bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2120: Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells
Authors: Wang Jo-Hsin , Li Pei-Chi , Lin Li-Chiung , Hsu Fu-Ning , Chen Mei-Chih , Lin Ho
Published: May 2015

Signal transducer and activator of transcription 3 (Stat3), a common transcription factor, has been reported to regulate cancer development, including prostate cancer. Stat3 has also been suggested that its transcriptional activity is initiated by phosphorylation. The tyrosine 705 (Y705) and serine 727 (S727) phosphorylation of Stat3 were documented to Stat3 activation. Androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. Cyclin-dependent kinase 5 (Cdk5), which belongs to Cdk family, is a proline-directed serine/threonine kinase. Our previous results indicate that Cdk5 may phosphorylate AR at serine 81 site (S81) and increase AR stabilization and transactivation. On the other hand, previous studies have shown that Interleukin-6 (IL-6), which is a cytokine, activates androgen receptor (AR) via MAPK and Stat3-related pathway. Therefore, the aim of this study is to investigate if Cdk5 regulates S81 phosphorylation-related AR activation through S727 Stat3 phosphorylation under IL-6 treatment. First we observed IL-6 enhanced S727 phosphorylation of Stat3 and S81 phosphorylation of AR as well as AR protein level. Next, IL-6 increased AR biochemical interaction with Stat3 and AR stabilization, nuclear localization, and transactivation, which is correlated to S727 phosphorylation of Stat3. Subsequently, we found that IL-6 induced tyrosine 15 (Y15) phosphorylation of Cdk5, which is an indicator of Cdk5 activation, and this phosphorylation was inhibited by AG490 (JAK inhibitor). We also found that Y15-Cdk5 mutant (Y15F) decreased IL-6-induced phosphorylation of AR S81 and Stat3 S727 and the biochemical interaction between AR and Stat3 was also affected. In summary, these results suggest that IL-6 activated AR by S81 phosphorylation via S727 phosphorylation of Stat3 and Cdk5 might be an upstream regulator in the pathway.

Citation Format: Jo-Hsin Wang, Pei-Chi Li, Li-Chiung Lin, Fu-Ning Hsu, Mei-Chih Chen, Ho Lin. Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2014-2120
Abstract 2124: Analysis of FAM111A, a newly identified AR regulated gene, in prostate cancer
Authors: Mudryj Maria , Libertini Stephen J. , Lombard Alan P. , Saddiqui Salma , Ghosh Paramita M.
Published: May 2015

Prostate carcinoma (PCa) is the most commonly diagnosed cancer in men in the United States. Most PCas are dependent on the androgen receptor (AR) for growth and survival, and this dependency is exploited as androgen deprivation is the major therapeutic intervention. However, PCa inevitably progress to become castration resistant, yet remain reliant on the activity of the AR. Further understanding the mechanisms that mediate castration resistance and the pathways downstream of the AR will enhance our ability to treat this stage of the disease. RNA-seq studies of two castrate resistant cell lines following AR ablation identified a number of transcripts that were AR regulated. The studies identified FAM111A as an AR regulated gene. While little is known about FAM111A, a previous study has shown that the FAM111A gene harbors a PCa susceptibility SNP and that the FAM111A protein interacts with SV40 T-Ag. Our studies indicate that AR represses FAM111A in cell culture and xenograft models of CaP. Additionally, the expression of the only known FAM111A paralogue, FAM111B, was reciprocally regulated in cell lines and in the xenograft. FAM111A is expressed in all cultured prostate derived cell lines we looked at, and we found that there are two FAM111A isoforms. Furthermore, a siRNA mediated ablation of FAM111A modified apoptotic responses to chemotherapeutic stimuli. An immunohistochemical analysis of a prostate tumor tissue array was used to assess the expression of FAM111A. FAM111A is expressed in the cytoplasmic and nuclear compartments and expression in the cytoplasmic compartment in non-tumor prostate tissue is higher than in adjacent tumor cells. In conclusions, FAM111a is an AR regulated gene, has been associated with PCa in a GWAS study, interacts with the SV40 T-antigen and is expressed at lower levels in tumor cells. This suggests that FAM111A may be have a role in prostate tumorigenesis.

Citation Format: Maria Mudryj, Stephen J. Libertini, Alan P. Lombard, Salma Saddiqui, Paramita M. Ghosh. Analysis of FAM111A, a newly identified AR regulated gene, in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2124. doi:10.1158/1538-7445.AM2014-2124
Abstract 2138: 6-Shogaol from dried ginger inhibits growth of prostate cancer cells both in vitro and in vivo
Authors: Saha Achinto , Blando Jorge , Silver Eric , Beltran Linda , Sessler Jonathan , DiGiovanni John
Published: May 2015

