Jae Hong No

Targeting nrf2 signaling to combat chemoresistance.

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that upregulates expression of a battery of genes to combat oxidative and electrophilic stress. Modification of Kelch-like ECH-associated protein 1 (Keap1) by reactive oxygen species stabilizes Nrf2 by escaping from degradation. Nrf2 then binds to antioxidant response elements (AREs) on the promoter region of various genes. Activation of the Keap1-Nrf2-ARE pathway plays critical roles in the chemopreventive effect of various phytochemicals. However, Nrf2 can protect cancer cells from oxidative stress and promote cell proliferation. Moreover, recent studies reveal that activation of the Nrf2 pathway is critical for resistance to chemotherapeutic agents. The aim of this review is to provide a molecular basis for the use of Nrf2 inhibitors in overcoming chemoresistance.

Metabolic approaches to overcoming chemoresistance in ovarian cancer.

The poor prognosis in the treatment of ovarian cancer is mainly attributed to chemoresistance. The development of new strategies is urgently necessary to overcome chemoresistance because of the low efficacy of the current standard chemotherapy in ovarian cancer. Metabolic alterations have been suggested to have a crucial role in cancer development. The key metabolic changes in cancer include aerobic glycolysis and macromolecular synthesis, causing antiapoptosis in cancer cells. Therefore, the manipulation of the metabolic derangement could be an effective strategy to overcome chemoresistance in ovarian cancer. In this review, we will discuss metabolic interventions as promising anticancer strategies in ovarian cancer, focusing on the glycolytic, mitochondrial apoptotic, and necrotic pathways. In addition, the role of p53 in relation to metabolic alterations in cancer will be mentioned.

Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer

OBJECTIVE Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer. METHODS Immunohistochemical staining with antibodies against p-4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6months. RESULTS Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p=0.04), histologic grade (p<0.01), residual mass (p<0.01), shorter disease-free survival rate (p=0.01) and chemoresistance (p=0.02). p-p70S6K was associated with residual mass with marginal significance (p=0.06). p-4EBP1 expression was correlated with p-p70S6K expression (r=0.42, p<0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors. CONCLUSIONS Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer.

Human papillomavirus vaccine: Widening the scope for cancer prevention

Human papillomavirus (HPV) is the necessary cause of cervical cancer. The HPV oncoproteins E6 and E7 have crucial roles in various steps of carcinogenesis, inducing degradation of p53 and destabilization of pRb. Several clinical trials show that recombinant HPV vaccines are safe and effective in preventing persistent infection of HPV and associated anogenital lesions. Although most clinical studies to date have investigated the effectiveness of HPV vaccines in young female subjects, elderly females and males may also be candidates for HPV vaccines. Prophylactic HPV vaccination may be an ideal preventive method for other HPV‐associated cancers in addition to cervical carcinoma. Carcinogenesis by HPV, efficacy trials of currently available HPV vaccines, and the possible roles of HPV vaccines in the prevention of HPV‐associated cancers are reviewed in this article.

Systemic Inflammatory Response Markers and CA-125 Levels in Ovarian Clear Cell Carcinoma: A Two Center Cohort Study

Purpose We compared the predictive and prognostic values of leukocyte differential counts, systemic inflammatory (SIR) markers and cancer antigen 125 (CA-125) levels, and identified the most useful marker in patients with ovarian clear cell carcinoma (OCCC). Materials and Methods The study included 109 patients with OCCC who did not have any inflammatory conditions except endometriosis, and underwent primary debulking surgery between 1997 and 2012. Leukocyte differential counts (neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet), SIR markers including neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), and platelet to lymphocyte ratio (PLR), and CA-125 levels were estimated to select potential markers for clinical outcomes. Results Among potential markers (neutrophil, monocyte, platelet, NLR, MLR, PLR, and CA-125 levels) selected by stepwise comparison, CA-125 levels were best at predicting advanced stage disease, suboptimal debulking and platinum-resistance (cut-off values, ≥ 46.5, ≥ 11.45, and ≥ 66.4 U/mL; accuracies, 69.4%, 78.7%, and 68.5%) while PLR ≥ 205.4 predicted non-complete response (CR; accuracy, 71.6%) most accurately. Moreover, PLR < 205.4 was an independent factor for the reduced risk of non-CR (adjusted odds ratio, 0.17; 95% confidence interval [CI], 0.04 to 0.69), and NLR < 2.8 was a favorable factor for improved progression-free survival (PFS; adjusted hazard ratio, 0.49; 95% CI, 0.25 to 0.99) despite lack of a marker for overall survival among the potential markers. Conclusion CA-125 levels may be the most useful marker for predicting advanced-stage disease. Suboptimal debulking and platinum-resistance, and PLR and NLR may be most effective to predict non-CR and PFS in patients with OCCC.

