Hye Won Lee

Comparative assessment of a single surgeon's series of laparoscopic radical prostatectomy: conventional versus robot-assisted.

PURPOSEnTo directly compare the outcome of laparoscopic radical prostatectomy (LRP) with robot-assisted laparoscopic prostatectomy (RALP) performed by a single laparoscopic surgeon with intermediate experience-one who is between a novice and an expert.nnnPATIENTS AND METHODSnConsecutive 106 patients with prostate cancer who were treated with radical prostatectomy (62 with LRP and 44 with RALP) were included. The preoperative characteristics, the perioperative surgical outcomes, and the functional outcomes were compared between the two groups.nnnRESULTSnThe mean operative time was longer in the RALP group (371u2009min vs 308u2009min, Pu2009=u20090.00), conceivably because of more nerve-sparing procedures (84% vs 57%). The other perioperative parameters, including the surgical margin, were comparable, except for two major complications (rectourethral fistula and ureteral injury) in the LRP group. The RALP group recovered continence faster than those in the LRP, but the eventual continence rate at 12 months was similar (95% for LRP vs 94.4% for RALP, Pu2009=u20091.00). The potency rate ≥u20096 months postsurgery was 47.6% in the LRP group and 54.5% in the RALP group (Pu2009=u20090.65).nnnCONCLUSIONSnRALP was beneficial for the earlier recovery of continence, although LRP and RALP had comparable safety and efficacy as minimally invasive surgery for prostate cancer when performed by a laparoscopic surgeon with intermediate experience. Long-term follow-up data are needed for further evaluation of oncologic and functional outcomes for both techniques.

Alpha-Smooth Muscle Actin (ACTA2) Is Required for Metastatic Potential of Human Lung Adenocarcinoma

Purpose: Metastatic relapse of primary lung cancer leads to therapeutic resistance and unfavorable clinical prognosis; therefore, identification of key molecules associated with metastatic conversion has significant clinical implications. We previously identified a link between early brain metastasis of lung adenocarcinoma and amplification of the α-smooth muscle actin (ACTA2) gene. The aim of present study was to investigate the prognostic and functional significance of ACTA2 expression in cancer cells for the metastatic potential of lung adenocarcinomas. Experimental Design: ACTA2 expression was analyzed in tumor cells from 263 patients with primary lung adenocarcinomas by immunohistochemistry, and was correlated with clinicopathologic parameters. The expression of ACTA2 in human lung adenocarcinoma cells was modulated with short hairpin RNAs (shRNA) and siRNAs specifically targeting ACTA2. Results: The patients with lung adenocarcinomas with high ACTA2 expression in tumor cells showed significantly enhanced distant metastasis and unfavorable prognosis. ACTA2 downregulation remarkably impaired in vitro migration, invasion, clonogenicity, and transendothelial penetration of lung adenocarcinoma cells without affecting proliferation. Consistent with the in vitro results, depletion of ACTA2 in human lung adenocarcinoma PC14PE6 cells significantly reduced their metastatic potential without altering their tumorigenic potential. Expression of c-MET and FAK in lung adenocarcinoma cells was also reduced by ACTA2-targeting siRNAs and shRNAs, and was accompanied by a loss of mesenchymal characteristics. Conclusions: These findings indicate that ACTA2 regulates c-MET and FAK expression in lung adenocarcinoma cells, which positively and selectively influence metastatic potential. Therefore, ACTA2 could be a promising prognostic biomarker and/or therapeutic target for metastatic lung adenocarcinoma. Clin Cancer Res; 19(21); 5879–89. ©2013 AACR.

Genomic copy number alterations associated with the early brain metastasis of non-small cell lung cancer

