• Journal of Life Science
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• v.26 no.8
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• pp.983-989
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• 2016

All cells composing of our body undergo their destiny such as proliferation, differentiation, necrosis, apoptosis and senescence depending on their circumstance with time. The errors occurring in these processes develop several aberrations in phenotypes including cancer, inflammation, aging and diseases. New strategy and approach are required to screen anti-aging compounds derived from natural products. Therefore, here we explain the target proteins to play a key role in aging mechanism. In the first place, matrix metalloproteinases (MMPs) are involved in metastasis, chronic inflammation and skin aging as an aging marker. In particular, histone deacetylases (HDACs) give a great attention to aging researchers who try to extend the life span of animal model. In addition, we describe the signaling pathway related to senescence which p53, IGF-1 and SIRT1 play an important role in. Furthermore, autophagy is involved in the signaling pathway associated with aging. Several new compounds modulating the signaling pathway of senescence are introduced in this review. Here, we try to provide a new insight in the molecular basis for the aging mechanism and development of aging marker. In addition, the compounds introduced here could be available for pharmaceutical applications for the prevention and the treatment of diseases related to aging.

• Journal of Biomedical Engineering Research
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• v.33 no.4
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• pp.213-222
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• 2012

While much has been learned about the mechanisms of metastatic spread of cancer to bone, there has been little headway in establishing guidelines for monitoring the alteration in bone quality and estimating fracture risk. The aims of this study are, therefore, 1) to evaluate bone quality induced by metastatic bone tumor by analyzing the characteristics on bone microarchitecture and degree of bone mineralization and 2) analyze fracture risk increased secondary to the bone quality changes by metastatic bone tumor through calculating mechanical rigidities based on in-vivo micro CT images. For this study, eighteen female SD rats (12 weeks old, approximate 250 g) were randomly allocated in Sham and Tumor groups. W256 (Walker carcinosarcoma 256 malignant breast cancer cell) was inoculated in the right femur (intraosseous injection) in Tumor group, while 0.9% NaCl (saline solution) was injected in Sham group. The right hind limbs of all rats were scanned by in-vivo micro-CT to acquire structural parameters and degree of bone mineralization at 0 week, 4 weeks, 8 weeks, and 12 weeks after surgery. At the same time, urine was collected by metabolic cages for a biochemical marker test in order to evaluate bone resorption. Then, bone metastasis had been directly identified by positron emission tomography. Finally, axial, bending and torsional rigidities had been calculated based on in-vivo micro CT images for predict fracture risk. The results of this study showed that metastatic bone tumor might induce significant decrease in bone quality and increase of fracture risk. This study may be helpful to monitoring a degree of bone metastasis and predicting fracture risk due to metastatic bone tumor. In addition, this noninvasive diagnostic methodology may be utilized for evaluating other bone metabolic diseases such as osteoporosis.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3903-3909
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• 2016

Purpose: To evaluate the expression of Her2/neu and Ki-67 in benign and malignant gallbladder lesions, and to establish correlations with clinico-pathologic parameters. Materials and Methods: A retrospective analysis was conducted on formalin fixed paraffin embedded (FFPE) benign (n=25) and malignant gallbladder (n=25) tissue samples. Hematoxylin and eosin stained slides of each case were reviewed for: type of malignancy (whether adenocarcinoma, squamous cell carcinoma, or any other type), grade (well, moderate, and poor), depth of invasion, pre-neoplastic changes in adjacent mucosal epithelium like metaplasia and dysplasia. Immunohistochemistry for Her 2 neu and Ki-67 was performed and data analysis was conducted using SPSS 17 software. Chi-square test was used to compare categorical/dichotomous variables. P value of ${\leq}0.05$ was considered significant. Results: The difference of Her 2 neu expression and Ki67 index between benign and malignant groups was found to be statistically significant. Her2/neu positivity did not have any significant correlation with various clinicopathological parameters other than liver involvement. 5 cases of gallbladder cancer showed both Her2/neu and Ki67 positivity. Ten cases were Ki67 positive but Her2/neu negative while one case was Her2/neu positive but Ki67 negative. Conclusions: The present study demonstrated overexpression of Her2/neu and Ki67 in gallbladder cancer. A trend of decreasing Her2/neu expression with increasing grade of tumor was observed. Furthermore, greater Ki67 positivity was found in cases with lymph node metastasis and distant metastasis. Future studies with a larger number of patients will be required to precisely define the correlation of Her2/neu expression and Ki67 positivity with clinicopathological parameters. The results however are encouraging and suggest evaluation of Her2/neu as a candidate for targeted therapy.

