bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C29: Association of interferon-induced protein with tetratricopeptide repeats 1 gene family with human papilloma virus infection in patients with oral squamous cell carcinoma
Authors: Yen Ai-Hsin , Lai Kuo-chu , Chen Ying-Chen , Liu Chung-Ji , Chang Kuo-Wei , Lee Te-Chang 
Published: August 2014

Abstract
Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene family is one of most responsive interferon-stimulated gene families. Four members have been characterized in humans, namely, IFIT1, IFIT2, IFIT3, and IFIT5. The encoded proteins mediate a variety of protein—protein interactions by tetratricopeptide repeat helix-turn-helix motifs to modulate on cellular functions, such as translation initiation, double-stranded RNA-induced signaling, cell proliferation and migration. We have previously demonstrated that IFIT2 silencing activates atypical PKC signaling and induces epithelial-mescenchymal transition (EMT), cell migration, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells in cultured or animal models. Our results also showed that IFIT2 is potentially a prognosis biomarker of patients with OSCC. In the present study, we further explore the roles of IFIT1 family proteins involved in the regulatory mechanism of metastasis in OSCC cells. We first confirmed that the proteins of various IFIT1 family members are significantly induced by interferon in a dose-dependent manner. We further characterized the expression of IFIT1, IFIT3, and IFIT5 proteins in patients with OSCC. Our present results revealed that most OSCC tumor tissues expressed a variety of amounts of IFIT2 proteins by immunohistochemical analysis. Although the expression levels of IFIT1 and IFIT3 were relatively lower than IFIT2, we observed a close association between IFIT1 and IFIT3 protein expression in OSCC patient-derived tumor specimens. Numerous studies have pointed out that human papillomavirus (HPV) infection is associated with a high risk of oral cancer. Among these 4 IFIT1 family members, we preliminarily demonstrated a well correlation between HPV E6 and IFIT5 protein expression in tumor specimens of OSCC patients, implying a critical role of IFIT5 in response of HPV infection. Accordingly, our present studies implicate that all IFIT1 family are activated by interferon but each member apparently participates in different cellular activities. Their roles involving in OSCC metastasis warrant our further investigation.
Citation Format: Ai-Hsin Yen, Kuo-chu Lai, Ying-Chen Chen, Chung-Ji Liu, Kuo-Wei Chang, Te-Chang Lee. Association of interferon-induced protein with tetratricopeptide repeats 1 gene family with human papilloma virus infection in patients with oral squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C29.
Abstract C30: Resistance to fluid shear stress is a conserved biophysical property of malignant cells
Authors: Barnes James Matthew , Nauseef Jones T. , Henry Michael D. 
Published: August 2014

Abstract
During metastasis, cancer cells enter the circulation in order to gain access to distant tissues, but how this fluid microenvironment influences cancer cell biology is poorly understood. A longstanding view is that circulating cancer cells derived from solid tissues may be susceptible to damage from hemodynamic shear forces, contributing to metastatic inefficiency. However, there have been few efforts to directly test this hypothesis. Here we report that compared to non-transformed epithelial cells, transformed cells are remarkably resistant to fluid shear stress (FSS) in a microfluidic protocol, exhibiting a biphasic decrease in viability when subjected to a series of millisecond pulses of high (750-6,300 dyn/cm2) FSS. We show that magnitude of FSS resistance is influenced by several oncogenes including myc, ras, and PI3K; is an adaptive and transient response triggered by reparable plasma membrane damage; and requires extracellular calcium and actin cytoskeletal dynamics, including the activity of Rho kinase. This novel property of malignant cancer cells may facilitate hematogenous metastasis and indicates, contrary to expectations, that cancer cells are quite resistant to destruction by hemodynamic shear forces.
Citation Format: James Matthew Barnes, Jones T. Nauseef, Michael D. Henry. Resistance to fluid shear stress is a conserved biophysical property of malignant cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C30.
Abstract C31: Downregulation of IL-12 through IL-6 production increased cancer metastasis after radiotherapy
Authors: Seong Jinsil , Lee Eun Jung , Jeong Keun Young 
Published: August 2014