Prostate cancer (PCa) is the most common non-cutaneous neoplasm and is the second leading cause of cancer death in American men. Approximately 1 in 6 men will be diagnosed with PCa during their lifetime and about 1 in 36 will die of PCa. It is estimated that approximately 238,590 new cases of PCa will be diagnosed and 29,720 PCa-related deaths will occur in the United States in 2013. 6-Shogaol (6-SHO), a potent bioactive compound in ginger (Zingiber officinale Roscoe), has been shown to possess anti-inflammatory and anticancer activity. In the present study, the effect of 6-SHO on the growth of PCa cell lines was investigated. 6-SHO effectively reduced survival and induced apoptosis of cultured human (LNCaP, DU145 and PC3) and mouse (HMVP2) PCa cell lines. Mechanistic studies revealed that 6-SHO reduced constitutive and IL-6 induced STAT3 activation and inhibited both constitutive and TNF-α induced NF-κB activity in these cell lines. In addition, 6-SHO decreased the level of several STAT3 and NF-κB regulated target genes at the protein level (including cyclin D1, survivin and cMyc) and modulated mRNA levels of chemokine, cytokine, cell cycle and apoptosis regulatory genes (IL-7, CCL5, BAX, BCL2, p21 and p27). 6-SHO was more effective than two other compounds found in ginger, 6-gingerol and 6-paradol, at reducing survival of PCa cell lines and reducing STAT3 and NF-κB signaling. 6-SHO also showed significant tumor growth inhibitory activity in an allograft model using HMVP2 cells. Overall, the current results lead us to suggest that 6-SHO may have potential as a chemopreventive and/or therapeutic agent for PCa and that further study of this compound is warranted

Citation Format: Achinto Saha, Jorge Blando, Eric Silver, Linda Beltran, Jonathan Sessler, John DiGiovanni. 6-Shogaol from dried ginger inhibits growth of prostate cancer cells both in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2138. doi:10.1158/1538-7445.AM2014-2138
Abstract 2143: Inhibiting fatty acid synthase for chemoprevention of chemically induced colorectal tumors
Authors: Orita Hajime , Tanaka Sigekazu , Maekawa Hiroshi , Sakurada Mutsumi , Kushida Tomonori , Ito Tomoaki , Miyazaki Masahiro , Shiroishi Toshihiko , Sato Koichi
Published: May 2015

Purpose: Fatty acid synthase (FAS) is overexpressed in colorectal cancer, and we have investigated the potential use of FAS inhibitors for chemoprevention of colorectal cancer.

Experimental Design: Expression of FAS was evaluated in human colorectal lesions and in murine models of colorectal tumorigenesis [AOM and DSS induced colorectal tumors in mice]. Then, the ability of pharmacologic inhibitors of FAS to prevent development of the murine tumors was investigated.

Results: Immunohistochemical studies show that human colorectal cancers express high levels of FAS compared with normal tissues, suggesting that FAS might be a target for intervention in colorectal carcinogenesis. FAS is also expressed at high levels in chemically induced murine colorectal tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with berberine include, Chinese traditional drug, Kampo.

Conclusions: We conclude that increased levels of FAS are common in human colorectal cancer. Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of colorectal tumors that have high expression of this enzyme.

Citation Format: Hajime Orita, Sigekazu Tanaka, Hiroshi Maekawa, Mutsumi Sakurada, Tomonori Kushida, Tomoaki Ito, Masahiro Miyazaki, Toshihiko Shiroishi, Koichi Sato. Inhibiting fatty acid synthase for chemoprevention of chemically induced colorectal tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2143. doi:10.1158/1538-7445.AM2014-2143
Abstract 2147: The effects of artemisinin, dihydroartemisinin and artemisinin-glycolipid on non-small cell lung cancer induced bone destruction
Authors: Ma Gwang-Taek , Park Kwang-Kyun , Chung Won-Yoon
Published: May 2015

Lung cancer is the major cause of cancer-related death in males worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of entire lung cancer and largely metastasizes to bone. Bone consistently maintains the balance between osteoclasts and osteoblasts, but NSCLC metastasized to bone interacts with normal bone cells and abnormally enhances osteoclasts-mediated bone resorption. As a result, enhanced bone resorption results in the release of transforming growth factor-beta (TGF-β) and insulin-like growth factor -1 (IGF-1) which promote cancer progression. Plant-derived compounds have been received attention as therapeutic agents for many human diseases. Artemisinin (ART) which is isolated from chinese medicinal herb, Artemisia annua and its derivative dihydroartemisinin (DHA) have been known as outstanding anti-malarial agents and have also potent anti-cancer activities. ART-glycolipid is ART's derivative that combined ART with the glycolipid daumone in order to enhance anti-cancer activity. We found that cell viability was decreased in A549 cells treated with ART, DHA and ART-glycolipid. ART, DHA and ART-glycolipid decreased the migration of A549 cells treated with or without TGF- β1 and IGF-1 which are highly discovered in bone metastasis of NSCLC. In addition, they inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). In particular, ART-glycolipid showed the most potent inhibitory effect. Therefore, we expect that ART, DHA and ART-glycolipid can inhibit metastatic ability of A549 cells and bone resorbing activity of osteoclasts by reducing secretion of matrix metalloproteinases- 9 (MMP-9) and cathepsin K activities in BMM. These results indicate that ART, DHA and ART-glycolipid may serve as useful agents for attenuating NSCLC induced bone destruction.

