, BIAM, was used to monitor thiol proteome changes on 2D gel. We constructed a dynamic model and evaluated the relative importance of proteins mediating the cellular responses to selenium. Information from this study will provide new clues to unravel mechanisms of anticancer action of selenium. High impact selenium targets could also serve as biomarkers to gauge the efficacy of selenium chemoprevention.

Antineoplastic Agents↗

PubMed2006

Analysis of protein redox modification by hypoxia.

We examined hypoxia-induced changes in global thiol proteome profile in human prostate cancer cells using a BIAM-based display method. We analyzed the kinetics of protein thiol modification by using a pattern recognition algorithm, self-organizing maps (SOM) clustering, and identified the BIAM-labeled proteins by MALDI-TOF and ESI-tandem mass spectrometry. We found 99 out of 215 of total BIAM-labeled proteins were affected by hypoxia treatment and, yet, with diverse patterns and kinetics of redox modification. Our study proved that proteomics analysis employing the BIAM-labeling method can provide valuable information pertaining to global changes in the redox status of proteins in response to hypoxia.

Apoptosis↗

PubMed2006

Prospective analysis of treatment outcome and prognostic factors in patients with T-cell lymphomas treated by CEOP-B: single institutional study.

The important prognostic factors were evaluated for T-cell non-Hodgkin lymphoma (NHL) patients in a prospective study using the CEOP-B protocol [a modified cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like regimen that uses epirubicin instead of doxorubicin with the addition of bleomycin]. Fifty-two patients were enrolled in the study. The overall response rate was 63.5%. The median progression-free survival (PFS) and median overall survival (OS) was 18.0 and 39.5 months respectively. The most common toxicity was neutropenia. The factors related to poor outcome were a high International Prognostic Index (IPI) and a high 'B' score (bone marrow involvement, B symptoms, bulky disease). We developed a new prognostic model, namely the Prognostic Group for T cell NHL (PGT) that included four groups: PGT1 (low IPI/low B score), PGT2 (low IPI/high B score), PGT3 (high IPI/Low B score) and PGT4 (high IPI/Low B score). OS and PFS (not reached, 48 months) in the PGT1 group were significantly longer than those (11.5 and 4.8 months) in PGT2. The same result was observed in the PGT3 and PGT4 groups. The CEOP-B regimen was moderately active and tolerable for T-cell NHL patients, and the PGT system might be useful for the prediction of long-term survival of T-cell NHL patients.

Adolescent↗

PubMed2005

Hematopoietic differentiation of embryoid bodies derived from the human embryonic stem cell line SNUhES3 in co-culture with human bone marrow stromal cells.

Human embryonic stem (ES) cells can be induced to differentiate into hematopoietic precursor cells via two methods: the formation of embryoid bodies (EBs) and co-culture with mouse bone marrow (BM) stromal cells. In this study, the above two methods have been combined by co-culture of human ES-cell-derived EBs with human BM stromal cells. The efficacy of this method was compared with that using EB formation alone. The undifferentiated human ES cell line SNUhES3 was allowed to form EBs for two days, then EBs were induced to differentiate in the presence of a different serum concentration (EB and EB/high FBS group), or co- cultured with human BM stromal cells (EB/BM co-culture group). Flow cytometry and hematopoietic colony-forming assays were used to assess hematopoietic differentiation in the three groups. While no significant increase of CD34+/CD45- or CD34+/CD38- cells was noted in the three groups on days 3 and 5, the percentage of CD34+/CD45- cells and CD34+/ CD38- cells was significantly higher in the EB/BM co-culture group than in the EB and EB/high FBS groups on day 10. The number of colony-forming cells (CFCs) was increased in the EB/BM co-culture group on days 7 and 10, implying a possible role for human BM stromal cells in supporting hematopoietic differentiation from human ES cell-derived EBs. These results demonstrate that co-culture of human ES-cell-derived EBs with human BM stromal cells might lead to more efficient hematopoietic differentiation from human ES cells cultured alone. Further study is warranted to evaluate the underlying mechanism.

ADP-ribosyl Cyclase 1↗

PubMed2005

Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC. PATIENTS AND METHODS: All 53 patients received epirubicin (50 mg/m2 i.v.) on day 1 and cisplatin (60 mg/m2 i.v.) after epirubicin administration. Oral UFT 400-600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval. RESULTS: Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0-26.8%) with median response duration of 17.1 weeks (95% CI; 5.0-29.3 weeks, range; 7.1-51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3-31.9 weeks, range; 3.0-131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%). CONCLUSION: The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Adult↗

PubMed2005

Autocrine vascular endothelial growth factor/vascular endothelial growth factor receptor-2 growth pathway represents a cyclooxygenase-2-independent target for the cyclooxygenase-2 inhibitor NS-398 in colon cancer cells.

