Ah-Young Kwon

MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3

To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone. miR-136 overexpression downregulated cell survival- (survivin, DNA-PK, pS6, S6) and cell cycle- (Cyclin D1, NF-κB) related proteins, and anti-apoptotic proteins (BCL2, and BCL-XL), and upregulated pro-apoptotic proteins (Bim, Bid, and Bax). Taken together, miR-136 targets the Notch3 oncogene and functions as a tumor suppressor. miR-136 overexpression resensitized paclitaxel-resistant ovarian cancer cells and reduced CSC activities, suggesting a promising new target for the treatment of chemoresistant ovarian cancers.

Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.

Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence. Gamma‐secretase inhibitor (GSI) is a broad‐spectrum Notch inhibitor, but it has serious side effects. The efficacy of Notch3‐specific inhibition in paclitaxel‐resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI. To analyze the effect of Notch3‐specific inhibition on paclitaxel‐resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel‐resistant SKpac cells and parental SKOV3 cells. Expression levels of survival, cell cycle, and apoptosis‐related proteins were measured and compared between groups. Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group. In paclitaxel‐resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel. Spheroid formation was also significantly reduced. Both Notch3 siRNA‐treated cells and GSI‐treated cells arrested in the G2/M phase of the cell cycle. Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated. Both GSI and Notch3 siRNA treatment reduced expression of anti‐apoptotic proteins (BCL‐W, BCL2, and BCL‐XL) and increased expression of pro‐apoptotic proteins (Bad, Bak, Bim, Bid, and Bax). These results indicate that Notch3‐specific inhibition sensitizes paclitaxel‐resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI. This approach would be likely to avoid the side effects of broad‐spectrum GSI treatment.

Molecular genotyping of noninvasive encapsulated follicular variant of papillary thyroid carcinoma

The non‐invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has been managed as a low‐risk malignancy. Recently, a proposal was made to reclassify this tumour type as a premalignant lesion and rename it non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP). This study aims to provide the first comprehensive study on molecular genotype–phenotype correlations of encapsulated FVPTC.

Fibulin-5 is a tumour suppressor inhibiting cell migration and invasion in ovarian cancer

Aims Fibulin-5 is an extracellular matrix (ECM) glycoprotein which has a role in the organisation and stabilisation of ECM structures and regulating cell proliferation and tumourigenesis. Here, the expression of fibulin-5 and its functional effects on the migration and invasion of ovarian cancer cells were assessed. Methods Expression of fibulin-5 was detected in 44 ovarian tumour tissues by qRT-PCR, Western blotting and immunohistochemistry. We performed cell migration and invasion assays, and cell cycle analysis in fibulin-5 transfected SKOV3 (SKOV3-FBLN5) cells and the parental SKOV3 cells. We further examined the expression of three tissue inhibitors of metalloproteinases (TIMPs) and seven matrix metalloproteinases (MMPs) by RT-PCR. Results mRNA and protein expression of fibulin-5 were down-regulated (0.05-fold and 0.1-fold) in ovarian carcinomas compared with control tissues (p<0.01 and p=0.022). In wound-healing and invasion assays, significantly fewer SKOV3-FBLN5 cells than SKOV3 control cells migrated and invaded (39.1%, p=0.046 and 70%, p=0.03, respectively), which was reversed by siRNA-treatment. Overexpression of fibulin-5 induced G2/M arrest and increased cyclin B1, CDC2 and CDC25C. Expression of TIMP-2 (0.56-fold), MMP-3 (0.43-fold) and MMP-13 (0.18-fold) was lower and MMP-9 expression (2.20-fold) was higher in SKOV3-FBLN5 cells than in control cells. Conclusions Fibulin-5 is significantly down-regulated in ovarian carcinoma and acts as a tumour suppressor by inhibiting the migration and invasion of ovarian cancer cells.

Histologic characteristics of thymic adenocarcinomas: Clinicopathologic study of a nine-case series and a review of the literature.

Primary thymic adenocarcinoma is an extraordinarily rare malignancy; only 49 cases have been reported in the medical literature to date. Because of its rarity, clinical and pathologic characteristics of thymic adenocarcinoma are unclear. We present nine cases of primary thymic adenocarcinoma and discuss clinicopathologic findings in the context of the existing literature. Two-hundred twenty-six thymic carcinoma cases were diagnosed at Samsung Medical Center in Korea, from January, 2001 to July, 2016. Nine of these 226 cases were primary thymic adenocarcinomas. The mean age of primary thymic adenocarcinoma patients was 53.6 years, slightly younger than the mean age of patients with thymic squamous cell carcinomas. The male to female ratio was 2:1. Symptoms, if present, were usually due to compression by the tumor. Tumors showed an extra- or intra-cellular mucin and tubular growth pattern, with CK20- and CDX2-immunoreactivity, similar to adenocarcinomas of the lower intestinal tract. Twenty-five previously reported cases, classified as mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, also had similar characteristics to enteric-type adenocarcinoma and generally expressed CK20, CDX2, CEA, and/or MUC2. Some of these cases had a thymic cyst. These characteristics are different from those of papillary thymic carcinomas, which are morphologically similar to papillary thyroid carcinomas, express CK7 but not CK20, and are often associated with thymoma. The prognosis of thymic adenocarcinoma, enteric type appeared to be worse than the prognosis of papillary thymic carcinoma or carcinoma with adenoid cystic carcinoma-like features. In summary, we demonstrated that common primary thymic adenocarcinomas show enteric-type differentiation with mucin. This tumor type has distinct clinical, pathological, immunohistochemical and prognostic characteristics and is different from other subtypes of thymic adenocarcinoma, papillary thymic carcinoma, and carcinoma with adenoid cystic carcinoma-like features.

