Sang Jae Noh

Expression of DBC1 and SIRT1 Is Associated with Poor Prognosis of Gastric Carcinoma

Purpose: SIRT1 (silent mating-type information regulation 2 homologue 1) expression has been reported to predict poor survival in some cancers. We therefore investigated the expression levels of SIRT1 and its negative regulator, DBC1 (deleted in breast cancer 1), in gastric cancer patients. Experimental Design: We evaluated immunohistochemical expression of DBC1, SIRT1, and p53 using 3-mm tumor cores from 177 gastric cancer patients for tissue microarray. Results: Positive expressions of DBC1 and SIRT1 were seen in 62% (109 of 177) and in 73% (130 of 177) of patients, respectively. Expression of DBC1 was significantly correlated with tumor stage (P = 0.007), lymph node metastasis (P < 0.001), tumor invasion (P = 0.001), venous invasion (P = 0.001), histologic types (P < 0.001), p53 expression (P < 0.001), and SIRT1 expression (P < 0.001). SIRT1 expression was also significantly correlated with tumor stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P < 0.001), histologic types (P < 0.001), and p53 expression (P = 0.001). In addition, expression of DBC1 was significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P < 0.001 and P < 0.001, respectively). SIRT1 expression was also significantly associated with shorter overall survival and relapse-free survival by univariate analysis (P = 0.001 and P = 0.001, respectively). Multivariate analysis showed that tumor stage and expression of DBC1 were independent prognostic factors significantly associated with overall survival and relapse-free survival. Conclusion: This study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for gastric carcinoma patients.

Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma.

Recently, it has been reported that SIRT1 and DBC1 may be involved in the development of tumors and predict poor survival in some cancers. However, their exact role is not clear. Therefore, we investigated the expression status and clinical significance of DBC1 and SIRT1 expression in breast carcinomas. We evaluated the immunohistochemical expression of DBC1, SIRT1, and p53 using a 3-mm core from 122 patients with breast cancer for tissue microarray. Positive expression of DBC1 and SIRT1 were seen in 71% and 67% of patients, respectively. In the patients with breast cancer, overall, expression of DBC1 and SIRT1 was significantly associated with distant metastatic relapse and shorter relapse-free survival and overall survival by univariate analysis. Tumor stage and DBC1 and SIRT1 expression were also independent prognostic factors by multivariate analysis. Among the patients who had received chemotherapy, DBC1 and SIRT1 expression was significantly associated with distant metastatic relapse and shorter survival by univariate analysis. DBC1 expression was also associated with distant metastatic relapse and shorter survival in patients who had received endocrine therapy, according to univariate and multivariate analysis. In conclusion, this study shows that expression of DBC1 and SIRT1 is a significant prognostic indicator for breast carcinoma patients.

SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas.

The increased expression of SIRT1 has recently been identified in numerous human tumors and a possible correlation with c-Myc oncogene has been proposed. However, it remains unclear whether SIRT1 functions as an oncogene or tumor suppressor. We sought to elucidate the role of SIRT1 in liver cancer under the influence of c-Myc and to determine the prognostic significance of SIRT1 and c-Myc expression in human hepatocellular carcinoma. The effect of either over-expression or knock down of SIRT1 on cell proliferation and survival was evaluated in both mouse and human liver cancer cells. Nicotinamide, an inhibitor of SIRT1, was also evaluated for its effects on liver tumorigenesis. The prognostic significance of the immunohistochemical detection of SIRT1 and c-Myc was evaluated in 154 hepatocellular carcinoma patients. SIRT1 and c-Myc regulate each other via a positive feedback loop and act synergistically to promote hepatocellular proliferation in both mice and human liver tumor cells. Tumor growth was significantly inhibited by nicotinamide in vivo and in vitro. In human hepatocellular carcinoma, SIRT1 expression positively correlated with c-Myc, Ki67 and p53 expression, as well as high á-fetoprotein level. Moreover, the expression of SIRT1, c-Myc and p53 were independent prognostic indicators of hepatocellular carcinoma. In conclusion, this study demonstrates that SIRT1 expression supports liver tumorigenesis and is closely correlated with oncogenic c-MYC expression. In addition, both SIRT1 and c-Myc may be useful prognostic indicators of hepatocellular carcinoma and SIRT1 targeted therapy may be beneficial in the treatment of hepatocellular carcinoma.

Expression of SIRT1 and cortactin is associated with progression of non-small cell lung cancer.