Citation Format: Gwang-Taek Ma, Kwang-Kyun Park, Won-Yoon Chung. The effects of artemisinin, dihydroartemisinin and artemisinin-glycolipid on non-small cell lung cancer induced bone destruction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2147. doi:10.1158/1538-7445.AM2014-2147
Abstract 2148: Inhibitory effects of liensinine and nuciferine on breast cancer-associated bone loss
Authors: Kang Eun-Ji , Chung Won-Yoon , Park Kwang-Kyun
Published: May 2015

Breast cancer is the most common cause of cancer death in women and has a propensity to metastasize to bone. Once tumor cells become lodged in the skeleton, they interact with bone microenvironment establishing the “vicious cycle” that accelerates both tumor growth and bone destruction. Therefore, the vicious cycle between metastatic cancer cells and bone cells can be a possible target for cancer therapy.

Nelumbo nucifera (Lotus) has been used for various medicinal purposes in some parts of the world for treatment of several disorders including skin disease, cough, inflammation, fever. Liensinine and nuciferine are active components in Lotus but it is still unknown whether they can effectively inhibit breast cancer associated bone destruction.

In this study, we found that liensinine and nuciferine inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in mouse bone marrow macrophage cells at non-cytotoxic concentrations. In addition, liensinine and nuciferine inhibited cell proliferation and induced apoptosis in MDA-MB-231 human breast cancer cells. Liensinine also displayed an inhibitory effect on the migration and invasion ability of MDA-MB-231 cells compared with nuciferine. Furthermore, liensinine and nuciferine may modulate cell cycle distribution and expression of apoptosis-related proteins in MDA-MB-231 cells and inhibit breast cancer-induced bone resorption in vivo. Therefore, liensinine and nuciferine can possess the potential to prevent breast cancer-mediated osteolysis.

Citation Format: Eun-Ji Kang, Won-Yoon Chung, Kwang-Kyun Park. Inhibitory effects of liensinine and nuciferine on breast cancer-associated bone loss. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2148. doi:10.1158/1538-7445.AM2014-2148
Abstract 217: Salinomycin have antiproliferative and apoptotic effects on ovarian cancer stem-like cell
Authors: Shin So-Jin , Kim Jin-Young , Lee Hyun-Gyo , Nam Eun-Ji , Cho Chi-Heum
Published: May 2015

OBJECTIVE: Cancer stem cells (CSCs) represent a subpopulation of undifferentiated tumorigenic cells responsible for tumor initiation, maintenance, drug resistance and metastasis of tumors. CSCs involved in drug resistance and relapse of cancers can significantly affect ovarian cancer therapy. The antibiotics salinomycin has recently been shown to be a potent compound to deplete chemoresistant cells in adenocarcinoma. The objective of the present study was to evaluate the effect of salinomycin on ovarian CSC whereby salinomycin mono-and combination treatment with paclitaxol regimend were analyzed.

METHODS: The CD44+CD117+CSCs were isolated from the primary ovarian cancer cells derived from ascites fluids of patients with epithelial ovarian cancer by using immune magnetic-activated cell sorting system. To evaluate the effect of salinomycin on ovarian CSC, cells were treated in single and combined treatment. The expression was Nanog, Oct3/4, Sox2 and ABCG2 mRNA was determined by RT-PCR and protein expression was detected by Western blot analysis. The cell viability assay, gelatin zymography and apoptosis assay were applied to evaluate the effects of salinomycin compared with parental tumor cells and CSCs.

RESULTS: The combination of salinomycin with paclitaxel (PTX) was enhanced change cell viability or activating apoptosis in CD44+CD117+ cells, whereas the salinomycin monotreatment did not cause significant changes. Salinomycin treatment reduced stemness gene expression and suppressed invasion of CSCs.

CONCLUSIONS: Based on our findings, we concluded that anti-cancer effect of salinomycin with PTX reduced stemness and induced apoptosis in ovarian cancer and cancer stem cells.

Citation Format: So-Jin Shin, Jin-Young Kim, Hyun-Gyo Lee, Eun-Ji Nam, Chi-Heum Cho. Salinomycin have antiproliferative and apoptotic effects on ovarian cancer stem-like cell. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 217. doi:10.1158/1538-7445.AM2014-217
Abstract 2181: Association of sleep duration, daytime napping, and night shift work with breast cancer risk
Authors: Ren Zefang
Published: May 2015

Sleep habit is closely related to melatonin which protect against breast cancer (BC). Sleep duration, nap habit, and shift work have been separately investigated to associate with BC risk, but the combination has not been reported. In this study, we collected all the sleep habits data from 712 women with incident invasive BC before their treatments and 742 age-matched female controls between July 2010 and January 2012 in Guangzhou, China. We found that the women with either shorter or longer sleep duration had increased BC risk compared to the women with normal sleep time of 6.1-8.9h/day [OR (95%CI: 1.62 (1.18-2.24) and 1.55 (1.14-2.10), respectively]. Night shift work also increased the risk of BC [1.36 (1.07-1.73)] and nap habits marginally associated a decreased risk [0.83 (0.66-1.04)]. Women with night shift work and longer sleep duration had an increased risk of BC [3.80 (1.99-7.26)] compared to the women with normal sleep time and no night shift work. The interaction on BC risk was significant (P for interaction=0.009). We conclude that abnormal sleep increases BC risk and longer sleep duration may not compensate the effect of night shift work on risk of BC.

