bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 692: Identifying genes that regulate bladder cancer progression and invasion
Authors: Han Amy L. , Veeneman Brendan , Tomlins Scott A. , Keller Evan T. 
Published: July 2016

Abstract
Transitional cell carcinoma (TCC) is the most common type of bladder cancer and can be categorized as either non-muscle invasive (Ta-T1) or muscle invasive (≥T2). Approximately 50% of bladder cancers are T1 at initial diagnosis; however, the recurrence rate for these tumors is high and they may progress into T2. In this study, we aimed to determine if there are specific gene expression differences between T1 vs. T2 bladder cancer that can help identify key regulators in bladder cancer progression and invasion. T1 and T2 bladder cancer tissues were subjected to RNA-Seq to evaluate for differences among these stages. Additionally, the Oncomine database was examined to further narrow down potential candidates that differentiate T1 from T2. These efforts led to the identification of an extracellular matrix glycoprotein, fibulin-3 (FBLN3), as being highly expressed in T2 compared to T1 tissues. To validate these findings, FBLN3 expression was measured using qRT-PCR from formalin fixed and paraffin embedded tissues from patient bladder samples ranging from stages Ta-T4. These studies confirmed that FBLN3 expression was elevated in muscle-invasive compared to non-muscle invasive bladder cancer. Consistent with these findings, FBLN3 expression level correlated with the invasive ability of several bladder cancer cell lines. Specifically, FBLN3 expression was determined using both qRT-PCR and western blotting amongst the T24, UMUC-13, UMUC-3, RT4, and 5637 bladder cancer cell lines. The most invasive cell lines, T24 and UMUC-13, demonstrated the highest FBLN3 expression. In contrast, the least invasive cells, RT4 and 5637, demonstrated the least FBLN3 expression. To determine a functional role for FBLN3 in bladder cancer invasion, we knocked down or increased FBLN3 expression in bladder cancer cell lines using lentiviral transduction. Knockdown of FBLN3 expression in the T24 and UMUC-13 cells inhibited the invasion and migration of these bladder cancer cells; whereas, FBLN3 overexpression in the 5637 cells promoted the invasiveness of the bladder cancer cells. Furthermore, cell viability and growth rates were not affected by manipulation of FBLN3 expression. Our results indicate that FBLN3 serves as a pro-invasive factor in bladder cancer. These findings suggest that FBLN3 could serve as (1) a biomarker to differentiate T1 from T2 bladder cancers and (2) a promising therapeutic target.
Citation Format: Amy L. Han, Brendan Veeneman, Scott A. Tomlins, Evan T. Keller. Identifying genes that regulate bladder cancer progression and invasion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 692.
Abstract 699: Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target
Authors: Rubinstein Maria M. , Segall Jeffrey 
Published: July 2016