Sox10 expression in ovarian epithelial tumors is associated with poor overall survival

Sox10 is a transcription factor regulating the development of several cell lineages and is involved in tumor development. However, the clinicopathological relevance of Sox10 expression in ovarian cancer has not been examined. We assessed expression of Sox10 in ovarian epithelial tumors by immunohistochemistry and assessed its prognostic value by analyzing the correlation between its expression and clinicopathological factors. We used tissue microarrays including 244 ovarian epithelial tumors. Sox10 staining was found in the cytoplasm or nucleus of tumor cells. Malignant serous, mucinous, and endometrioid tumors were significantly more likely to express Sox10 than benign and borderline tumors. Expression patterns in adenocarcinomas were different for histologic subtypes: nuclear Sox10 staining was common in clear-cell adenocarcinomas and serous adenocarcinomas, whereas all cases of mucinous and endometrioid tumors were negative for nuclear staining. Nuclear Sox10 staining was also associated with chemoresistance and shorter overall survival in ovarian adenocarcinomas, notably in high-grade serous adenocarcinoma. Sox10 is expressed in many ovarian carcinomas, suggesting that it might be involved in oncogenesis of ovarian carcinoma. Expression pattern of Sox10 differs between histological subtypes. Nuclear Sox10 expression is an independent indicator of poor prognosis in ovarian adenocarcinomas, notably in high-grade serous adenocarcinomas.

Cytologic Characteristics of Thymic Adenocarcinoma with Enteric Differentiation: A Study of Four Fine-Needle Aspiration Specimens

Thymic adenocarcinoma is extremely rare. Although its histologic features have been occasionally reported, a lack of description of the cytologic features has hampered the prompt and accurate diagnosis of this condition. Herein, we describe the cytologic findings and histology of four aspiration cytology specimens of thymic adenocarcinoma. The specimens were obtained from primary tumors, metastatic lymph nodes, and pericardial effusions. All four specimens showed three-dimensional glandular clusters with a loss of polarity and nuclear overlapping. One specimen had extensive extracellular mucinous material. Three specimens contained tumor cells with intracytoplasmic vacuoles. While the specimen with extracellular mucin showed relatively mild cytologic atypia, other specimens exhibited more atypical cytologic changes: irregular nuclear membranes, a coarse chromatin pattern, and prominent nucleoli. The cytologic features were correlated with the histologic features in each case of enteric type thymic adenocarcinoma. The differential diagnosis included other thymic carcinomas, yolk sac tumors, and metastatic adenocarcinoma from the lung or colorectum.

Fascin expression is inversely correlated with breast cancer metastasis suppressor 1 and predicts a worse survival outcome in node-negative breast cancer patients

Background: Fascin is an actin-bundling protein that promotes cancer cell migration and invasion. By contrast, breast cancer metastasis suppressor 1 (BRMS1) inhibits cancer metastasis by targeting multiple steps of the metastatic cascade. We evaluated whether expression patterns of fascin and BRMS1 correlate with clinicopathological features and patient outcome. Methods: Immunohistochemistry for fascin and BRMS1 was performed using a tissue microarray constructed from 183 human breast cancer tissues. Fascin expression determined by the proportion of stained tumor cells (0: 0-5%, 1: 6-25%, 2: 26-50%, 3: 51-75%, or 4: >75%) and staining intensity (0: negative, 1: weak, 2: moderate, or 3: strong) were multiplied and defined as negative (0-3) or positive (4-12). BRMS1 expression was scored separately based on nuclear and cytoplasmic staining intensity (0: negative, 1: weak, 2: moderate, 3: strong). We obtained the BRMS1 H score by summing the nuclear and cytoplasmic scores and defined it as negative (0-2) or positive (3-6). Results: Expression of BRMS1 showed a significant inverse correlation with that of fascin. Fascin+ tumors were significantly associated with no lymph node metastasis, higher histological and higher nuclear grade, ER/PR/HER2 negativity, and triple-negative subtype (all ps < 0.05). These clinicopathological differences showed the same trend in a comparison of fascin-/BRMS1+ and fascin+/BRMS1- tumors. Negative or weak BRMS1 cytoplasmic expression was significantly associated with shorter disease-free survival (DFS; p = 0.043). Fascin positivity was significantly associated with shorter DFS (p = 0.005) and overall survival (p = 0.020) when analyses were confined to node-negative patients. Conclusions: This study confirms an inverse correlation between expression of fascin and expression of BRMS1 using a quite large cohort of human breast cancer tissues. Fascin alone or combined with BRMS1 was a worse prognostic marker, particularly in node-negative breast cancer patients.

Intrahepatic Cholangiocarcinoma with Ductal Plate Malformation-like Feature Associated with Bile Duct Adenoma.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with biliary epithelial differentiation. Malignant transformation of von Meyenburg complex (VMC) to ICC has been reported [1,2], and a new subtype of ICC with ductal plate malformation (DPM) pattern has been suggested [3]. However, bile duct adenoma (BDA) is a rare entity and is not as well known as DPM. Moreover, it has not been determined whether BDA is a risk factor of ICC. We present a rare case of ICC with DPM-like features associated with BDA.

Endometrioid adenocarcinoma arising from endometriosis of the pelvic peritoneum mimicking advanced ovarian cancer: A case report.

Gee Hoon Lee, Mi Sun Kim, Min Chul Choi, Sang Geun Jung, Ah-Young Kwon, Haeyoun Kang and Kyoung Ah Kim Department of Obstetrics and Gynecology, Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Korea; Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Korea; Department of Radiology, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Korea