Soon Won Hong

Gene expression signature-based prognostic risk score in gastric cancer

Purpose: Despite continual efforts to develop a prognostic model of gastric cancer by using clinical and pathologic parameters, a clinical test that can discriminate patients with good outcomes from those with poor outcomes after gastric cancer surgery has not been established. We aim to develop practical biomarker-based risk score that can predict relapse of gastric cancer after surgical treatment. Experimental Design: Microarray technologies were used to generate and analyze gene expression profiling data from 65 gastric cancer patients to identify biomarker genes associated with relapse. The association of expression patterns of identified genes with relapse and overall survival was validated in independent gastric cancer patients. Results: We uncovered two subgroups of gastric cancer that were strongly associated with the prognosis. For the easy translation of our findings into practice, we developed a scoring system based on the expression of six genes that predicted the likelihood of relapse after curative resection. In multivariate analysis, the risk score was an independent predictor of relapse in a cohort of 96 patients. We were able to validate the robustness of the six-gene signature in an additional independent cohort. Conclusions: The risk score derived from the six-gene set successfully prognosticated the relapse of gastric cancer patients after gastrectomy. Clin Cancer Res; 17(7); 1850–7. ©2011 AACR.

Ectopic expression of neutrophil gelatinase-associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells.

Neutrophil gelatinase‐associated lipocalin (NGAL), also known as lipocalin 2, is a 25‐kDa lipocalin initially purified from neutrophil granules. It is thought to play a role in regulating cellular growth since its expression is highly upregulated in a variety of proliferative cells such as cancer cells. However, experimental evidence showing a clear causal relationship between NGAL expression and the proliferation of tumor cells is lacking. Here, we found NGAL expression in highly and poorly metastatic colon cancer cell lines of the same genetic origin correlated inversely with the metastatic potential of these cells, which suggests NGAL participates in the metastatic process. To explore the role NGAL plays in tumor growth and metastasis, the KM12SM human colon cancer cell line, which is highly metastatic while showing decreased NGAL expression, was genetically manipulated to overexpress NGAL. The effects of this on tumor growth and liver metastasis were then analyzed using experimental animal models established by injecting BALB/c nude mice with tumor cells subcutaneously or intrasplenically. Ectopic expression of NGAL in the colon cancer cells had little effect on the growth and viability of the tumor cells both in vitro and in vivo. However, NGAL expression not only suppressed the ability of the colon carcinoma cells to invade Matrigel in vitro, it also substantially inhibited liver metastasis in an experimental animal model. Collectively, these results indicate that NGAL may be a candidate metastasis suppressor in colon cancer cells.

Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition.

Protein O‐phosphorylation often occurs reciprocally with O‐GlcNAc modification and represents a regulatory principle for proteins. O‐phosphorylation of serine by glycogen synthase kinase‐3β on Snail1, a transcriptional repressor of E‐cadherin and a key regulator of the epithelial–mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O‐phosphorylation‐mediated degradation, O‐GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E‐cadherin mRNA expression. Hyperglycaemic condition enhances O‐GlcNAc modification and initiates EMT by transcriptional suppression of E‐cadherin through Snail1. Thus, dynamic reciprocal O‐phosphorylation and O‐GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT.

Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma

Aberrant expressions of specific microRNAs are recently known in many malignancies, including gastric carcinoma. The prognostic implication of oncogenic microRNA dysregulation was investigated in advanced gastric carcinomas undergoing radical resection and adjuvant systemic chemotherapy, and observed on long‐term follow‐up.

Delayed Treatment with Lithospermate B Attenuates Experimental Diabetic Renal Injury