Table 1.Age-adjusted and multivariate-adjusted odds rations for the associations between sleep habits and breast cancer riskVariablesCases Controls OR#(95%CI)OR* (95%CI)OR^ (95%CI)(n=712) (%)(n=742)(%) Shift worknever443 (67.0)527 (73.8)1.00 (reference)1.00 (reference)1.00 (reference)ever218 (33.0)187 (26.2)1.39 (1.10-1.75)1.36 (1.07-1.73)1.34 (1.04-1.71)Napping statusnever293 (44.5)254 (37.7)1.00 (reference)1.00 (reference)1.00 (reference)ever365 (55.5)420 (62.3)0.75 (0.61-0.94)0.83 (0.66-1.04)0.83 (0.66-1.06)24-hour sleep duration≤6.0116 (17.7)85 (12.8)1.62 (1.18-2.21)1.62 (1.18-2.24)1.52 (1.10-2.11)6.1-8.9409 (62.6)485 (72.7)1.00 (reference)1.00 (reference)1.00 (reference)≥9.0129 (19.7)97 (14.5)1.58 (1.18-2.12)1.55 (1.14-2.10)1.59 (1.17-2.17)P-continuous0.6460.8830.451P-trend0.9090.9960.661OR#: Adjusted for age.OR*: Adjusted for age, education, BMI, marital status, age at menarche, menopausal status, parity, activity, breastfeeding and family history of breast cancer.OR^: Adjusted for age, education, BMI, marital status, age at menarche, menopausal status, parity, activity, breastfeeding, family history of breast cancer, and other sleep factors.

Citation Format: Zefang Ren. Association of sleep duration, daytime napping, and night shift work with breast cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2181. doi:10.1158/1538-7445.AM2014-2181
Abstract 2189: A rare copy number variant at chromosome 14q11 was associated with sporadic colorectal cancer risk in Singapore Chinese
Authors: Cheah Peh Yean , Thean Lai Fun , Teo Yik-Ying , Koh Woon-Puay , Yuan Jian-Min , Koh Poh Koon , Chew Min Hoe , Tang Choong Leong
Published: May 2015

Colorectal cancer (CRC) is one of the most frequent cancers and leading cause of cancer mortality in the developed world. Twin study has attributed about 35% of the etiology of sporadic CRC to genes. Structural variations in the human genome have recently been associated with complex neurological diseases. Their role in CRC, however, is unclear. We performed genome-wide association study (GWAS) on 2,000 ethnicity-, age-, and gender-matched Singapore Chinese CRC patients (aged 50 or more and with no dominant family history of CRC) and healthy controls. Genome-wide genotyping was performed using Affymetrix SNP 6 platform, and rare copy number variants (CNV) were interrogated in 1830 samples that passed the quality assurance tests. A 400 kb region at chromosome 14q11 was identified to be significantly associated (-log10 p-value = 11) with sporadic CRC risk. A chromatin modifier implicated in the β-catenin/Wnt signalling pathway is one of the candidate genes found in the region. Primers unique for this gene applied to an optimal real-time copy number assay verified the CNV region in an independent replication panel comprising another 1,000 sporadic CRC cases. About 6% of the cases exhibit copy number alterations at this region compared to 1% in the healthy controls. A second gene, a small guanosine triphosphatase (GTPase) involved in protein trafficking and preferentially up-regulated in colonic tumors , was shown by long-range polymerase chain reaction to have more structural variations in the cases compared to the controls. Furthermore, expression of the H1 binding domain of the chromatin modifier was positively correlated to the expressions of Cyclin D1 and C-myc. The data suggest that the rare CNV in 14q11 was dynamically associated with the activation of genes implicated in sporadic CRC in the Singapore Chinese.

Citation Format: Peh Yean Cheah, Lai Fun Thean, Yik-Ying Teo, Woon-Puay Koh, Jian-Min Yuan, Poh Koon Koh, Min Hoe Chew, Choong Leong Tang. A rare copy number variant at chromosome 14q11 was associated with sporadic colorectal cancer risk in Singapore Chinese. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2189. doi:10.1158/1538-7445.AM2014-2189
Abstract 219: Inhibition of CD133 expression induce the chemoresistance to 5-fluorouracil in the colon cancer cell line
Authors: Lee Mi-Ra , Ji Sun-Young , Mia-Jan Khalilullah , Cho Mee-Yon
Published: May 2015