CA19-9 elevation in ovarian mature cystic teratoma: Discrimination from ovarian cancer – CA19-9 level in teratoma

Background We aimed to identify clinical characteristics of ovarian mature cystic teratoma (MCT) in association with CA19-9 elevation, and to determine if CA19-9 is a useful marker in discrimination of MCT from ovarian cancer (OC). Material/Methods Medical records of 322 women with pathologically-confirmed MCT or OC (stage 1 or 2) were reviewed retrospectively. The relationships between the characteristics of MCT (mean diameter, bilaterality, and pathologic components) and elevated CA19-9 were evaluated. Tumor markers in MCT were compared to those in OC. Results MCTs with CA19-9 elevation were correlated with a larger diameter (8.53±3.84 cm vs. 6.95±3.97 cm, p=0.002) and presence of fat component (67.1% vs. 32.9%, p<0.001), compared to those with normal CA 19-9. Although the incidence of CA19-9 elevation was not different between patients with MCT and OC (p=0.700), the mean value of CA19-9 was higher in those with OC (114.66±20.66 U/mL vs. 508.58±261.63 U/mL, p=0.013). In addition, simultaneous elevation of CA125 and CA19-9 was associated with a higher probability of malignant neoplasm (p<0.001; odds ratio: 23.7; 95% confidence interval: 8.863–63.576) than single elevation of CA 19-9. Conclusions CA19-9 could be an important tool in the diagnosis of ovarian mature cystic teratoma. CA19-9, in combination with CA125, might be a useful marker in discrimination of MCT from cancer.

Prognostic Significance of Serum Soluble CD163 Level in Patients with Epithelial Ovarian Cancer

Background: The purpose of this study was to investigate the prognostic significance of serum sCD163 in patients with epithelial ovarian cancer. Methods: Preoperative serum samples from 55 patients with epithelial ovarian cancers were analyzed for sCD163 using a commercially available enzyme-linked immunosorbent assay kit. A Cox proportional hazard model was used to calculate hazard ratio (HR) and 95% confidence interval (CI) for disease-free survival (DFS) and overall survival (OS). Results: Median serum sCD163 levels were higher in patients with a high-grade tumor. High serum sCD163 levels (3.43 mg/l) were associated with poor prognostic factors such as advanced stage (p = 0.024) and positive peritoneal cytology (p = 0.015). Univariate survival analysis showed that elevated sCD163 levels were associated with short DFS (8.0 vs. 32.4 months, p = 0.04) and OS (19.7 vs. 40.0 months, p = 0.027). Multivariate survival analysis revealed that high serum sCD163 levels were negatively associated with DFS (HR 3.1, 95% CI 1.2-8.1, p = 0.039). Conclusions: Our study shows that elevated serum sCD163 levels were associated with poor prognosis in patients with ovarian cancer. Impact: The prognostic significance of serum sCD163 in patients with epithelial ovarian cancer is described.