Abstract
Glioblastoma multiforme is a fatal primary brain cancer. It has remained one of the most difficult cancers to treat because of glioblastomas’ aggressive and local invasive nature. Glioblastoma tumors have many myeloid cells, especially microglia. Increased levels of microglia result in increased glioblastoma invasion and are associated with worse clinical outcomes. Glioblastomas’ infiltrative mechanisms are mostly unknown which hinder the efficacy of current treatments. Therefore, further investigations on the mechanisms responsible for local invasion are potential targets for therapeutic interventions.
Recently, there has been interest in evaluating the role of kinesin family members (KIFs) and cathepsins (CTS) as possible targets for therapeutic interventions. KIFs play an essential role in both physiological axonal transport processes and in processes of cell division. Previous studies have investigated the inhibition of KIF11 as a possible therapeutic target in glioblastoma. Preliminary studies in our group have found that the inhibition of KIF9 reduces microglia-stimulated glioma invasion. CTS, which are proteases that function in many pathways and increase neoplastic progression, are other possible therapeutic targets. Specifically in glioblastoma, inhibition of cathepsin L1 (CTSL1) (i) promotes tumor cell death, (ii) decreases apoptosis threshold and (iii) sensitizes glioblastoma cells to radiation. Our study investigated the role of KIF9 suppression in secretion and production of CTSL1.
In order to investigate this relationship, U87 cells were incubated with and without the presence of microglia. Non-targeting and stable KIF9 knockdown cells were incubated with and without the presence of microglia. CTSL1 concentration levels were measured by enzyme immunoassay (ELISA). We investigated CTSL1 concentrations in the cell lysates as well as the cell supernatants. Our results demonstrated an overall decrease in production and secretion of CTSL1 in KIF9 knockdown cells as compared to non-targeting shRNA cells. The effect of KIF9 knockdown was evident in the presence and absence of microglia. Although the exact mechanism needs to be further clarified, inhibition of CTSL1 by KIF9 suppression could be a possible potential target for therapeutic intervention.
Citation Format: Maria M. Rubinstein, Jeffrey Segall. Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 699.
Abstract 702: Serglycin promotes cell migration via modulating cytoskeleton reorganization and enhancing focal adhesion turnover
Authors: Chen Jeou-Yuan , Guo Jing-You 
Published: July 2016

Abstract
Serglycin (SRGN), a hematopoietic cell granule proteoglycan, has recently been shown to be overexpressed in several aggressive cancer types. In nasopharyngeal and hepatocellular carcinomas, elevated expression of SRGN was shown to correlate with poor prognosis. However, the molecular mechanisms underlying SRGN-mediated malignancies remain to be explored. In this study, we showed that SRGN is expressed at elevated levels in several lung cancer-derived cell lines. By gain-of-function and loss-of-function approaches, we showed that SRGN promoted NSCLC cell migration. SRGN modulated actin cytoskeleton reorganization and promoted lamellipodia and filopodia formation at the leading edge, facilitating a directional movement during wound closure in NSCLC cells. In consistence, increased levels of activated Rac1, which is required for lamellipodia formation, and CDC42, which is required for filopodia formation, were detected. Increased focal adhesion (FA) turnover, the process of continuous assembly and disassembly of adhesions, would lead to increased cell migration. We further showed that SRGN promoted Src activation, leading to increased phosphorylation of paxillin (PAX) at Y118 as well as reduced PAX/FAK complex formation, which were well-defined indicators of FA turnover. Taken together, these data suggested that SRGN promotes cell migration through inducing cytoskeleton reorganization and focal adhesion turnover.
Citation Format: Jeou-Yuan Chen, Jing-You Guo. Serglycin promotes cell migration via modulating cytoskeleton reorganization and enhancing focal adhesion turnover. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 702.
Abstract 705: PRL-3/PTP4A3 phosphatase promotes uveal melanoma cell migration through the regulation of integrin â1 in focal adhesion
Authors: Foy Malika , Anezo Oceane , Planque Nathalie , Saule Simon 
Published: July 2016