Abstract
Radiotherapy (RT) is a potent antitumor modality. However, unwanted effect is also reported such as increased metastasis through complex molecular mechanism including cytokines. Cytokines are soluble messengers that directly stimulate immune cells and stromal cells at the tumor site and enhance cancer cells recognition by immune cells. Numerous studies have investigated that cytokines have anti-tumor efficacy for cancer therapy. In this study, we investigated levels of 6 cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12 and TNF-α) in serum of before and after RT of HCC patients treated with RT and evaluate its significance in relation to clinical outcome. As a result, intrahepatic metastasis out of RT field increased in patients with IL-12 decreas after RT (p = 0.043).
IL-12 is an inflammatory cytokine that induces interferon-γ production from Th1 and NK cells. IL-12 mainly produced from antigen presenting cells as dendritic cells (DCs) which against many tumors is probably the result of its stimulatory effects on cell mediated immune responses.
Therefore, we investigated anti-tumor and anti-metastatic effects of mesenchymal stem cells expressing IL-12 (MSC/IL-12) treatment with ionizing radiation (IR) in murine hepatic cancer (HCa-1) model. Tumor bearing syngenic mice were treated with IR, MSC/IL-12 or combination of both. Combination of MSC/IL-12 and IR resulted in suppression of lung metastasis as well as significantly growth delay of Hca-1. Especially, expressions of CD4, CD8 and CD11C were increased in tumors of MSC/IL-12 and IR treated group compared with only IR.
Also, to understand the detailed mechanism on anti-tumor effect of IL-12 in IR treated HCC, splenocyte were irradiated with 2, 5 Gy and measured IL-6 and IL-12 by ELISA after cultured. As results, IL-6 significantly increased by IR, while IL-12 increased at 1 day but it was decreased in dose dependent manner at 3days. These results indicated that IL-12 production could be mediated by IL-6 signaling. To prove that, DCs were irradiated with 5 and 10 Gy in presence or absence of LPS after differentiated from mice bone marrow and analyzed expressions of CD80 and 86 by FACS. The expression of CD80 and 86 decreased in irradiated-DCs comparing to no-irradiated DCs. Also, LPS-induced expressions of CD 80, 86 and IL-12 increased in α-IL-6 treated DCs compared with no-treated DCs.
Taken together, diminishing IL-12 via IL-6 production by IR seems to increase the treatment failure after radiotherapy in hepatocellular carcinoma.
Citation Format: Jinsil Seong, Eun Jung Lee, Keun Young Jeong. Downregulation of IL-12 through IL-6 production increased cancer metastasis after radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C31.
Abstract C44: Activation of focal adhesion kinase by direct interaction with β4 integrin in an EGFR-Src-dependent pathway in tumor progression
Authors: Tai Yu-Ling , Shen Tang-Long 
Published: August 2014

Abstract
Although β4 integrin and FAK (focal adhesion kinase) are individually known to be associated with tumor progression, only recently have they been suggested to function in a signaling axis. Here, we demonstrate in vivo and in vitro physical and functional interactions between β4 integrin and FAK. An 11-amino acid motif of FAK was identified as essential for interaction with the cytodomain of β4 integrin in malignant cells but not in less malignant cells, implicating the role of this interaction in malignancies. Furthermore, this interaction occurs in an adhesion-dependent manner and results in autophosphorylation of FAK's Tyr-397. EGF signaling and Src activity were indispensable for this interaction. Finally, disruption of the β4 integrin/FAK complexes reduced cell proliferation, migration and invasion as well as tumorigenesis, in concurrence with the decreases in phospho-Akt and phospho-p38. Together, our data elucidate an underlying mechanism for the regulation of tumor progression by the novel β4 integrin/FAK complexes through a physical interaction that is EGF/Src dependent. The significance of this finding is highlighted by often co-overexpression of both integrin β4 and FAK in patients' cancerous tissues with colon cancer revealed by immunohistochemistry analyses. Based on the structural prediction for the complex of integrin β4 and FAK, it may lead us to gain more insight on the anticancer therapies of aggressive cancers.
Citation Format: Yu-Ling Tai, Tang-Long Shen. Activation of focal adhesion kinase by direct interaction with β4 integrin in an EGFR-Src-dependent pathway in tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C44.
Abstract C49: Tissue tranglutaminase regulates β-catenin signaling in ovarian cancer cells
Authors: Condello Salvatore , Cao Liyun , Matei Daniela 
Published: August 2014