Frequent early development of systemic metastasis leads to unfavourable clinical prognosis of non-small cell lung cancer (NSCLC). Although brain metastasis (BM) contributes significantly to morbidity and mortality of NSCLC, relevant driver mechanisms are largely unknown. To elucidate genetic alterations associated with early BM of NSCLC, we retrospectively collected 18 NSCLC cases with BM [12xa0adenocarcinomas (ADC) and 6 squamous cell carcinomas (SQCC)] whose surgical tissues of both primary and brain metastatic tumors were preserved as formaldehyde-fixed and paraffin-embedded (FFPE) pathological samples. When chromosomal copy number alterations (CNA) of those FFPE samples were analysed by the Molecular Inversion Probe (MIP) technology, the most frequent CNAs detected in primary lung ADCs were gains of 3q, 5p, 5q, 6p, 8q, 9p, 11p, 15q, 17q and losses of 10q and 22q whereas primary lung SQCCs revealed gains in 4q and 12q and loss in 9q. In particular, when comparative MIP was performed in primary 12 ADCs depending on the pattern of BM to uncover predetermining signatures that can predict the risk of BM, selectively amplified regions of primary lung ADCs (5q35, 10q23 and 17q23-24) were identified as significantly associated with the development of early BM within 3 months after first diagnosis of primary tumors. Those regions harbour several candidate genes including NeurL1B, ACTA2, FAS and ICAM2. Although more validation is needed, the genetic signatures elucidated in this study help to identify useful molecular markers defining an NSCLC patient subgroup at risk of early BM, guiding therapeutic decisions.

Tpl2 Kinase Impacts Tumor Growth and Metastasis of Clear Cell Renal Cell Carcinoma

Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC. Implications: Tpl2 kinase activity has prognostic and therapeutic targeting potential in aggressive clear cell renal cell carcinoma. Mol Cancer Res; 11(11); 1375–86. ©2013 AACR.

Radiosensitization of brain metastasis by targeting c-MET.

Radiotherapy is the most widely used therapeutic modality in brain metastasis; however, it only provides palliation due to inevitable tumor recurrence. Resistance of tumor cells to ionizing radiation is a major cause of treatment failure. A critical unmet need in oncology is to develop rationale driven approaches that can enhance the efficacy of radiotherapy against metastatic tumor. Utilizing in vivo orthotopic primary tumor and brain metastasis models that recapitulate clinical situation of the patients with metastatic breast cancer, we investigated a molecular mechanism through which metastatic tumor cells acquire resistance to radiation. Recent studies have demonstrated that the hepatocyte growth factor (HGF)-c-Met pathway is essential for the pathologic development and progression of many human cancers such as proliferation, invasion and resistance to anticancer therapies. In this study, c-Met signaling activity as well as total c-Met expression was significantly upregulated in both breast cancer cell lines irradiated in vitro and ex vivo radio-resistant cells derived from breast cancer brain metastatic xenografts. To interrogate the role of c-Met signaling in radioresistance of brain metastasis, we evaluated the effects on tumor cell viability, clonogenicity, sensitivity to radiation, and in vitro/in vivo tumor growth after targeting c-Met by small-hairpin RNA (shRNA) or small-molecule kinase inhibitor (PF-2341066). Although c-Met silencing or radiation alone demonstrated a modest decrease in clonogenic growth of parental breast cancers and brain metastatic derivatives, combination of two modalities showed synergistic antitumor effects resulting in significant prolongation of overall survival in tumor-bearing mice. Taken together, optimizing c-Met targeting in combination with radiation is critical to enhance the effectiveness of radiotherapy in the treatments of brain metastasis.

A comparison of surgical and functional outcomes of robot-assisted versus pure laparoscopic partial nephrectomy.

Robotic-assisted partial nephrectomy is comparable with laparoscopic partial nephrectomy, offering equivalent oncological and functional outcomes.

Association of Serum Total Bilirubin with Serum High Sensitivity C-reactive Protein in Middle-aged Men.

Background It has been suggested that bilirubin has an inverse association with cardiovascular disease (CVD) due to its antioxidant properties. However, there are few data regarding the relationship between serum total bilirubin (sTB) and risk factors for CVD in Koreans. This study aimed to evaluate the relationship between sTB and high sensitivity C-reactive protein (hsCRP), which is an independent risk factor for CVD. Methods We performed a cross sectional study in 6,800 men who were examined at a health promotion center at a university hospital in Korea between May 2005 and June 2006. We grouped the subjects according to values of serum hsCRP (above or below 1.0 mg/L) and compared the characteristics of the two groups. To evaluate the relationship between sTB and hsCRP, we classified the subjects according to quartile values of sTB. Multivariate logistic regression analyses were used to analyze the relationship of levels of sTB and hsCRP after adjusting for known risk factors for CVD. Results Serum hsCRP was significantly associated with body mass index (BMI), smoking, diabetes, hypertension, fasting plasma glucose, systolic blood pressure, alanine aminotransferase, and total cholesterol/high density lipoprotein (TC/HDL-C) ratio, but not with age or alcohol use. As levels of sTB increased, there was a decrease in age, numbers of smokers, BMI, and TC/HDL ratio. Compared to the lowest quartile of sTB, levels of hsCRP decreased with odds ratios of 0.82 (95% CI, 0.71 to 0.96), 0.75 (95% CI, 0.65 to 0.88), and 0.63 (95% CI, 0.54 to 0.74) in the 2nd, 3rd, and 4th quartiles of bilirubin, respectively. Conclusion Bilirubin may be inversely associated with hsCRP