Cortactin is an F-actin binding protein involved in cell migration and tumor metastasis. Recent reports suggest that silent mating-type information regulation 2 homologue 1 (sirtuin1; SIRT1) enhances the function of cortactin and promotes cell migration. We investigated SIRT1 and cortactin expression in 144 invasive non-small cell lung cancers (NSCLC) and 19 adenocarcinomas in situ (AIS) by immunohistochemistry and evaluated their clinicopathological significance in NSCLC. Positive SIRT1 and cortactin expression was observed in 67% (96 of 144) and 58% (84 of 144) of patients with invasive NSCLC, respectively. SIRT1 and cortactin expression was significantly associated with unfavorable clinicopathological factors, including high pathological T stage, lymph node metastasis, and advanced tumor invasion (AIS vs. invasive adenocarcinoma). Cortactin was significantly associated with high pathological T stage and lymph node metastasis in SIRT1-positive tumors. Cytoplasmic SIRT1 was significantly associated with high pathological T stage and large tumor size compared to that of nuclear SIRT1. Large tumor size, high pathological T stage, lymph node metastasis, and cytoplasmic SIRT1 expression were significantly associated with shorter overall survival in a univariate analysis. Our findings suggest that SIRT1 and cortactin may play a role in the progression of NSCLC and may cooperate during tumor progression in NSCLC.

Acetylation status of P53 and the expression of DBC1, SIRT1, and androgen receptor are associated with survival in clear cell renal cell carcinoma patients

Aims: Recently, the important role of silent mating type information regulation 2 homolog 1 (SIRT1) and deleted in breast cancer 1 (DBC1) in human cancer has been extensively studied and their role has been closely related with the control of P53 and androgen receptor (AR) functions. However, their role in clear cell renal cell carcinoma (CRCC) is still unknown. Methods: We evaluated the expression of SIRT1, P53, acetylated-P53, DBC1 and AR and their prognostic significance in 200 CRCC patients. Results: The expression of SIRT1, P53, DBC1, and AR significantly correlated with each other and all of them predicted shorter overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS). In contrast, the expression of acetylated-P53 predicted favourable OS, RFS, and CSS. Combined expression pattern of acetylated-P53 and P53 (Ac-P53/P53) also closely correlated with survival of CRCC patients. Multivariate analysis revealed DBC1, acetylated-P53, and Ac-P53/P53 expression as independent prognostic indicators for OS and RFS, and Ac-P53 expression as an independent prognostic indicator for CSS. Conclusions: This study demonstrates that the acetylation status of P53 and the expression of SIRT1, DBC1, and AR could be new prognostic indicators for CRCC and suggest that SIRT1-P53 and DBC1-AR related pathways could be new therapeutic targets for the treatment of CRCC.

Expression of nerve growth factor and heme oxygenase-1 predict poor survival of breast carcinoma patients

BackgroundNerve growth factor (NGF) is a neurotrophin and has been suggested to induce heme oxygenase-1 (HO1) expression. Although the role of HO1 in tumorigenesis remains controversial, recent evidence suggests NGF and HO1 as tumor-progressing factors. However, the correlative role of NGF and HO1 and their prognostic impact in breast carcinoma is unknown.MethodsWe investigated the expression and prognostic significance of the expression of NGF and HO1 in 145 cases of breast carcinoma.ResultsImmunohistochemical expression of NGF and HO1 was observed in 31% and 49% of breast carcinoma, respectively. The expression of NGF and HO1 significantly associated with each other, and both have a significant association with histologic grade, HER2 expression, and latent distant metastasis. The expression of NGF and HO1 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis. NGF expression was an independent prognostic indicator for relapse-free survival by multivariate analysis. The combined expression pattern of NGF and HO1 was also an independent prognostic indicator of overall survival and relapse-free survival. The patients with tumors expressing NGF had the shortest survival and the patients with tumor, which did not express NGF or HO1 showed the longest survival time.ConclusionsThis study has demonstrated that individual expression of NGF or HO1, and the combined NGF/HO1 expression pattern could be prognostic indicators for breast carcinoma patients.

Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication

Background E-cadherin, cortactin, and matrix metalloproteinase (MMP)-9 have roles in tumor development or progression, but their expression has not been fully investigated in pseudoepitheliomatous hyperplasia (PEH) and squamous cell carcinoma (SCC) of the head and neck. Methods We evaluated the immunohistochemical expression of E-cadherin, cortactin, and MMP-9 in 29 cases of PEH and 97 cases of SCC. Additionally, we evaluated their relationship with clinicopathologic factors and prognostic implications in SCC. Results Thirty-five cases of SCC showed reduced expression of E-cadherin, whereas none of the PEH did. A total of 20 cases and 11 cases of SCC were immunoreactive for cortactin and MMP-9, respectively, whereas none of the PEH did. In SCC, reduced expression of E-cadherin was correlated with cortactin expression and invasion depth. Cortactin expression was correlated with differentiation, T classification, and recurrence and/or metastasis. MMP-9 expression was correlated with invasion depth. Cortactin expression was correlated with poor overall survival and relapse-free survival and it was an independent prognostic factor. Conclusions The reduced expression of E-cadherin and the expression of cortactin may be helpful for the differential diagnosis of PEH and SCC. Furthermore, cortactin expression in association with reduced E-cadherin expression is correlated with poor prognosis in SCC.

Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients

BACKGROUND: Poly(ADP-ribose) polymerase 1 (PARP1), γH2AX, BRCA1, and BRCA2 are conventional molecular indicators of DNA damage in cells and are often overexpressed in various cancers. In this study, we aimed, using immunohistochemical detection, whether the co-expression of PARP1, γH2AX, BRCA1, and BRCA2 in breast carcinoma (BCA) tissue can provide more reliable prediction of survival of BCA patients. MATERIALS AND METHODS: We investigated immunohistochemical expression and prognostic significance of the expression of PARP1, γH2AX, BRCA1, and BRCA2 in 192 cases of BCAs. RESULTS: The expression of these four molecules predicted earlier distant metastatic relapse, shorter overall survival (OS), and relapse-free survival (RFS) by univariate analysis. Multivariate analysis revealed the expression of PARP1, γH2AX, and BRCA2 as independent poor prognostic indicators of OS and RFS. In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph) was an additional independent prognostic predictor for OS (P < .001) and RFS (P < .001). The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1) subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4) subgroup. CONCLUSION: This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

Multicystic biliary hamartoma of the liver.

Multicystic biliary hamartoma (MCBH) is a very rare hamartomatous cystic nodule of the liver, which has recently been described as a new entity of a hepatic nodular lesion. We report a unique case of MCBH with a review of the literatures. A hepatic multicystic mass of segment 3 was detected in a 52-year-old male by abdominal computed tomography, and resection of this lesion was performed. Macroscopic examination revealed a 2.7×2.0 cm nodular mass with a multicystic honeycomb cut surface. Histologically, this lesion consisted of multiple dilated cystic ducts lined by biliary type epithelial cells, periductal glands and connective tissue, which included small amounts of hepatic parenchyma and blood vessels. Recognition of this unusual lesion is essential to avoid confusion with other cystic tumors of the liver, and to learn more about its natural history and response to treatment.

Immunohistochemical Expression and Clinical Significance of Suggested Stem Cell Markers in Hepatocellular Carcinoma

Background: Increasing evidence has shown that tumor initiation and growth are nourished by a small subpopulation of cancer stem cells (CSCs) within the tumor mass. CSCs are posited to be responsible for tumor maintenance, growth, distant metastasis, and relapse after curative operation. We examined the expression of CSC markers in paraffin-embedded tissue sections of hepatocellular carcinoma (HCC) and correlated the results with clinicopathologic characteristics. Methods: Immunohistochemical staining for the markers believed to be expressed in the CSCs, including epithelial cell adhesion molecule (EpCAM), keratin 19 (K19), CD133, and CD56, was performed in 82 HCC specimens. Results: EpCAM expression was observed in 56% of the HCCs (46/82) and K19 in 6% (5/82). EpCAM expression in HCC significantly correlated with elevated α-fetoprotein level, microvessel invasion of tumor cells, and high histologic grade. In addition, EpCAM expression significantly correlated with K19 expression. The overall survival and relapsefree survival rates in patients with EpCAM-expressing HCC were relatively lower than those in patients with EpCAM-negative HCC. All but two of the 82 HCCs were negative for CD133 and CD56, respectively. Conclusions: Our results suggest that HCCs expressing EpCAM are associated with unfavorable prognostic factors and have a more aggressive clinical course than those not expressing EpCAM. Further, the expression of either CD133 or CD56 in paraffin-embedded HCC tissues appears to be rare.