Impact of Underweight after Treatment on Prognosis of Advanced-Stage Ovarian Cancer

This study aimed to investigate the impact of underweight status on the prognosis of advanced-stage ovarian cancer. A total of 360 patients with stage III-IV epithelial ovarian cancer were enrolled and divided into three groups by body mass indexes (BMIs): underweight (BMI < 18.5 kg/m2); normal weight to overweight (18.5 kg/m2 BMI < 27.5 kg/m2); obesity (BMI ≥ 27.5 kg/m2). Progression-free survival (PFS), overall survival (OS), CA-125, and neutrophil to lymphocyte ratio (NLR) as a marker reflecting host inflammation and immunity were compared among the three groups according to the three treatment times: at diagnosis; after surgery; and after treatment. Only underweight status after treatment was associated with poor OS in comparison with normal weight to overweight or obesity (mean value, 44.9 versus 78.8 or 67.4 months; P = 0.05); it was also an unfavorable factor for OS (adjusted HR, 2.29; 95% CI, 1.08–4.85). Furthermore, NLR was higher in patients with underweight than in those with obesity after treatment (median value, 2.15 versus 1.47; P = 0.03), in spite of no difference in CA-125 among the three groups at the three treatment times. In conclusion, underweight status after treatment may be a poor prognostic factor in patients with advanced-stage ovarian cancer, which accompanies increased host inflammation and decreased immunity.

Expression of MMP‐2, MMP‐9, and Urokinase‐Type Plasminogen Activator in Cervical Intraepithelial Neoplasia

Matrix metalloproteinase‐2 (MMP‐2), MMP‐9, and urokinase‐type plasminogen activator (uPA) are important factors for cancer invasion and metastasis, degrading the extracellular matrix. They are also associated with angiogenesis. Angiogenic phenotype is another feature of high‐grade cervical intraepithelial neoplasia (CIN). However, their associations with the progression of low‐grade CIN to high‐grade CIN are unexplored. We investigated whether these proteolytic enzyme expressions correlate with the progression of CIN. A total of 39 paraffin‐embedded specimens from 10 patients with CIN grade 1, nine with CIN grade 2, and 20 with CIN grade 3 were assessed immunohistochemically by specific antibodies against MMP‐2, MMP‐9, and uPA. MMP‐9 expression was higher in CIN 3 lesions (47.4%) than in CIN 1 (22.2%) and CIN 2 (20.2%) lesions, although the difference failed to reach statistical significance. The expression level of uPA and MMP‐2 was not associated with the grade of CIN lesions. Interestingly, we found a significant association between expressions of uPA and MMP‐2 (P= 0.028). Our results suggest that MMP‐9 might play a role in the progression of CIN.

Association of cyclin D1 G870A polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2

BACKGROUND Many studies have shown that a polymorphism (G870A) in cyclin D1 (CCND1) is associated with carcinogenesis in a variety of cancers. Our aim was to determine if an association exists between the CCND1 G870A polymorphism and uterine leiomyoma in Korean women. METHODS Blood samples of 331 cases and 204 controls aged 47.4 +/- 7.6 and 46.8 +/- 10.4 years (mean +/- SD), respectively, were collected. CCND1 genotyping was determined by PCR and restriction fragment length polymorphism. RESULTS Allelic frequencies of cases (A, 0.53; G, 0.47) were not significantly different from those of controls (A, 0.49; G, 0.51) (P = 0.22). After adjustment for menarche age and BMI, multivariate logistic regression analysis showed that the AA genotype was not associated with increased risk for uterine leiomyoma [odds ratio (OR) = 1.38, 95% confidence interval (CI); 0.85-2.26, P = 0.19]. However, in stratification analysis of cases and controls with BMI >25 kg/m(2), allelic frequencies of cases (A, 0.56; G, 0.44) were significantly different from controls (A, 0.36; G, 0.64) (P = 0.005), and the AA genotype was associated with increased risk for uterine leiomyoma (OR = 3.61, 95% CI; 1.02-12.73, P = 0.046). Furthermore, the OR for AA compared with combined GG and AG genotypes was 3.16 (95% CI 1.01-9.92, P = 0.048). CONCLUSIONS The A allele and AA genotype of CCND1 G870A polymorphism have a significant association with an increased risk of the uterine leiomyoma in obese Korean women.