Abstract
Using transcriptomic analysis, we found that Phosphatase of Regenerating Liver-3 (PRL-3) overexpression is highly correlated with metastatic tumors and predicts poor prognosis in patients with uveal melanoma. PRL-3 is a dual specific phosphatase with a carboxy-terminal farnesylation motif, allowing anchorage to the plasma membrane. PRL-3 overexpression in ocular melanoma cell line-1 (OCM1) significantly increases cell migration in vitro and invasiveness in vivo, suggesting a direct role of PRL-3 in metastasis (Laurent et al, Cancer Res 2011; 71:666). Despite its role in the metastatic process of various cancers, its mechanism of action and its intracellular substrates remain largely unknown. It has been shown that the anchorage of PRL-3 to the plasma membrane plays an important role in the metastatic process, suggesting that the phosphatase regulates transmembrane substrates. Among potential targets involved in extracellular matrix adhesion, we focused on integrin â1 which we found overexpressed in the transcriptomic analysis of our uveal melanoma cohort.We showed that FTI-277, a farnesyltransferase inhibitor that prevents PRL-3 anchorage to the plasma membrane, abolishes PRL-3-induced OCM1 cell migration on collagen I in vitro, specifically enhances the spreading of OCM1 cells overexpressing PRL-3, and allows the formation of large focal adhesions involving integrin â1. Knockdown of integrin â1 in OCM1-PRL3 cells partially restores the spreading and migration. Furthermore, in focal adhesions, we observed that PRL-3 specifically regulates the aggregation of integrin â1 but does not affect integrin â3. Our results suggest the involvement of integrin â1 in PRL-3-mediated cell migration. To go further, we are currently investigating the phosphorylation status of specific integrin â1 residues, known to be involved in cell adhesion. The present study highlights the importance of PRL-3 membrane localization in uveal melanoma cell migration, by regulating adhesion to the extracellular matrix through integrin â1.
Citation Format: Malika Foy, Oceane Anezo, Nathalie Planque, Simon Saule. PRL-3/PTP4A3 phosphatase promotes uveal melanoma cell migration through the regulation of integrin â1 in focal adhesion. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 705.
Abstract 708: Defensin-alpha 6 (DEFA6) as a protumorigenic function in vitro and prognostic marker in colorectal cancer
Authors: Jeong Dongjun , Kim Hyungjoo , Oh Seunghyun , Ban Seona , Ji Sanghee , Kim Han Jo , Ahn Tae Sung , Kim Tae Hyun , Kwon Hyog Young , Jeon Seob , Bae Sang Byung , Kim Chang-Jin , Lee Moon Soo , Baek Moo-Jun 
Published: July 2016

Abstract
Objective
DEFA6 also known as human alpha defensing 6 (HD6) is a member of the alpha defensins family that defends the host against bacteria and viruses. Expression of DEFA6 is enhanced in colorectal cancer tissue and cells. The mechanism and function of DEFA6 have not been reported to play an important role in carcinogenesis and cancer progression. The goal of this study was to evaluate the protumorigenic functions of DEFA6 in the colorectal cancer cell line and to evaluate the clinical significance of DEFA6 expression in colorectal cancer patients.
Methods
DEFA6 was highly expressed in colorectal cancer cell lines. Colorectal cancer cell, HCT116, expressing high level of DEFA6 was used for the biological roles of DEFA6 by siRNA transfection. The protumorigenic functions of DEFA6 was evaluated by MTT assay, migration and invasion transwell assay and plate colony forming assay. DEFA6 expression was investigated by immunohistochemistry in 60 cases of colorectal cancer tissue and the association of DEFA6 expression was correlated with patient's survival.
Results
Immunohistochemistry analysis showed that the DEFA6 protein was expressed higher in death group (survival &lt;5 years) than survival group (survival &gt;5 years), (p = 0.02). The HCT116 of knockdowned DEFA6 by siRNA showed significant decrease in proliferation by MTT assay (p&lt;0.05) and plate colony forming assay (p = 0.00). Also, the ability of migration and invasion was significantly reduced in DEFA6 knockdowned HCT116 compared to control HCT116 cell (both, p&lt;0.05).
Conclusion
DEFA6 plays important roles in invasion and migration of colorectal cancer cell according to the functional study. As patient's survival mostly depends on the migration and invasion of the tumor cells, the high expression of DEFA6 in colorectal cancer is associated with patient's survival and could be a good prognostic marker.
Citation Format: Dongjun Jeong, Hyungjoo Kim, Seunghyun Oh, Seona Ban, Sanghee Ji, Han Jo Kim, Tae Sung Ahn, Tae Hyun Kim, Hyog Young Kwon, Seob Jeon, Sang Byung Bae, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. Defensin-alpha 6 (DEFA6) as a protumorigenic function in vitro and prognostic marker in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 708.
Abstract 709: In vitro functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients
Authors: Jeong Dongjun , Ban Seona , Kim Hyungjoo , Oh Seunghyun , Ji Sanghee , Kim Han Jo , Ahn Tae Sung , Kim Tae Hyun , Kwon Hyog Young , Jeon Seob , Bae Sang Byung , Kim Chang-Jin , Lee Moon Soo , Baek Moo-Jun 
Published: July 2016