• Journal of Gastric Cancer
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• v.3 no.1
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• pp.33-37
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• 2003

Purpose: Alpha-fetoprotein (AFP) is widely accepted as a useful tumor marker for diagnosis of hepatocellular carcinomas. On rare occasions, however, an abnormal elevation of serum AFP also has been reported in an adenocarcinoma of the gastrointestinal tract. We evaluated the influence of preoperative abnormal elevation of serum AFP (AFP positivity) on the prognosis of resectable gastric cancers. Materials and Methods: 812 gastric cancer patients, who were investigated for serum AFP before their operations and who underwent gastric resections with D2 or more extended lymph node dissection, were enrolled in the study. The survival rates were calculated by using the Kaplan-Meier method and were compared by using the log-rank test. A multivariate analysis was performed using the Cox proportional hazards model. Results: Fifty patients ($6.2\%$) were AFP positive (10.1. 4322.6 ng/ml). The survival rate of the AFP positive group was significantly lower than that of the AFP negative group ( $46.6\%\;vs.\;67.0\%$; P=0.0002). The depth of tumor invasion, the degree of regional lymph node metastasis, distant metastases, the TNM stage, the gross type, differentiation, the extent of gastric resection, and the curability of the surgery also significantly influenced survival. Multivariate analysis revealed that the depth of tumor invasion, the degree of regional lymph node metastasis, the curability of the surgery, and AFP positivity were independent prognostic indicators. Conclusion: Preoperative serum AFP can be used as an independent prognostic factor of resectable gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3973-3976
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• 2015

Objectives: To explore the expression of aquaporin 1 ($AQP_1$) in bladder uroepithelium cell carcinoma (BUCC) and its relevance to recurrence. Materials and Methods: Tissue samples from 45 BUCC patients who underwent total cystectomy or transurethral resection of bladder tumor (TURBT) and from 40 patients with non-bladder cancers who underwent special detection or treatments were collected. The level of expression of $AQP_1$ in BUCC tissues and normal bladder tissues was assessed by immunohistochemistry so as to analyze the relevance to pathological patterns and time of recurrence in BUCC patients. Results: The expression levels of $AQP_1$ normal bladder tissues and BUCC tissues were $2.175{\pm}0.693$ and $3.689{\pm}0.701$, respectively, and the difference was significant (t=9.99, P<0.0001). Marked increase was noted with BUCC histological grade and pathological stage (P<0.01). Moreover, the expression of $AQP_1$ was evidently higher in cancerous tissues with lymph node metastasis than in those without (P<0.01). With short-term recurrence, the positive cell expression rate of $AQP_1$ was higher in primary tissues, which increased obviously after recurrence. Additionally, the recurrent time of BUCC was negatively associated with the positive cell expression rate of $AQP_1$ and the difference between the expression of $AQP_1$ before and after recurrence (r=-0.843, F=39.302, P=0.000; r=-0.829, F=35.191, P=0.000). Conclusions: $AQP_1$, which reflects the grade, stage, lymph node metastasis and recurrence of BUCC, has potential guiding significance in the diagnosis and treatment of bladder cancarcinoma.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1015-1018
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• 2016

Background: Overexpression or amplification of human epidermal growth factor receptor-2 (HER2) is associated with grade of malignancy and a poor prognosis in breast cancer (BC). The aim of this study was to evaluate of value of HER2 as a prognostic marker, and to analyze associations with common histopathological parameters in BC cases. Materials and Methods: Between of 2007 to 2014, 260 patients with BC referred to Oncology Clinic provided cancer tissue samples which underwent immunohistochemistry (IHC) for markers. ER and PR positivity was defined as ${\geq}10%$ positive tumor cells with nuclear staining. HER2-positive was defined as either HER2 gene amplification by fluorescent in situ hybridization (FISH) or scored as 3+ by IHC. For HER2 (2+), FISH was performed to determine HER2 positivity. Results: The mean age at diagnosis for the patients with HER2-negative was significantly higher than in HER2-positive cases. Also, there were significant correlations between histological grade, nuclear grade, lymph node metastasis, tumor size, ER status, PR status, p53 overexpression and Ki-67 index with HER2 expression. HER2-negative lesions were of higher grade and more likely to be ER-negative, PR-negative, p53-positive, lymph node metastasis, with a tumor size<2cm and also $Ki-67{\geq}20%$ as compared to the HER2-positive group. Conclusions: Contrary to the results of other studies, HER2-positive tumors in our study had a lower Ki-67 index and were p53-positive. Also, Ki-67 proliferation index ${\geq}20%$ in more studies was associated with p53-positive.Therefore, tumors which are HER2-positive and have a Ki-$67{\geq}20%$ had a more aggressive behavior compared to HER2-positive and Ki-67<20% lesions.

• Journal of Gastric Cancer
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• v.17 no.4
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• pp.363-373
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• 2017

Purpose: The aims of this study were to evaluate the expression of the large tumor suppressor (LATS) genes LATS1 and LATS2 by immunohistochemical staining of gastric cancer, and to evaluate the clinicopathological significance of LATS expression and its correlation with overall survival (OS). Materials and Methods: LATS1 and LATS2 expression in a tissue microarray was detected by immunohistochemistry, using 264 gastric cancer specimens surgically resected between July 2006 and December 2009. Results: Low expression of LATS1 was significantly associated with more advanced American Joint Committee on Cancer (AJCC) stage (P=0.001) and T stage (P=0.032), lymph node (LN) metastasis (P=0.040), perineural invasion (P=0.042), poor histologic grade (P=0.007), and diffuse-type histology by the Lauren classification (P=0.033). Low expression of LATS2 was significantly correlated with older age (${\geq}65$, P=0.027), more advanced AJCC stage (P=0.001) and T stage (P=0.001), LN metastasis (P=0.004), perineural invasion (P=0.004), poor histologic grade (P<0.001), and diffuse-type histology by the Lauren classification (P<0.001). Kaplan-Meier survival analysis revealed significantly poor OS rates in the groups with low LATS1 (P=0.037) and LATS2 (P=0.037) expression. Conclusions: Expression of LATS1 or LATS2 is a significant marker for a good prognosis in patients with gastric cancer.