Oxidative stress induced by low-dose doxorubicin promotes the invasiveness of osteosarcoma cell line U2OS in vitro

Reactive oxygen species (ROS) are known to mediate doxorubicin (DOX)-induced apoptosis and are the major cause of DOX toxicity. We introduce a novel in vitro phenomenon of osteosarcoma (OS) cell line caused by low-dose DOX-induced oxidative stress. Human osteosarcoma cell line U2OS was used for the experiments. Hydrogen peroxide (H2O2) and the antioxidant compound N-acetylcysteine (NAC) were used to investigate the involvement of oxidative stress. In proliferation assays, low dose of DOX (below 200xa0nM) did not affect U2OS proliferation significantly for up to 48xa0h. In MatrigelTM invasion assay, DOX increased the invasiveness of U2OS at around 100xa0nM, which is a subclinical concentration. Quantitative real-time polymerase chain reaction and gelatin zymography showed increased MMP-9 expression and increased MMP-9 enzymatic activity, respectively, in the presence of DOX doses that increased the invasiveness of U2OS. H2O2, a representative source of ROS, also increased the invasiveness of U2OS as DOX did, with similar patterns. However, when the cells were pre-treated with NAC, no DOX- or H2O2-mediated increase of invasiveness or MMP-9 expression was evident. The results suggest that oxidative stress induced by low-dose DOX promotes the invasiveness of osteosarcoma cell line U2OS in vitro, through MMP-9 induction.

Gene silencing of c-Met leads to brain metastasis inhibitory effects

An unfortunate consequence of improvements in the treatments of advanced primary cancers is the concurrent increase of metastatic brain tumors. Despite of unfavorable clinical prognosis, radiation therapy is still the only viable treatment option for brain metastases. Expression of c-Met induces cell migration and invasion in many cancers, which are indispensable steps for metastasis. Accordingly, we examined the effects of gene silencing of c-Met on brain metastasis to evaluate the possibility of c-Met as a potential target. MDA-MB-435 cells were transfected with c-Met targeting short hairpin RNAs (shRNAs). Effects of c-Met shRNAs on the expression of epithelial mesenchymal transition (EMT) related proteins, in vitro migration, and in vivo brain metastasis were examined. Expression of mesenchymal markers and in vitro migration of MDA-MB-435 cells were significantly inhibited by introduction of c-Met shRNAs. When c-Met-silenced MDA-MB-435 cells were stereotactically implanted into the brains of immune-compromised mice or injected into the right internal carotid arteries, c-Met-silenced MDA-MB-435 cells produced significantly smaller tumor masses or survival time was significantly prolonged, respectively, compared with MDA-MB-435 cells transfected with control shRNA. The data reveal the novel function of c-Met in the process of brain metastasis and its potential as a preventive and/or therapeutic target in this disease.

RRP12 is a crucial nucleolar protein that regulates p53 activity in osteosarcoma cells.

RRP12 (ribosomal RNA processing 12 homolog), a nucleolar protein, plays important roles in cell cycle progression and the response to deoxyribonucleic acid (DNA) damage in yeast cells. However, its role has not been investigated in mammalian cells that possess p53, which has close functional association to nucleolus. We explored the role of RRP12 in nucleolar stress condition using an osteosarcoma cell line, U2OS. To induce DNA damage and nucleolar disruption, two cytotoxic drugs, doxorubicin and actinomycin D were used. Cytotoxic stress resulted nucleolar disruption induced cell cycle arrest and apoptosis in U2OS cells. However, RRP12 overexpression promoted resistance to cytotoxic stress. In contrast, RRP12 silencing enhanced susceptibility to cytotoxic stress. During drug treatment, p53 activity and cell death were suppressed by RRP12 overexpression but promoted by RRP12 silencing. This study demonstrated that RRP12 was crucial for cell survival during cytotoxic stress via the repression of p53 stability. Thus, targeting RRP12 may enhance chemotherapeutic effect in cancers.