• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5799-5804
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• 2012

Family with sequence similarity 189, member B (FAM189B), alias COTE1, a putative oncogene selected by microarray, for the first time was here found to be significantly up-regulated in hepatocellular carcinoma (HCC) specimens and HCC cell lines. mRNA expression of COTE1 in HCC samples and cell lines was detected by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR, while protein expression of COTE1 in HCC tissues was assessed by immunohistochemistry. In addition, invasion of HCC cells was observed after overexpressing or silencing COTE1. In the total of 48 paired HCC specimens, compared with the adjacent non-cancer tissues, the expression of COTE1 was up-regulated in 31 (p<0.01). In HCC cell lines, COTE1 expression was significantly higher than in normal human adult liver (p<0.01). Overexpression of COTE1 enhanced HCC-derived LM6 and MHCC-L cellular invasion in vitro. In contrast, COTE1 knockdown via RNAi markedly suppressed these phenotypes, as documented in LM3 and MHCC-H HCC cells. Mechanistic analyses indicated that COTE1 could physically associate with WW domain oxidoreductase (WWOX), a tumor suppressor. COTE1 may be closely correlated with invasion of hepatocellular carcinoma (HCC) cells and thus may serve as an effective target for gene therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9687-9692
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• 2014

Background: Biliary tract cancers are rare, and surgical resection is the standard treatment at early stages. However, reports on the benefits of adjuvant treatment following surgical resection are conflicting. This study aimed to evaluate the factors affecting survival and adjuvant treatments in patients with surgically treated biliary tract cancers. Materials and Methods: Patient clinical features, adjuvant treatments, and efficacy and prognostic factor data were evaluated. Survival analyses were performed using SPSS 15.0. Results: The median overall survival was 30.7 months (95% confidence interval [CI], 18.4-42.9 months). Median survival was 19 months (95% CI, 6-33) for patients treated with fluorouracil based chemotherapy and 53 months (95% CI, 33.2-78.8) with gemcitabine based chemotherapy(p=0.033). On univariate analysis, poor prognostic factors for survival were galbladder localization, perineural invasion, hepatic invasion, a lack of adjuvant chemoradiotherapy treatment, and a lack of lymph node dissection. On multivariate analysis, perineural invasion was a poor prognostic factor (p=0.008). Conclusions: Biliary tract cancers generally have poor prognoses. The main factors affecting survival are tumour localization, perineural invasion, hepatic invasion, adjuvant chemoradiotherapy, and lymph node dissection. Gemcitabine-based adjuvant chemotherapy is more effective than 5-fluorouracil-based chemotherapy.

• Korean Journal of Head & Neck Oncology
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• v.27 no.1
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• pp.3-11
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• 2011

Hepatocyte growth factor(HGF) and c-Met play an important role in the control of tumor growth and invasion, and they are known to be good prognostic indicators of patient outcome. Epigallocatechin-3-gallate (EGCG) has been shown to have chemopreventive and therapeutic properties by modulating multiple signal pathways regarding the control of proliferation and invasion of cells. In this study, we evaluated the role of c-Met in EGCG-induced inhibition of invasion and apoptosis in an oral cancer cell line. In KB cells where c-Met was knocked down with siRNA, we performed invasion assay and FACS with Annexin V-FITC/PT staining. In addition, we checked the change of mitochondrial membrane potential(MMP) and the generation of reactive oxygen species(ROS). EGCG-induced inhibition of invasiveness was significantly decreased after the knock-down of c-Met. EGCG-induced apoptosis, MMP change and ROS generation was also reduced in c-Met knock-ed-down KB cells. These results suggest that c-Met is involved in EGCG-induced apoptosis and inhibition of invasiveness of oral cancer cell line.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5505-5510
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• 2012

Objective: The aim of this retrospective study is to analyze the clinical and pathological factors related to the prognosis of Chinese patients with stage Ib to IIb cervical cancer. Methods and Results: 13 clinical pathological factors in 255 patients with stage Ib to IIb cervical cancer undergoing radical hysterectomy and systematic lymphadenectomy were analyzed to screen for factors related to prognosis. The cumulative 5-year survival of the 255 patients was 75.7%. The result of the univariate analysis suggested that clinical stage, cell differentiation, depth of cervical stromal invasion, parametrial tissue involvement, and lymph node metastasis were prognostic factors for patients with stage Ib to IIb cervical cancer (P<0.05). Compared with cases with involvement of iliac nodes, obturator nodes, or inguinal lymph nodes, cases with metastasis to the common iliac lymph nodes had a poorer prognosis (P<0.05). Cases with involvement of four or more lymph nodes had a poorer prognosis than those with involvement of three or fewer lymph nodes (P<0.05). Using multivariate Cox proportional hazards model regression analysis, non-squamous histological type, poor differentiation, parametrial tissue involvement, and outer 1/3 stromal invasion were found to be independently related to patients poor prognosis (P<0.05). Conclusion: Non-squamous histological type, poor cell differentiation, parametrial tissue involvement, and outer 1/3 stromal invasion are the independent poor prognostic factors for patients with stage Ib to IIb cervical cancer.