Background: The cancer stem cell (CSC) theory which postulates a small subset of tumor cells have the capacity in tumor initiation, progression and importantly resistance to chemotherapy. CD133 is a transmembrane glycoprotein that serves as a putative cancer stem cell (CSC) marker in colon cancer and its relationship with the chemoresistance has been on debate. In our previous clinical study, we found the patients with CD133+ colon cancer have better prognosis after 5 fluorouracil (5-FU) chemotherapy compared to CD133- tumors. Purpose: To understand the role of CSC marker expression in relation to chemoresistance in colon cancer, we evaluated the effect of CD133 inhibition in colorectal cancer (CRC) cell line on the genes expression which are related to chemoresistance or cell survival. Materials & Methods: CD133 siRNA transfection was performed on CD133+ colon cancer cell line (Caco-2). The proliferation assay used to detect the cytotoxic effect of 5-FU chemotherapy. The change in expression of chemoresistance related genes (AKT1, ABCG2 and MDR1) and cell survival related genes (survivin and beta-catenin) were evaluated by qRT-PCR and western blotting at 48hrs and 72hrs after CD133 siRNA transfection. Results: The proliferation assay demonstrated the increased chemoresistance of colon cancer cells after inhibition of CD133 expression when 5µM 5-FU was treated (p=0.0014). The mRNA expression of chemoresistance related genes (AKT1, ABCG2, MDR1) and cell survival related genes (survivin and β-catenin) were all significantly increased after transfection (p<0.05) but there was no significant changes in expression at the protein level of all genes. Conclusions: The inhibition of CD133 expression in CD133+colon cancer cell line induce the chemoresistance to 5-FU chemotherapy through the increased expression of chemoresistance related genes. Therefore, CD133 expression seems to be related with the chemosensitivity to 5-FU in colon cancer despite the mechanism needs to be proven.

Citation Format: Mi-Ra Lee, Sun-Young Ji, Khalilullah Mia-Jan, Mee-Yon Cho. Inhibition of CD133 expression induce the chemoresistance to 5-fluorouracil in the colon cancer cell line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 219. doi:10.1158/1538-7445.AM2014-219
Abstract 22: Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in endothelial cells
Authors: Gu Xin , Cheng Tao , Li Luyuan
Published: May 2015

Endothelial cells in an established vasculature secrete tumor necrosis factor superfamily-15 (TNFSF15; VEGI; TL1A) that functions as a negative modulator of neovascularization to maintain blood vessel stability. TNFSF15 gene expression diminishes at angiogenesis and inflammation sites such as in cancers and wounds. Interferon-γ (IFNγ) is a pleiotropic cytokine expressed primarily by lymphocytes of T cell and NK cell lineages. IFNγ may mediate anti-tumor effects either directly on cancer cell growth or indirectly through immunomodulatory and antiangiogenic responses. However, it was also reported that IFNγ promotes angiogenesis under certain circumstances. Here we show that IFNγ suppresses TNFSF15 expression in human umbilical cord vein endothelial cells (HUVEC). This activity is mediated by IFNγ receptor and the transcription factor STAT1. Since tumor-infiltrating NK and CD4+ T cells are the main sources of IFNγ in tumor lesions, we isolated these cells from peripheral blood of healthy individuals, treated the cells with ovarian cancer OVCAR3 cell-conditioned media, and found a 1- and 10-fold increase of IFNγ production in NK and CD4+ T cells, respectively, compared with that in vehicle-treated cells. These findings support the view that tumor-infiltrating NK and CD4+ T cells under the influence of cancer cells significantly increase the production of IFNγ, which in turn inhibits TNFSF15 expression in tumor vascular endothelial cells, shifting the balance of pro- and anti-angiogenic factors toward escalated angiogenesis potential in the tumor.

Citation Format: Xin Gu, Tao Cheng, Luyuan Li. Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in endothelial cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 22. doi:10.1158/1538-7445.AM2014-22
Abstract 2202: PIK3CA amplification was not associated with serrated polyps but tubular adenomas in colorectal lesions
Authors: Lee Jae-Ho , Kim Dae-Kwang , Choi In-Jang , Hwang IlSeon , Kang Yu-Na , Kim Shin
Published: May 2015

Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and serrated polyps (SPs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SPs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SPs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR. PIK3CA amplification was found in 25% of TAs and 9.4% of SPs, respectively and low and high grade of TAs showed similar frequency of PIK3CA amplification. KRAS and BRAF mutations were mutually exclusive in both TAs and SPs. In TAs, PIK3CA amplification was associated with distal colon and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of TAs independently with KRAS mutation.

Keyword: colorectal cancer, PIK3CA amplification, serrated polyps, tubular adenomas

Note: This abstract was not presented at the meeting.

Citation Format: Jae-Ho Lee, Dae-Kwang Kim, In-Jang Choi, IlSeon Hwang, Yu-Na Kang, Shin Kim. PIK3CA amplification was not associated with serrated polyps but tubular adenomas in colorectal lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2202. doi:10.1158/1538-7445.AM2014-2202
Abstract 2204: Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations reveals new susceptibility loci
Authors: Wu Chen , Wang Zhaoming , Song Xin , Feng Xiao-Shan , Abnet Christian C. , He Jie , Hu Nan , Zuo Xian-Bo , Tan Wen , Zhang Xue-Jun , Freedman Neal D. , Goldstein Alisa M. , Lin Dongxin , Taylor Philip R. , Wang Li-Dong , Chanock Stephen J.
Published: May 2015

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% Confidence Interval (CI) = 0.82-0.88; P = 7.72x10-20) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10x10-13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (per-allele OR = 1.33, 95% CI = 1.22-1.46; P = 1.99x10-10). Our joint analysis revealed new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.