Abstract
Background: Tissue transglutaminase (TG2) is a multifunctional enzyme involved in protein crosslinking and cell adhesion to fibronectin (FN). In cancer, TG2 induces epithelial-to-mesenchymal transition (EMT) contributing to metastasis. As cadherins bind β-catenin at cell-cell junctions, disruption of adherens junctions destabilizes cadherin-catenin complexes. The goal of the present study was to analyze whether and how TG2 interacts with and regulates β–catenin signaling in ovarian cancer (OC) cells.
Methods: Western blotting, immuno-fluorescence and immunohistochemistry measured TG2 and β-catenin expression in OC cells and human tumors. B-catenin function was analyzed by TCF/LEF1 promoter reporter assay and Q-RT-PCR based quantification of mRNA levels for target genes (c-myc and cyclin D1). Protein-protein interaction was analyzed by co-immunoprecipitation and confocal microscopy. Cell proliferation was measured by MTT assay.
Results: We observed a significant correlation between TG2 and β-catenin expression levels in OC cells and tumors. TG2 augmented Wnt/β-catenin signaling, as evidenced by enhanced β-catenin transcriptional activity, inducing transcription of target genes cyclin D1 and c-Myc. By promoting integrin-mediated cell adhesion to FN, TG2 associates with and recruits c-Src, which in turn phosphorylates β-catenin at Tyr654, releasing it from E-cadherin, and rendering it available for transcription regulation. Ultimately the TG2—FN interaction stimulates OC cell proliferation by enhancing β-catenin signaling.
Conclusions: Our data show that TG2 regulates β-catenin expression and function in OC cells and define a c-Src dependent mechanism through which this occurs. We posit that the TG2-FN interaction initiates this process and could be a new cancer target.
Citation Format: Salvatore Condello, Liyun Cao, Daniela Matei. Tissue tranglutaminase regulates β-catenin signaling in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C49.
Abstract C5: Study of the relationship between RAR-beta2 hypermethylation and invasive esophageal squamous cell carcinoma
Authors: Wu Ruei-Siang , Yu Chun-Chieh , Li Yue-Yuah , Wu Ming-Tsang , Li Ruei-Nian 
Published: August 2014

Abstract
Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer death among men in Taiwan, and the five-year survival rate is below 10%. The retinoic acid receptor beta2 (RAR-beta2) is frequently deleted or silenced at early stages in tumor progression. Most of RAR-beta2 repressions was associated with promoter hypermethylation in several epithelial carcinomas. The aim of this study is to investigate RAR-beta2 promoter methylation status in different stages of ESCC patients. Through methylation-specific PCR analysis, methylation rate of RAR-beta2 was 21.1% (15/71) in tumor cases, but unmethylated in all normal counterparts. In RAR-beta2 promoter hypermethylation cases, the methylation frequency of lymph nodes invasion and tumor metastasis was twofold increased. Moreover, RAR-beta2 promoter methylation frequency was increased with 14.7% and showed significant decrease survival rate in advanced stage. Esophageal cancer cell lines 81T, 81T 1-1 and 81T 1-4 were treated with 5-aza-dC (DNA methylation inhibitor), the level of RAR-beta2 methylation was decreased in all ESCC cell lines. Moreover, migration ability was inhibited in 81T cell line. The migration ability of 81T 1-1 and 81T 1-4 cell lines were decreased about 50%. Our findings indicate that RAR-beta2 hypermethylation in ESCC could be useful for prognosis marker. RAR-beta2 methylation may become one of the clinical therapy targets and invasion-migration markers.
Citation Format: Ruei-Siang Wu, Chun-Chieh Yu, Yue-Yuah Li, Ming-Tsang Wu, Ruei-Nian Li. Study of the relationship between RAR-beta2 hypermethylation and invasive esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C5.
Abstract C51: c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion, proliferation, survival, and drive metastatic progression
Authors: Ganguly Sourik S. , Fiore Leann S. , Sims Jonathan T. , Friend J Woodrow , Srinivasan DivyaMani , Thacker Matthew , Cibull Michael L. , Chi Wang , