Nak Woo Lee

The expression of the miRNA-200 family in endometrial endometrioid carcinoma

OBJECTIVE Recent reports suggest that targeting the unique miRNAs highly expressed in several cancers may be a promising approach in the development of new cancer therapeutic tools. The purpose of this study was to evaluate the roles of miRNAs as therapeutic targets in human endometrial endometrioid carcinomas (EECs). METHODS We evaluated the differential expressions of miRNAs in EECs and normal endometrial tissues using microarrays and cluster analysis. After validation of differentially expressed miRNAs in another set of EECs and normal endometrial tissues, we performed the in vitro experiment using endometrial cancer cells with anti-miRNA (anti-miR) to evaluate the roles of miRNAs that are highly expressed in EECs for cell proliferation and chemosensitivity. RESULTS A miRNA microarray showed that the miR-200 family, including hsa-miR-141, hsa-miR-200a, hsa-miR-200b, hsa-miR-200c, and hsa-miR-429, was up-regulated in EECs as compared with that in normal endometrial tissues. When we treated endometrial cancer cells with specific anti-miRs, including anti-miR-141, -200a, -200b, -200c, or -429, we found that anti-miR-200a, -200b, -200c, and -429 significantly inhibited the growth of HEC-1A cells and anti-miR-141, -200c, and -429 significantly inhibited the growth of Ishikawa cells. Moreover, transfection with anti-miR-429 enhanced the cytotoxic effect of cisplatin in HEC-1A cells. CONCLUSIONS These results indicate that the miR-200 family is highly expressed in EECs compared with that of normal endometrial tissues and could play an important role in cancer growth. Specifically, anti-miR-429 could enhance the cytotoxic activity with cisplatin in EECs. Therefore, the miR-200 family may offer new candidate targets to be exploited in therapeutic strategies for patients with these carcinomas.

Detection of Microrna as Novel Biomarkers of Epithelial Ovarian Cancer From the Serum of Ovarian Cancer Patient

Objective MicroRNA (miRNA) is an abundant class of small noncoding RNAs that act as gene regulators. Recent studies have suggested that miRNA deregulation is associated with the initiation and progression of human cancer. However, information about cancer-related miRNA is mostly limited to tissue miRNA. The aim of this study was to find specific profiles of serum-derived miRNAs of ovarian cancer based on a comparative study using a miRNA microarray of serum, tissue, and ascites. Methods From 2 ovarian cancer patients and a healthy control, total RNA was isolated from their serum, tissue, and ascites, respectively, and analyzed by a microarray. Under the comparative study of each miRNA microarray, we sorted out several miRNAs showing a consistent regulation tendency throughout all 3 specimens and the greatest range of alteration in serum as potential biomarkers. The availability of biomarkers was confirmed by qRT-PCR of 18 patients and 12 controls. Results Out of 2222 kinds of total miRNAs that were identified in the microarray analysis, 95 miRNAs were down-regulated and 88 miRNAs were up-regulated, in the serum, tissue, and ascites of cancer patients. Among the miRNAs that showed a consistent regulation tendency through all specimens and showed more than a 2-fold difference in serum, 5 miRNAs (miR-132, miR-26a, let-7b, miR-145, and miR-143) were determined as the 5 most markedly down-regulated miRNAs in the serum from ovarian cancer patients with respect to those of controls. Four miRNAs (miR-132, miR-26a, let-7b, and miR-145) out of 5 selected miRNAs were significantly underexpressed in the serum of ovarian cancer patients in qRT-PCR. Conclusions Serum miR-132, miR-26a, let-7b, and miR-145 could be considered as potential candidates as novel biomarkers in serous ovarian cancer. Also, serum miRNAs is a promising and useful tool for discriminating between controls and patients with serous ovarian cancer.

Microarray analysis of normal cervix, carcinoma in situ, and invasive cervical cancer: identification of candidate genes in pathogenesis of invasion in cervical cancer

The objective of this study was to identify genes that are related to pathogenesis of carcinoma in situ (CIS) to invasive cervical cancer with the use of oligonucleotide microarray and reverse transcription-polymerase chain reaction (RT-PCR). Each two cases of normal cervix, CIS, and invasive cervical cancer were investigated with DNA microarray technology. Differential gene expression profiles among them were analyzed. Expression levels of selected genes from the microarray results were confirmed by RT-PCR. The expressions of 15,286 genes were compared and 458 genes were upregulated or downregulated by twofold or more compared with each other group. Among 458 genes, 22 genes were upregulated and 40 genes were downregulated by twofold or more in invasive cervical cancer group compared with CIS group. RT-PCR analysis confirmed upregulation of 18 genes and downregulation of 5 genes in invasive cervical cancer group. RBP1, TFRC, SPP1, SAA1, ARHGAP8, and NDRG1, which were upregulated, and GATA3, PLAGL1, APOD, DUSP1, and CYR61, which were downregulated, were considered as candidate genes associated with invasion of cervical cancer.

Interferon-γ (IFN-γ): A possible prognostic marker for clearance of high-risk human papillomavirus (HPV)

OBJECTIVES The goal of this study was to identify cytokines that may predict high-risk HPV clearance or persistence in untreated patients with mild dysplasia or less of the uterine cervix. METHODS A prospective analysis was performed on 57 patients who harbored high-risk HPV with histologically verified mild dysplasia or less between May 2005 and March 2006. All patients underwent follow-up evaluation at 12 months. Real-time PCR was used to quantify interferon-gamma (IFN-gamma), interleukin-10 (IL-10), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) transcripts. Hybrid Capture II testing was used to detect HPV DNA. RESULTS Among the 57 patients that were untreated with mild dysplasia, or less, 46 (80.7%) had no detectable HPV after 12 months of follow-up. Univariate analysis showed that a negative HPV test, of untreated mild dysplasia or less, occurred in 93.3% (28/30) of patients who were IFN-gamma-positive and in 66.7% (18/27) of patients who were IFN-gamma-negative (P=0.0109). Other factors such as age, lesion grade in the colposcopic biopsy, IL-10, IL-6, TNF-alpha, day of menstrual cycle, smoking, and use of oral contraceptives were not significantly associated with high-risk HPV negative or positive results after 12-months of follow-up in patients with untreated mild dysplasia or less. The multivariate logistic regression analysis showed that only IFN-gamma-positive results were significantly associated with clearance of high-risk HPV after 12 months of follow-up (OR: 8.26; 95% CI: 1.24-54.94). CONCLUSIONS These results suggest that intralesional IFN-gamma may be a prognostic marker for clearance of high-risk HPV.

Obesity and epithelial ovarian cancer survival: a systematic review and meta-analysis

BackgroundStudies on the association between obesity and ovarian cancer survival have had conflicting results. We reviewed and quantitatively summarized the existing evidence, exploring potentially important sources of variability, such as the timing of body mass index (BMI) assessment, BMI cut points, references used in multivariate analysis, and ovarian cancer stage.MethodsEligible studies were searched using MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials, relevant bibliographies were manually reviewed for additional studies. Adjusted hazard ratios (HRs) from individual studies were pooled using a random effects model.Results17 cohort studies of 929 screened articles were included in the final analysis. Obesity in early adulthood and obesity 5 years before ovarian cancer diagnosis were associated with poor patient survival (early adulthood: pooled HR 1.67; 95% CI 1.29-2.16; 5 years prediagnosis: pooled HR 1.35; 95% CI 1.03-1.76). However, the results for obesity at diagnosis depended on whether BMI was analyzed as a categorical or continuous variable. Analysis of obesity with BMI as a categorical variable did not affect ovarian cancer prognosis (pooled HR 1.07; 95% CI 0.95-1.21); obesity with BMI as a continuous variable showed slightly poorer survival with each incremental increase in BMI (pooled HR 1.02; 95% CI 1.01-1.04).ConclusionsObesity 5 years before ovarian cancer diagnosis and obesity at a young age were associated with poor prognosis. The association between obesity at diagnosis and survival of ovarian cancer patients still remains equivocal. BMI at diagnosis cannot be a prognostic factor for the survival of ovarian cancer patients. Further well-designed studies are needed to elucidate the variety effect of obesity on the survival of ovarian cancer patients.

The interactions between MicroRNA-200c and BRD7 in endometrial carcinoma

OBJECTIVE Increased expression of miR-200c was recently reported in endometrial carcinoma compared with normal tissues. In this study, we evaluated the role of miR-200c in cell growth and drug sensitivity in endometrial carcinoma and investigated the underlying mechanisms. METHODS The expression of miR-200c in human endometrial tissues was detected by quantitative RT-PCR. The transfection with anti-miRNA (anti-miR) or the premature form of miRNA (pre-miR) was performed to regulate the level of expression of miRNA-200c in endometrial carcinoma cells, HEC-1A and Ishikawa. To identify the target genes for miR-200c, we performed mRNA microarray after pre-miR-200c transfection in HEC-1A cells. RESULTS We found that miR-200c expression was increased in endometrial carcinoma compared with normal endometrial tissues. Anti-miR or pre-miR-200c could regulate cell survival, proliferation, and apoptosis and affect cytotoxicity in endometrial cancer cells. Through mRNA microarray analysis, we found that miR-200c inhibits the expression of BRD7, which was recently reported as a potential tumor suppressor gene. MiR-200c regulated the translocation of β-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc. CONCLUSION The interaction between miR-200c and BRD7 might have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

Significance of CD44v6 expression in gynecologic malignancies

Aim:  Variants of CD44 have been proposed to be important in cancer invasion and metastasis. The purpose of this study was to evaluate the diagnostic and prognostic value of CD44v6 expression in gynecologic malignancies.

High‐risk human papillomavirus testing for monitoring patients treated for high‐grade cervical intraepithelial neoplasia

Aim:  The aim of the present study was to examine the accuracy of high‐risk human papillomavirus (HR‐HPV) DNA detection as a predictor of residual or recurrent cervical intraepithelial neoplasia (CIN) after treatment of high‐grade CIN.

Vaginal Cuff Closure: A Comparison between the Vaginal Route and Laparoscopic Suture in Patients Undergoing Total Laparoscopic Hysterectomy

Background: To compare the vaginal route and laparoscopic suture for vaginal cuff closure (VCC) in patients undergoing a total laparoscopic hysterectomy (TLH). Methods: A total of 471 women who required hysterectomy were allocated to two groups. 261 women had TLH via VCC by the vaginal route and 210 women had TLH via VCC by laparoscopic suture. All TLHs were performed by the same laparoscopic surgeon. Results: The cuff-related complications included vaginal disruption (3.4%), dehiscence (1.27%), vaginal vault bleeding (1.91%), vaginal spotting (19.32%), granulation (1.27%), cuff infection (1.49%), and yellowish vaginal discharge (6.16%). No difference in vaginal cuff complications was found between the laparoscopic and vaginal approach. The median operation time was significantly shorter for the laparoscopic suture (76.74 min, range 40–220; 95% CI 74.84–83.45) than the vaginal route for VCC (85.77 min, range 45–290; 95% CI 86.87–95.36) after hysterectomy (p < 0.001). Conclusion: For VCC with TLH, laparoscopic suture was a safe and less time-consuming procedure. The cuff-related complications were similar in the two groups.

Factors Affecting the Clearance of High-Risk Human Papillomavirus Infection and the Progression of Cervical Intraepithelial Neoplasia

OBJECTIVE: This study aimed to identify factors that predict clearance of high-risk human papillomavirus (HPV) infection and progression to cervical intraepithelial neoplasia (CIN) 2 or higher, in women with normal cervical histology or CIN 1. METHODS: A retrospective analysis was performed on 817 high-risk HPV-infected women with histologically verified CIN 1 or normal cervical histology. Patients were followed-up for a maximum of 24 months. Cervical HPV DNA tests were performed at every visit. RESULTS: At the end of follow-up, 648/817 (79.3%) patients were free from HPV infection and 66/817 patients (8.1%) progressed to CIN 2 or higher. Age, parity, cytology and viral load at diagnosis were significantly and inversely associated with HPV clearance. Cytology, viral load and presence of CIN 1 lesions were significantly associated with lesion progression. CONCLUSIONS: Cytology and high-risk HPV viral load may be useful markers for the likelihood of high-risk HPV clearance and lesion progression. Histological status, parity and marital status may also be useful factors to consider when predicting progression.