• Radiation Oncology Journal
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• v.37 no.2
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• pp.73-81
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• 2019

Purpose: There is sparse literature on treatment outcomes research on resectable oral tongue squamous cell carcinoma (OTSCC). The aim of this study was to measure the treatment outcomes, explore the failure patterns, and identify the potential clinicopathological prognostic factors affecting treatment outcomes for resectable OTSCC. Materials and Methods: It is a retrospective analysis of 202 patients with resectable OTSCC who underwent upfront primary surgical resection followed by adjuvant radiotherapy with or without concurrent chemotherapy if indicated. Results: The median follow-up was 35.2 months (range, 1.2 to 99.9 months). The median duration of locoregional control (LRC) was 84.9 months (95% confidence interval, 67.3-102.4). The 3- and 5-year LRC rate was 68.5% and 58.3%, respectively. Multivariate analysis showed that increasing pT stage, increasing pN stage, and the presence of extracapsular extension (ECE) were significantly associated with poorer LRC. The median duration of overall survival (OS) was not reached at the time of analysis. The 3- and 5-year OS rate was 70.5% and 66.6%, respectively. Multivariate analysis showed that increasing pT stage and the presence of ECE were significantly associated with a poorer OS. Conclusion: Locoregional failure remains the main cause of treatment failure in resectable OTSCC. There is scope to further improve prognosis considering modest LRC and OS. Pathological T-stage, N-stage, and ECE are strong prognostic factors. Further research is required to confirm whether adjuvant therapy adds to treatment outcomes in cases with lymphovascular invasion, perineural invasion, and depth of invasion, and help clinicians tailoring adjuvant therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1489-1492
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• 2016

Background: Although there are no biomarkers that are routinely used in endometrial cancer (EC) management, many studies have found that serum human epididymis protein 4 (HE4) is superior to cancer antigen 125 (CA125) in the detection of EC. The correlation of HE4 with two prognostic factors for EC, primary tumor diameter (PTD) and depth of myometrial invasion (DMI) may be useful in identifying EC patients at high risk of lymphatic dissemination. Objective: To evaluate the correlation of serum HE4 with PTD and DMI in patients with EC. Materials and Methods: A cross-sectional study was conducted on 70 EC patients who were scheduled for elective surgery at Rajavithi Hospital between 1st September 2013 and 30th May 2014. Preoperative serum levels of HE4 and CA125 were investigated, and then gross measurement of PTD was taken and postoperative pathologic slides were reviewed for DMI including histologic types, grading and staging. Results: Preoperative serum HE4 levels were strongly correlated with PTD (r=0.65, p<0.001) and moderately correlated with DMI (r=0.46, p<0.001). Moreover, serum HE4 levels were significantly elevated in EC patients with PTD >2 cm (p<0.001) and DMI > 50% (p=0.004). The performance of serum HE4 in identifying EC patients at low risk and high risk of lymph node metastasis was significantly better than that of CA125 (AUC 0.88 vs. 0.65, p=0.003). At an optimal cut-off value of 70 pM/L, serum HE4 had a sensitivity of 83.3% and a specificity of 80.0%. Conclusions: In EC patients, preoperative serum HE4 is significantly correlated with PTD and DMI. Serum HE4 levels could be useful in identifying endometrial cancer patients at high risk of lymphatic spread who would benefit from systemic lymphadenectomy at the cut-off value of 70 pM/L.

• BMB Reports
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• v.52 no.12
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• pp.712-717
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• 2019

Translocase of outer mitochondrial membrane 20 (TOMM20) plays an essential role as a receptor for proteins targeted to mitochondria. TOMM20 was shown to be overexpressed in various cancers. However, the oncological function and therapeutic potential for TOMM20 in cancer remains largely unexplored. The purpose of this study was to elucidate the underlying molecular mechanism of TOMM20's contribution to tumorigenesis and to explore the possibility of its therapeutic potential using colorectal cancer as a model. The results show that TOMM20 overexpression resulted in an increase in cell proliferation, migration, and invasion of colorectal cancer (CRC) cells, while siRNA-mediated inhibition of TOMM20 resulted in significant decreases in cell proliferation, migration, and invasion. TOMM20 expression directly impacted the mitochondrial function including ATP production and maintenance of membrane potential, which contributed to tumorigenic cellular activities including regulation of S phase cell cycle and apoptosis. TOMM20 was overexpressed in CRC compared to the normal tissues and increased expression of TOMM20 to be associated with malignant characteristics including a higher number of lymph nodes and perineural invasion in CRC. Notably, knockdown of TOMM20 in the xenograft mouse model resulted in a significant reduction of tumor growth. This is the first report demonstrating a relationship between TOMM20 and tumorigenesis in colorectal cancer and providing promising evidence for the potential for TOMM20 to serve as a new therapeutic target of colorectal cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.2
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• pp.157-165
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• 2023