Abstract
Background: PRSS33, one of serine protease multigene family, has central roles in the regulation of a wide variety of physiological processes, including inflammation, development and malignancy. However, the function of this gene in colorectal cancer has not been elucidated. The goal of this study was to evaluate the oncogenic functions of PRSS33 in the colorectal cancer cell line and to evaluate the clinical significance of PRSS33 expression in colorectal cancer patients.
Method: PRSS33 was highly expressed in colorectal cancer cell lines, HCT116, SW480 and SW620. The oncogenic functions were evaluated in the cell lines by knocking down PRSS33 with siRNA transfection and compared them with PRSS33 highly expressing control cell lines. The functional studies included cell proliferation assay, invasion assay, migration assay and anchorage-independent semisolid agar colony forming assay. The clinical significance of PRSS33 expression was evaluated in 92 cases of colorectal cancer tissue by immunohistochemistry.
Results: The PRSS33 knockdowned cell lines by siRNA transfection showed significant decreases of proliferation, invasion, migration compared to those of control (p&lt;0.05) respectively. The oncogenic function of PRSS33 was confirmed by anchorage-independent semi-solid agar colony forming assay. The PRSS33 knockdowned cell lines revealed lower colony formation on semisolid agar compared to the PRSS33 highly expressing control cell lines. The disease-free survival rate was decreased in patients of PRSS33 high expression (p = 0.001). The overexpression of PRSS33 was associated with survival and death by chi-square test (p = 0.002). Multivariate Cox-regression analysis showed an association between PRSS33 expression and prognosis (HR = 2.71, 95% CI = 1.39-5.27: p = 0.003).
Conclusion: This study indicates that PRSS33 is a novel pro-oncogene and the expression is an independent prognostic factor in colorectal cancer patients. In the future, research on the oncogenic signal pathway of PRSS33 in colorectal cancer is necessary.
Citation Format: Dongjun Jeong, Seona Ban, Hyungjoo Kim, Seunghyun Oh, Sanghee Ji, Han Jo Kim, Tae Sung Ahn, Tae Hyun Kim, Hyog Young Kwon, Seob Jeon, Sang Byung Bae, Chang-Jin Kim, Moon Soo Lee, Moo-Jun Baek. In vitro functional study of novel oncogene serine protease 33 (PRSS33) and the clinical significance of PRSS33 expression in colorectal cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 709.
Abstract 710: Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation
Authors: Chen Ben-Kuen , Hsu Jinn-Yuan , Chang Wen-Chang 
Published: July 2016

Abstract
Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). However, whether the induction of pyruvate dehydrogenase kinase 1 (PDK1) mediates EGF-enhanced HNSCC metastasis remains unclear. Interestingly, we found that EGF induced PDK1 expression in HNSCC. The tumor cell transformation induced by EGF was repressed by the depletion of PDK1. The down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells and tumor cells metastastic seeding of the lungs. Knockdown of PDK1 also inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. These results demonstrate that EGF-induced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.
Citation Format: Ben-Kuen Chen, Jinn-Yuan Hsu, Wen-Chang Chang. Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 710.
Abstract 711: The essential role of NKX6.3 in gastric cancer cell migration and invasion through targeting of Wnt/â-catenin and Rho-GTPase signaling pathways
Authors: Yoon Jung Hwan , Choi Won Suk , Park Won Sang 
Published: July 2016