• Journal of Breast Cancer
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• v.21 no.4
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• pp.399-405
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• 2018

Purpose: Vesicle-associated membrane protein 8 (VAMP8) is a soluble N-ethylmaleimide-sensitive factor receptor protein that participates in autophagy by directly regulating autophagosome membrane fusion and has been reported to be involved in tumor progression. Nevertheless, the expression and prognostic value of VAMP8 in breast cancer (BC) remain unknown. This study aimed to evaluate the clinical significance and biological function of VAMP8 in BC. Methods: A total of 112 BC samples and 30 normal mammary gland samples were collected. The expression of VAMP8 was assessed in both BC tissues and normal mammary gland tissues via a two-step immunohistochemical detection method. Results: The expression of VAMP8 in BC tissues was significantly higher than that in normal breast tissues. Furthermore, increased VAMP8 expression was significantly correlated with tumor size (p=0.007), lymph node metastasis (p=0.024) and recurrence (p=0.001). Patients with high VAMP8 expression had significantly lower cumulative recurrence-free survival and overall survival (p<0.001 for both) than patients with low VAMP8 expression. In multivariate logistic regression and Cox regression analyses, lymph node metastasis and VAMP8 expression were independent prognostic factors for BC. Conclusion: VAMP8 is significantly upregulated in human BC tissues and can thus be a practical and potentially effective surrogate marker for survival in BC patients.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.380-388
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• 2022

Snail is implicated in tumour growth and metastasis and is up-regulated in various human tumours. Although the role of Snails in epithelial-mesenchymal transition, which is particularly important in cancer metastasis, is well known, how they regulate tumour growth is poorly described. In this study, the possible molecular mechanisms of Snail in tumour growth were explored. Baculoviral inhibitor of apoptosis protein (IAP) repeat-containing protein 3 (BIRC3), a co-activator of cell proliferation during tumourigenesis, was identified as a Snail-binding protein via a yeast two-hybrid system. Since BIRC3 is important for cell survival, the effect of BIRC3 binding partner Snail on cell survival was investigated in ovarian cancer cell lines. Results revealed that Bax expression was activated, while the expression levels of anti-apoptotic proteins were markedly decreased by small interfering RNA (siRNA) specific for Snail (siSnail). siSnail, the binding partner of siBIRC3, activated the tumour suppressor function of p53 by promoting p53 protein stability. Conversely, BIRC3 could interact with Snail, for this reason, the possibility of BIRC3 involvement in EMT was investigated. BIRC3 overexpression resulted in a decreased expression of the epithelial marker and an increased expression of the mesenchymal markers. siSnail or siBIRC3 reduced the mRNA levels of matrix metalloproteinase (MMP)-2 and MMP-9. These results provide evidence that Snail promotes cell proliferation by interacting with BIRC3 and that BIRC3 might be involved in EMT via binding to Snail in ovarian cancer cells. Therefore, our results suggested the novel relevance of BIRC3, the binding partner of Snail, in ovarian cancer development.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.2003-2007
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• 2015

Background: Elevated serum alpha-fetoprotein (AFP) levels in adults are considered abnormal. This parameter is used mostly in the diagnosis and follow-up of hepatocellular carcinomas and yolk sac tumors. Among the other rare tumors accompanied with elevated serum AFP levels, gastric cancer is the most common. In this study, we evaluated the follow-up and comparison of the treatment and marker response of patients with metastatic gastric cancer who had elevated serum AFP levels. Materials and Methods: We performed a retrospective study, including all consecutive patients with advanced gastric cancer, who received systemic chemotherapy with elevated AFP level. Results: Seventeen metastatic gastric cancer patients with elevated AFP levels at the time of diagnosis were evaluated. Fourteen (82.4%) were males and three (17.6%) were females. The primary tumor localization was the gastric body in 8 (76.4%), cardia in 7 (41.2%), and antrum in 2 (11.8%). Hepatic metastasis was observed in 13 (76.4%) at the time of diagnosis. When the relationship of AFP levels and carcinoembryonic antigen (CEA) response of the patients with their radiologic responses was evaluated, it was found that the radiologic response was compatible with AFP response in 16 (94.1%) patients and with CEA response in 12 (70.6%); however, in 5 (29.4%) patients no accordance was observed between radiological and CEA responses. Conclusions: Follow-up of AFP levels in metastatic gastric cancer patients with elevated AFP levels may allow prediction of early treatment response and could be more useful than the CEA marker for follow-up in response evaluation.