Extracellular matrix (ECM) accumulation in the glomerular mesangium is a characteristic feature of diabetic nephropathy. While transforming growth factor-beta1 (TGF-beta1) is the final mediator of ECM accumulation, reactive oxygen species (ROS) and protein kinase C (PKC) are the upstream signaling molecules that mediate hyperglycemia-induced ECM expansion. Magnesium lithospermate B (LAB) is an active component isolated from Salvia miltiorrhizae with known renoprotective properties due to its antioxidative effects. Thus, the present study examined the effects of LAB on renal injury in streptozotocin-induced diabetic rats (STZR) and on the activation of mesangial cells cultured under high glucose conditions. Ten micrtograms of LAB/kg per day was started 8 wk after streptozotocin injection and continued for a period of 8 wk. It significantly suppressed renal malondialdehyde (MDA), microalbuminuria, glomerular hypertrophy, mesangial expansion, and the upregulation of renal TGF-beta1, fibronectin, and collagen in STZR without significantly affecting plasma glucose. Both 30 mM of glucose and 100 uM of H(2)O(2) significantly increased TGF-beta1 and fibronectin protein secretion by mesangial cells. LAB at 10 micro g/ml inhibited high glucose- and H(2)O(2)-induced TGF-beta1 and fibronectin secretion. LAB also inhibited glucose-induced intracellular ROS generation and PKC activation in mesangial cells, but it did not directly inhibit PKC activity at dosages that inhibited ROS generation. The in vitro data of this study show that LAB inhibits ROS generation leading to PKC activation and TGF-beta1 and fibronectin upregulation in mesangial cells cultured under high glucose conditions. Moreover, delayed treatment with LAB was found to significantly suppress the progression of renal injury in STZR. LAB may become a new therapeutic agent for the treatment of diabetic nephropathy.

Sonographic differentiation of thyroid nodules with eggshell calcifications.

Objective. The purpose of this study was to assess the role of known suspicious sonographic findings and to find other additional sonographic findings to differentiate benign and malignant thyroid nodules with “eggshell” calcifications. Methods. Our Institutional Review Board approved this retrospective study, and informed consent was not required. We reviewed sonographic findings of thyroid nodules in 795 patients who underwent thyroid surgery in our institution between August 2006 and February 2007. Ninety‐three thyroid nodules with eggshell calcifications in 92 patients were included in this study. Each lesion was evaluated for known suspicious sonographic criteria, including marked hypoechogenicity, irregular or microlobulated margins, and a taller‐than‐wide shape, as well as 2 additional sonographic findings: a hypoechoic halo and disruption of eggshell calcifications (halo and disrupted calcification rim). The sensitivity and specificity based on the sonographic criteria were calculated and compared among the 2 types of criteria. Results. Among the 93 thyroid nodules, 59 were malignant and 34 were benign. The halo and disrupted calcification rim showed higher sensitivity (62.7% and 76.3%, respectively) than any of the known suspicious sonographic criteria (40.7%, 35.6%, and 55.9%). The combination of both the halo and the disrupted calcification rim showed significantly higher sensitivity (93.2%) than the combination of the known suspicious sonographic criteria (78%; P < .05), although both had the same specificity (64.7%). Conclusions. In thyroid nodules with eggshell calcifications but no other calcifications, the findings of a peripheral halo and disruption of the eggshell calcifications may be more useful sonographic predictors of malignancy than hypoechogenicity, microlobulated margins, and a taller‐than‐wide shape.

Diffuse sclerosing variant is a major subtype of papillary thyroid carcinoma in the young.

BACKGROUND Pediatric thyroid cancer differs from adult thyroid cancer in presentation and outcome. Pediatric thyroid cancer has a higher recurrence rate and greater percentage of lymph node and pulmonary metastasis. The clinicopathologic characteristics of pediatric thyroid cancer according to the histologic subtype have not been reported, however. In this study, we determined the histological subtypes of pediatric thyroid cancer and analyzed other clinicopathologic characteristics. METHODS All patients with thyroid cancer who were admitted to Severance Hospital, Seoul, South Korea, were retrospectively reviewed; their age was <20 years at diagnosis, and they were seen between January 1995 and August 2008. RESULTS Sixty-eight patients were identified. The histologic types of thyroid carcinoma were papillary thyroid carcinoma (PTC) in 57 (83.8%), follicular carcinoma in 8 (11.8%), and poorly differentiated carcinoma in 3 (4.4%). There were 28 (41.2%) cases of diffuse sclerosing variant of papillary carcinoma (DSVPC), 26 (38.2%) of conventional PTC, 2 (2.9%) of follicular PTC, and 1 (1.5%) cribriform-morular PTC. In patients with PTC, there was a higher incidence of bilateral thyroid involvement (p = 0.003), extrathyroidal extension (p = 0.009), and lymph node involvement (p = 0.018), and lower recurrence-free survival (p = 0.032) in DSVPC than in non-DSVPC. Univariate regression analysis revealed that extrathyroidal extension (p = 0.025) and tumor size (p = 0.001) were positively associated with a shorter time to recurrence. CONCLUSION DSVPC is a major subtype of PTC in the young.