Abstract
Despite ongoing research and recent progress, the prognosis for patients with advanced gastric cancer remains poor. Wnt/â-catenin and Rho-GTPase signaling pathways are known to play essential roles in malignant transformation and progression of various tumours, including gastric cancer. Here, we identify that NKX6 transcription factor, locus 3 (NKX6.3) binds directly to specific promoter regions of Wnt/â-catenin and Rho-GTPase pathway-related genes, resulting in inhibition of cancer cell migration and invasion. Additionally, we find that the expression level of NKX6.3 is involved in regulation of gastric cancer progression and expression of Wnt/â-catenin and Rho-GTPase pathway-related genes in clinical samples. These results suggest that NKX6.3 prevents EMT and cell migration, implying that NKX6.3 inactivation might be one of the key mechanisms of gastric cancer cell invasion and metastasis and might serve as a potential candidate for targeted gastric cancer therapy.
Citation Format: Jung Hwan Yoon, Won Suk Choi, Won Sang Park. The essential role of NKX6.3 in gastric cancer cell migration and invasion through targeting of Wnt/â-catenin and Rho-GTPase signaling pathways. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 711.
Abstract 712: Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome
Authors: Ollila Saara , Vaahtomeri Kari , Wong Iris , Laajanen Kaisa , Mäkelä. Tomi P. 
Published: July 2016

Abstract
Germline mutations in tumor suppressor kinase Lkb1 predispose to Peutz-Jeghers syndrome (PJS), with highly penetrant gastrointestinal polyposis and increased cancer risk. PJS polyps display abnormal growth of both stromal and epithelial cells. We have identified clonally expanding fibroblasts as the drivers of tumorigenesis in PJS mouse models by using Fsp1-Cre and Twist2-Cre mice to restrict Lkb1 deletion to stromal cells (unpublished), highlighting the importance of stromal-epithelial signaling in PJS tumorigenesis.
Here, we address the molecular mechanisms of the pathogenesis linked to stromal Lkb1 loss in PJS mouse models. Lkb1 is involved in tissue size control by inhibiting of mTORC1 pathway via AMPK (Shaw et al, Cancer Cell 2004) and by regulating Hippo pathway (Mohseni et al, Nat Cell Biol 2014). First, we investigated the involvement of Lkb1-AMPK-mTORC1 pathway in polyposis. We conditionally deleted both catalytic AMPKá subunits (á1 and á2) in mice using Fsp1-Cre. Surprisingly, Fsp1-Cre-AMPK mice did not develop any tumors by 17 months of age indicating that AMPK is not the critical mediator of Lkb1 tumor suppression in PJS. We next studied the Hippo pathway in polyps of PJS mouse models. Levels of Yap and Taz, the main downstream effectors of Hippo, were elevated in polyps as shown by Western blotting. Immunohistochemical staining revealed profound nuclear Yap/Taz localization indicating transcriptional activity in the stromal compartment throughout the polyps. In contrast, nuclear Yap/Taz staining in epithelial cells was only noted in a restricted polyp base stem cell zone. In addition, we performed RNA-seq analysis of the of Fsp1-Cre;Lkb1flox mouse polyps and noted shared gene expression changes with PJS patient polyps. RNA-seq also revealed significant enrichment of Yap signature, which was validated by qPCR. Finally, we used small intestinal epithelial organoid culture to study the potential of Yap/Taz induced secreted factors to stimulate growth of epithelial cells. We observed that Wnt5a and Epiregulin enhanced epithelial organoid growth, indicating them as candidates mediating the stromal-epithelial signaling and promoting tumorigenesis in PJS polyps.
In conclusion, we show that stromal Lkb1 mutations lead to phenotypes identical to germline Lkb1 heterozygosity in mice and propose increased stromal Yap/Taz activity as a potential mechanism to drive PJS tumorigenes.
Citation Format: Saara Ollila, Kari Vaahtomeri, Iris Wong, Kaisa Laajanen, Tomi P. Mäkelä. Mechanisms of stromal Lkb1 loss induced tumorigenesis in mouse models of Peutz-Jeghers syndrome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 712.