Citation Format: Chen Wu, Zhaoming Wang, Xin Song, Xiao-Shan Feng, Christian C. Abnet, Jie He, Nan Hu, Xian-Bo Zuo, Wen Tan, Xue-Jun Zhang, Neal D. Freedman, Alisa M. Goldstein, Dongxin Lin, Philip R. Taylor, Li-Dong Wang, Stephen J. Chanock. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations reveals new susceptibility loci. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2204. doi:10.1158/1538-7445.AM2014-2204
Abstract 2206: Genetic variants in selenoprotein genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population
Authors: Li Sharon , Hyland Paula L. , Freedman Neal D. , Hu Nan , Su Hua , Wang Lemin , Wang Chaoyu , Ding Ti , Wang Yuan , Fan Jin-Hu , Qiao You-Lin , Xiong Xiaoqin , Yu Kai , Goldstein Alisa M. , Dawsey Sanford M. , Taylor Philip R. , Abnet Christian C. , Lin Shih-Wen
Published: May 2015

PURPOSE: Several observational studies and multinutrient interventional trials suggest that selenium compounds have potential chemopreventive effects on esophageal and gastric carcinogenesis, presumably via their influence on selenoproteins. We aimed to investigate associations between genetic variants in selenoprotein genes and risk of esophageal squamous cell carcinoma (ESCC), gastric carcinoma (GC) and GC subsets: cardia (GCA) and non-cardia (GNCA) using data from a genome-wide association study in a Han Chinese population in which ESCC and GC are predominant cancers. METHODS: 1944 ESCC cases, 1758 GC cases (1126 GCA and 632 GNCA) and 2111 controls from the Shanxi Upper GI Cancer Genetics project and the Linxian Nutritional Intervential Trials were genotyped for 243 SNPs in 24 selenoprotein genes. Logistic regression models were applied to evaluate SNP-level associations. Pathway- and gene-level associations were determined using the resampling-based adaptive rank-truncated product approach. RESULTS: Selenoproteins as a whole pathway were not significantly associated with ESCC (p=0.398) or GC (p=0.608), but five significant (p<0.05) gene-level associations were identified, including GPX2 (p=0.008) and GPX5 (p=0.006) with ESCC, DIO2 (p=0.026) with GC, and SEPP1 (p=0.007) and SEPW1 (p=0.004) with GCA. CONCLUSION: Our results show evidence for an association between specific selenoprotein genes and the risk of ESCC and GC, warranting further studies to validate these associations and investigate underlying mechanisms.

Citation Format: Sharon Li, Paula L. Hyland, Neal D. Freedman, Nan Hu, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Yuan Wang, Jin-Hu Fan, You-Lin Qiao, Xiaoqin Xiong, Kai Yu, Alisa M. Goldstein, Sanford M. Dawsey, Philip R. Taylor, Christian C. Abnet, Shih-Wen Lin. Genetic variants in selenoprotein genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2206. doi:10.1158/1538-7445.AM2014-2206
Abstract 2207: An analysis of circulating sex steroid hormones in relation to Barrett's esophagus
Authors: Cook Michael B. , Wood Shannon , Cash Brooks D. , Young Patrick , Acosta Ruben D. , Falk Roni T. , Pfeiffer Ruth , Hu Nan , Giffen Carol , Turcotte Veronique , Caron Patrick , Guillemette Chantal , Dawsey Sanford M. , Abnet Christian C. , Hyland Paula L. , Taylor Philip R.
Published: May 2015

Introduction: Barrett's esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EA). The male-to-female incidence rate ratio of BE is ∼2 while EA is ∼6 for reasons that remain unknown. We assessed whether sex steroid hormones were associated with BE in a male population. Methods: The Barrett's Esophagus Early Detection Case Control Study (BEEDS) was based at the National Naval Medical Center (NMMC). We quantitated 13 sex steroid hormones, using mass spectrometry, and sex hormone binding globulin (SHBG), using ELISA, in 173 male BE patients and 213 endoscopy-negative controls. We also calculated free estradiol and free testosterone using formulas known to accurately estimate such. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for smoking status, alcohol consumption, body mass index (BMI; kg/m2), heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). Results: Free testosterone was positively associated with BE risk, peaking in the highest quartile with an OR of 4.42 (95%CI: 1.91, 10.24, p=0.0005). Estrone-sulphate was inversely associated with BE risk (OR 4th quartile=0.23, 95%CI:0.10, 0.53, p=0.0006). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. Conclusion: High testosterone may delay re-epithelization of esophageal lesions leading to increased risk of metaplastic growth.