OBJECTIVES: Coexpression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) has been reported in tumor cells, suggesting the presence of an autocrine VEGF/VEGFR-2 growth pathway in solid tumors. Thus, we hypothesize that the presence of this autocrine pathway in colon cancer cells may be a COX-2-independent target of COX-2 inhibitors and a mechanism behind the antitumor effects of these agents. METHODS: COX-2-positive (Caco2, HT-29) and COX-2-negative colon cancer cells (DLD-1, Hct-15) were used. Expression of VEGFR-2 was evaluated by Western blot and reverse transcriptase-polymerase chain reaction and VEGF production was measured from culture supernatant by enzyme-linked immunosorbent assay. Growth inhibition and the expression of VEGF and VEGFR-2 were compared after treatment with the COX-2 inhibitor, NS-398 at doses ranging from 5 to 100 microM. RESULTS: VEGF and VEGFR-2 were expressed in all four colon cancer cells and a blockade of VEGFR-2 with anti-VEGFR-2 antibody treatment induced growth inhibition of colon cancer cells, supporting the presence of autocrine VEGF/VEGFR-2 growth pathway. NS-398 suppressed the growth of colon cancer cells, independent of COX-2 expression. VEGFR-2 expression of tumor cells was reduced after NS-398 treatment at 100 microM, the concentration at which maximal growth inhibition was induced. The amount of VEGF in culture supernatant was increased by NS-398 at 100 microM, suggesting increased secretion of VEGF in compensation for reduced VEGFR-2 expression. CONCLUSION: The autocrine VEGF/VEGFR-2 growth pathway could be a COX-2-independent target of the COX-2 inhibitor, NS-398, in colon cancer cells.

Antineoplastic Agents↗

PubMed2005

Hyperacetylation enhances the growth-inhibitory effect of all-trans retinoic acid by the restoration of retinoic acid receptor beta expression in head and neck squamous carcinoma (HNSCC) cells.

The chemotherapeutic effects of all-trans-retinoic acid (atRA) are mediated by the retinoic acid receptor beta (RARbeta), but RARbeta expression is reduced in a number of head and neck carcinoma (HNSCC) cells which causes resistance to RA treatment in half the patients with HNSCC. The possible mechanism for the reduced RARbeta expression has been suggested as the methylation of the CpG islands adjacent to the RA response elements (RARE) in the RARbeta promoter and the loss of histone acetylation. The suppressed RARbeta expression can be reactivated by a demethylating agent (5-aza-2'-deoxycytidine, 5-AzaC) or a histone deacetylase inhibitor (trichostatin A, TSA). Therefore, we sought to determine if the restoration of RARbeta activity, or a combination of these drugs, could restore the sensitivity to RA in RARbeta-negative HNSCC cells with an epigenetically methylated RARbeta promoter region. SqCC/Y1 cells resistant to atRA showed methylated and unmethylated forms in the RARbeta promoter region. RARbeta expression of these cells was restored by 5-AzaC or TSA treatment. Also, treatment with TSA and atRA combined synergistically increased the growth-inhibitory effect and highly induced the transcriptional activation of the RARbeta promoter compared to atRA treatment in HNSCC cells. Additionally, TSA alone and the combination 5-AzaC and TSA increased lysine-9 (Lys-9) acetylation and Lys-4 methylation of the first exon at the RARbeta gene, while decreasing the methylation of Lys-9 in the HNSCC cells.

Acetylation↗

PubMed2005

Incidence of anemia in older Koreans: community-based cohort study.

Most epidemiologic data are related to the prevalence of anemia, and there is little information regarding the incidence or etiology of newly diagnosed anemia in older people. The purpose of this study was to define the incidence and characteristics of anemia in the elderly population of Korea. Three hundred thirty-two independent, community-living, elderly persons aged 60 years and older were enrolled, and laboratory tests including iron profiles were performed. The mean age was 72+/-4.8 years and the mean hemoglobin was 13.4+/-1.1g/dl. During the follow-up period of 3 years, 24 subjects (3 males and 21 females) were newly diagnosed with anemia, which led to a 3-year incidence of 7.2% (24/332). Among the 24 subjects with new-onset anemia, iron deficiency anemia (IDA) was diagnosed in 5 subjects, while anemia of chronic disease (ACD) was detected in 8 subjects. Underlying illnesses were diabetes mellitus, osteoarthritis, renal insufficiency, hypothyroidism and malignancy. In those subjects with new-onset anemia, the serum iron, ferritin, transferrin saturation and albumin were lower than in the normal group. In conclusion, the 3-year incidence of anemia among Korean elderly people was determined to be 7.2%, and ACD was the most commonly defined cause of anemia.