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and current therapeutic strategies are limited in their effectiveness. The expressions of Rab5 and the M2 tumor-associated macrophage marker CD163 in tissues were detected by Western blot. The migration and invasion of cells were determined using a Transwell assay. The expressions of the exosome markers were evaluated by Western blot. The polarization of human macrophages (THP-1) was determined by incubation of THP-1 cells with conditioned medium or exosomes collected from MDA-MB-231 cells with indicated transfections or by a coculture system of THP-1 and MDA-MB-231 cells. The M1 and M2 macrophage markers were evaluated by qRT-PCR. The expression of Rab5 in TNBC was significantly higher than that in normal breast tissue. Rab5 expressions in triple-negative and luminal A breast cancer were higher than those in other molecular subtypes. Higher CD163 expression was observed in triple-negative breast cancer and in triple-negative and luminal B subtypes. Rab5 knockdown suppressed but Rab5 overexpression promoted the migration and invasion capacity of MDA-MB-231 cells. The levels of CD63 and CD9 in the medium of Rab5 knockdown cells were lower than those in control cells, whereas higher levels of CD63 and CD9 were observed in Rab5 overexpression cells. Rab5 knockdown decreased the excretion but did not alter the diameter of the exosomes. Knockdown of Rab5 facilitated the anti-tumor polarization of macrophages, which was partially reversed by Rab5 overexpression. Therefore, Rab5 is expected to be a potential therapeutic target for triple-negative breast cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1589-1595
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• 2014

Objective: Forkhead box C2 (FOXC2) is a member of the winged helix/forkhead box (Fox) family of transcription factors. It has been suggested to regulate tumor vasculature, growth, invasion and metastasis, although it has not been studied in cervical cancer. Here, we analyzed FOXC2 expression in cervical tissues corresponding to different stages of cervical cancer development and examined its correlation with clinicopathological characteristics. In addition, we examined the effects of targeting FOXC2 on the biological behavior of human cervical cancer cells. Methods: The expression of FOXC2 in normal human cervix, CIN I-III and cervical cancer was examined by immunohistochemistry and compared among the three groups and between cervical cancers with different pathological subtypes. Endogenous expression of FOXC2 was transiently knocked down in human Hela and SiHa cervical cells by siRNA, and cell viability and migration were examined by scratch and CCK8 assays, respectively. Results: In normal cervical tissue the frequency of positive staining was 25% (10/40 cases), with a staining intensity (PI) of $0.297{\pm}0.520$, in CIN was 65% (26/40cases), with a PI of $3.00{\pm}3.29$, and in cancer was 91.8% (68/74 cases), with a PI of $5.568 {\pm}3.449$. The frequency was 100% in adenocarcinoma (5/5 cases) and 91.3% in SCCs (63/69 cases). The FOXC2 positive expression rate was 88.5% in patients with cervical SCC stage I and 100% in stage II, showing significant differences compared with normal cervix and CIN. With age, pathologic differentiation degree and tumor size, FOXC2 expression showed no significant variation. On transient transfection of Hela and SiHa cells, FOXC2-siRNA inhibition rates were 76.2% and 75.7%; CCK8 results showed reduced proliferation and relative migration (in Hela cells from $64.5{\pm}3.16$ to $49.5{\pm}9.24$ and in SiHa cells from $60.1{\pm}3.05$ to $44.3{\pm}3.98$) (P < 0.05). Conclusion: FOXC2 gene expression increases with malignancy, especially with blood vessel hyperplasia and invasion degree. Targeted silencing was associated with reduced cell proliferation as well as invasion potential.

• BMB Reports
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• v.40 no.3
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• pp.439-443
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• 2007

Tumor growth and metastasis are dependent on angiogenesis, and endothelial cell invasion and migration are apparent means of regulating tumor progression. We report here that saxatilin, a snake venom-derived disintegrin, suppresses the angiogenesis-inducing properties of NCI-H460 human lung cancer cells. Culture supernatants of NCI-H460 cells are able to induce human umbilical vascular endothelial cell (HUVEC) invasion and tube formation. However, treatment of the cancer cells with saxatilin resulted in reduced angiogenic activity of the culture supernatant. This suppressed angiogenic property was found to be associated with the level of vascular endothelial growth factor (VEGF) in the culture supernatant. Further experimental evidence indicated that saxatilin inhibits VEGF production in NCI-H460 cells by affecting hypoxia induced factor-1$\alpha$ (HIF-1$\alpha$) expression via the Akt pathway.