Expression of estrogen receptor-β in normal mammary and tumor tissues: Is it protective in breast carcinogenesis?

Using messenger RNA (mRNA) in situ hybridization, we investigated estrogen receptor-β (ERβ) mRNA levels in normal mammary, benign breast tumor (BBT), breast cancer (BC), and metastatic lymph node tissues to verify the role of ERβ in BC development and progression. ERβ expression was significantly decreased in BC and metastatic lymph node tissues compared with normal mammary and BBT tissues (p < 0.01). The intensity and extent of ERβ mRNA signals were also significantly lower in BC and metastatic lymph node tissues than in the normal mammary and BBT tissues (p < 0.01). An inverse relationship was found between ERβ mRNA level and both histologic grade (p = 0.091) and progesterone receptor expression (p = 0.052) with marginal significance, but no significant association was noted between ERβ expression in cancer tissues and the other clinico-pathologic data. The 3-year distant relapse-free survival probability was found to be independent of ERβ expression. Collectively, ERβ mRNA decreases in the process of BC development, but seems to be associated with poor differentiation.

Clinicopathologic Implications of the BRAFV600E Mutation in Papillary Thyroid Cancer: A Subgroup Analysis of 3130 Cases in a Single Center

BACKGROUND The BRAF mutation has been shown to be associated with aggressive clinicopathologic characteristics of papillary thyroid cancer (PTC). However, several studies that analyzed hundreds of patients have not demonstrated any correlation. The objective of this study was to investigate the relationship of the BRAF mutation with clinicopathologic factors in a large group of homogenous PTC patients. METHODS We collected data of PTC patients who received curative resection of the thyroid gland and who had undergone BRAF mutation tests of their thyroid cancer tissue. Minor variant PTCs and mixed-type thyroid cancers were excluded in this analysis. Clinicopathologic characteristics, including age, sex, BRAF mutation, tumor histology, size, extrathyroidal extension, tumor margin, lymph node metastasis, multifocality, stage, and associated thyroid disease, were collected. The relationship of the BRAF mutation with clinicopathologic factors was analyzed in each homogenous histologic PTC. RESULTS There were 3130 PTC patients who met the criteria, and these patients were divided into three major histologic groups: conventional PTC (n = 2947), diffuse sclerosing variant PTC (n = 98), and follicular variant PTC (n = 85). The BRAF mutation was variably detected in 75.3%, 61%, and 40% of patients, respectively. In conventional PTC cases, the BRAF mutation was significantly associated with large tumor size, extrathyroidal extension, and lymph node metastasis. Coexistent chronic lymphocytic thyroiditis was significantly less prevalent in the BRAF mutant group. Age, sex, and tumor margin status were not significantly correlated with the BRAF status. There was no evidence that any clinicopathologic factors were linked with the BRAF mutation status in diffuse sclerosing and follicular variant PTCs. CONCLUSIONS The BRAF mutation was differentially detected in each histologic subtype of PTC and was strongly correlated with pathologic factors, most strongly with no coexistent chronic lymphocytic thyroiditis, in conventional PTC. The BRAF mutation is suggested to be a poor prognostic marker in conventional PTC, and the BRAF mutational analysis may lead to better management for individual PTC patients.

Dual priming oligonucleotide-based multiplex PCR analysis for detection of BRAFV600E mutation in FNAB samples of thyroid nodules in BRAFV600E mutation-prevalent area.

To evaluate the diagnostic value of dual priming oligonucleotide (DPO)–based multiplex polymerase chain reaction (PCR) for the detection of BRAFV600E mutations in ultrasound‐guided fine‐needle aspiration biopsy (US‐FNAB) of thyroid nodules.