Age Distribution↗

PubMed2005

RASSF1A suppresses the c-Jun-NH2-kinase pathway and inhibits cell cycle progression.

Some oncogenes, such as activated Ras, cause the malignant transformation of lung cells. c-Jun-NH2-kinase (JNK) activation is essential for the oncogenic function of these cells. In this study, we show that RASSF1A inhibits the growth of lung cancer cells by blocking the JNK pathway. The exogenous expression of RASSF1A suppressed JNK phosphorylation, and cells stably transfected with RASSF1A showed reduced JNK and c-Jun phosphorylation and Cyclin D1 down-regulation. An in vitro kinase assay showed that the exogenous expression of RASSF1A inhibited JNK activity and that JNK activity suppression due to ectopically expressed RASSF1A was revived by RASSF1A siRNA treatment. Based on our data, we suggest that RASSF1A exerts a tumor-suppressing effect by blocking oncogene-mediated JNK activation in lung cells.

Azacitidine↗

PubMed2005

The cutoff value of serum ferritin for the diagnosis of iron deficiency in community-residing older persons.

The serum ferritin assay is the best single blood test for the diagnosis of iron deficiency. Previous studies with elderly anemic patients have suggested that ferritin level less than 45 mug/L is indicative of iron deficiency. The subjects of these studies were hospitalized patients with anemia, however. We thus conducted a prospective study to determine the normal minimum level of serum ferritin of community-dwelling older adults by assessing the ratio of serum transferrin receptor to the log ferritin level (sTfR-F index). We conducted the anemia survey between October and November 2002. A total of 1,254 apparently healthy older adults, aged between 60 and 95 years, from three urban community dwellings participated in the survey. Among these individuals, 156 subjects who were anemic or whose serum ferritin level was less than 100 microg/L were selected. The soluble transferrin receptor assay was performed and the sTfR-F index was calculated. The receiver operating characteristic curve analysis was performed. Based on the data, serum ferritin level of 22 microg/L was selected as the cutoff value for the diagnosis of iron deficiency in community-dwelling older adults. Applying the serum ferritin cutoff of 22 microg/L and the sTfR-F index cutoff of 1.5, the sensitivity of the assay was 89.5% (34 of 38) and the specificity was 89.0% (105 of 118). In conclusion, for the diagnosis of iron deficiency of community-residing older adults, we suggest the serum ferritin cutoff value of 22 microg/L obtained by use of the sTfR-F index. The value is lower than the previous value established for hospitalized and anemic older adults.

Activities of Daily Living↗

PubMed2005

CDK2/4 regulate retinoic acid-induced G1 arrest in hepatocellular carcinoma cells.

Retinoic acid (RA) is an important regulator of normal cellular proliferation and differentiation and suppressor of tumor growth by cell cycle arrest and apoptosis. Furthermore, RA showed a chemo-preventive activity in preclinical and/or clinical models of lung, head and neck, breast, and hepatocellular carcinoma (HCC). In this study, we examined the effect of RA on the proliferation of human HCC cells, in order to analyze its mode of action and, finally, we attempted to find a surrogate biomarker of RA for HCC chemopreventive treatment. Our findings suggested that the growth inhibition of RA in HCC cells differed according to G(1) phase delay by CDK2 or 4, finally induction of apoptosis. No correlation was found between RA sensitivity and the expression of nuclear retinoid receptors, such as RARs or RXRs in HCC cells. RA treatment caused cell cycle arrest at G(1) and decreased the expressions and activities of CDK2 or CDK4 in RA-sensitive HepG2 and SNU354 cells. On the other hand, RA-resistant Hep3B and SNU449 cells progressed into the S/G(2)+M phase and showed increased CDK2 and CDK4 expression and activity. Since the inhibition of CDK2 or 4 activities resulted in sensitization of HCC cells to RA, the combination of RA and compounds of inhibiting CDKs such as UCN01 and flavopiridol might be a useful targeted therapy strategy for HCC.

Journal Article↗