Citation Format: Michael B. Cook, Shannon Wood, Brooks D. Cash, Patrick Young, Ruben D. Acosta, Roni T. Falk, Ruth Pfeiffer, Nan Hu, Carol Giffen, Veronique Turcotte, Patrick Caron, Chantal Guillemette, Sanford M. Dawsey, Christian C. Abnet, Paula L. Hyland, Philip R. Taylor. An analysis of circulating sex steroid hormones in relation to Barrett's esophagus. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2207. doi:10.1158/1538-7445.AM2014-2207
Abstract 2212: Urinary biomarkers of catechins in relation to risk of hepatocellular carcinoma in the Shanghai Cohort Study
Authors: Huang Joyce Y. , Butler Lesley M. , Wang Renwei , Yang Chung S. , Yuan Jian-Min , Gao Yu-Tang
Published: May 2015

Background: Catechins from tea and non-tea sources are potential anti-carcinogenic compounds with potent antioxidant properties. Data supporting an effect of specific catechins on the risk of hepatocellular carcinoma (HCC) in humans are sparse. We examined the association between urinary biomarkers of catechins and their metabolites and risk of HCC. Methods: A nested case-control study of HCC (221 cases and 1072 matched controls) was conducted within the Shanghai Cohort Study, a cohort of 18,244 men who were enrolled in 1986-1989. Specific catechins and their metabolites including epicatechin (EC), epigallocatechin (EGC), 4′-O-methyl-epigallocatechin (4′-MeEGC), (-)-5-(3′, 4′, 5′-trihydroxyphenyl)-gamma-valerolactone (M4), and (-)-5-(3′, 4′-dihydroxyphenyl)-gamma-valerolactone (M6) were quantified in urine samples collected from study subjects at enrollment. Logistic regression methods were used to calculate odds ratios (OR) and 95% confidence intervals (CI) with adjustment for established risk factors for HCC, including hepatitis B surface antigen (HBsAg) serology status, self-reported physician-diagnosed cirrhosis, cigarette smoking, and alcohol drinking. Results: Compared with men who had no detectable EC, men with detectable levels of urinary EC had a statistically significant lower risk of HCC (OR=0.64; 95% CI: 0.45, 0.92). The inverse association between EC and HCC risk was not modified by smoking, alcohol intake or HBsAg/cirrhosis status. This inverse EC-HCC association strengthened in analyses restricted to cases that were diagnosed 10 or more years after specimen collection (OR=0.40; 95% CI: 0.22, 0.71). There was no association between urinary levels of EGC or other catechin metabolites and HCC risk. Conclusion: In our study population green tea is the sole source of dietary EGC while the major sources of EC include green tea, as well as apples, black grapes, soybeans, and broad beans. Thus, the findings of the present study support the notion that consumption of fruits and legumes may have a beneficial effect on HCC risk. Experimental studies are warranted to elucidate the biologic mechanisms of EC in hepatocarcinogenesis.

Citation Format: Joyce Y. Huang, Lesley M. Butler, Renwei Wang, Chung S. Yang, Jian-Min Yuan, Yu-Tang Gao. Urinary biomarkers of catechins in relation to risk of hepatocellular carcinoma in the Shanghai Cohort Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2212. doi:10.1158/1538-7445.AM2014-2212
Abstract 2216: 6q15 deletion impede development of ERG fusion in prostate cancer
Authors: Kluth Martina , Tsourlakis Maria Christina , Meyer David , Krohn Antje , Freudenthaler Fabian , Bauer Melanie , Salomon Georg , Heinzer Hans , Michl Uwe , Steurer Stefan , Simon Ronald , Sauter Guido , Schlomm Thorsten , Minner Sarah Jane Pauline
Published: May 2015

Deletions at chromosome 6q15 belong one to the most frequent alterations in pros-tate cancer, and are linked to poor prognosis. Furthermore, there is a marked inverse relationship between 6q15 deletions and TMPRSS2:ERG fusions in prostate cancer. While heterogeneity may limit the applicability of diagnostic molecular markers, it is important to estimate in vivo heterogeneity and the sequel of appearance of potential prognostic markers. In case of one alteration developing after the other, we would expect a small area of cancer having both alterations within a larger area having only one (the first appearing) of these changes.

In this study, we used our heterogeneity tissue microarray approach as a surrogate method to determine in vivo heterogeneity of 6q15 deletions and TMPRSS2:ERG fusions. We constructed a heterogeneity TMA containing samples taken from 10 dif-ferent tumor containing tissue blocks of 189 prostate cancers. Each prostate con-tained 1 to 6 individual cancer foci allowing the molecular analysis of more than 350 tumor foci. 6q15 deletion was analyzed by fluorescence in situ hybridization and ERG expression by immunohistochemistry.

Only 6.6% of 334 ERG positive but 28.4% of 440 ERG negative TMA spots showed 6q15 deletions (p<0.0001). A breakdown of these data to the level of tumor foci re-vealed 6q deletions in 34 tumor foci that were large enough to have at least 3 ana-lyzable TMA spots. The cohort included 42 tumor foci with a homogeneous ERG pos-itivity and 15 with a homogeneous 6q deletion. Remarkably, six of 42 homogeneously ERG positive tumor foci (14.3%) were focal 6q15-deleted, but none of 16 homogene-ous 6q15-deleted foci showed focal ERG positivity in the same tumor area (p=0.022).

In conclusion of our study, the complete absence of ERG positive tumor foci in 6q15-deleted cancers suggests that the functional consequences of 6q15 deletions may prevent the development of TMPRSS2:ERG fusions. However, the development of 6q15 deletions is independent of the ERG status.

Citation Format: Martina Kluth, Maria Christina Tsourlakis, David Meyer, Antje Krohn, Fabian Freudenthaler, Melanie Bauer, Georg Salomon, Hans Heinzer, Uwe Michl, Stefan Steurer, Ronald Simon, Guido Sauter, Thorsten Schlomm, Sarah Jane Pauline Minner. 6q15 deletion impede development of ERG fusion in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2216. doi:10.1158/1538-7445.AM2014-2216
Abstract 2218: Genomic characterisation of 1015 cancer cell-lines
Authors: Bignell Graham R. , Iorio Francesco , Futreal Andrew , Stratton Michael R. , Campbell Peter , McDermott Ultan
Published: May 2015

Over the last twenty years there has been a paradigm shift in cancer treatment, moving away from the cytotoxic effects of chemicals targeting all cells going through cell division to a more targeted approach aimed at inactivating specific cellular components upon which the cancers rely to drive cell growth, a process termed oncogene addiction. The ‘poster child’ for such therapies is ‘imatinib' a small molecule inhibitor of ABL kinase activity targeting the BCR-ABL fusion protein in CML.

We present the genomic characterisation of 1015 cancer cell lines currently being used as reagents in a high-throughput screen of anti-cancer agents. Future analysis combining these genomic and drug resistance data will aid in identifying the underlying genetics of drug sensitivity and allow for identification of biomarkers with which to stratify patients, identifying those most likely to respond to specific cancer therapies. To characterise the cell lines we performed exome sequencing and copy number analysis. Since most cell lines are unmatched we screened out germline variants by comparison to ∼8000 normal exomes, giving a set of ∼500,000 putative somatic non-synonymous variants. To reduce the ‘genetic space’ for the subsequent downstream correlation to drug response data we further filtered the variants to identify those most likely to have a functional effect or contribute to carcinogenesis. Two such filters were applied, the ‘Functional Analysis through Hidden Markov Models’ (FATHMM) algorithm and a series of checks identifying recurrence of variants in the ‘systematic screening data' held in the COSMIC database. Application of these filters reduced the number of variants to be taken forward to ∼115,000 and 30,000 respectively. The variant data for the cancer cell lines is available via the COSMIC web portal.

Citation Format: Graham R. Bignell, Francesco Iorio, Andrew Futreal, Michael R. Stratton, Peter Campbell, Ultan McDermott. Genomic characterisation of 1015 cancer cell-lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2218. doi:10.1158/1538-7445.AM2014-2218
Abstract 2222: Synergistic effects of NAT2 and GSTT1 null polymorphism in lung cancer: a study from North India
Authors: Shukla Rajni Kant , Kant Surya , Bhattacharya Sandeep , Mittal Balraj K.
Published: May 2015

Purpose: Polymorphism in carcinogen detoxification enzymes, NAT2 and GSTT1, has been suggested as susceptibility factor for DNA damage and lung cancer. However, little information is available on DNA adduct burden in lung tissue and polymorphisms in NAT2 and GSTs gene. We investigated the independent and combined effect of metabolic gene polymorphisms NAT2 and GSTs in lung cancer north India patients.

Aim: Present study was conducted to examine: 1) whether GSTT1 Null and NAT2 genotypes have combined risk factors for Lung cancer, 2) To study possible association of tobacco smoking with NAT2 and GSTT1 null genotype of these patients.

Materials and Methods: This case control study was undertaken over a period of 19 months and included 100 Lung cancer patients and 145 controls. The GSTT1 Null and NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by X2 test and Binary Logistic regression.

Results: The NAT2 slow acetylator genotype frequency of slow or fast acetylator genotypes was not significant in lung cancer patients alone (OR = 1.18, 95% CI: 0.69 - 2.03, p value = 0.583).when we combined GSTT1Null/NAT2 slow, then we found no significant association (OR = 0.85, 95% CI: 0.47 - 1.54, p value = 0.610) between case and controls. While on comparing data with smoker as well non-smoker NAT2 polymorphism have no association but GSTT1 null have significant association (P=0.004) in smoker patients.

Conclusion: These data demonstrate that there have no combined affect GSTT1 Null NAT2 slow acetylator genotype did not associated with the risk of developing lung cancer in North Indian population when compared with controls.

Note: This abstract was not presented at the meeting.

Citation Format: Rajni Kant Shukla, Surya Kant, Sandeep Bhattacharya, Balraj K. Mittal. Synergistic effects of NAT2 and GSTT1 null polymorphism in lung cancer: a study from North India. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2222. doi:10.1158/1538-7445.AM2014-2222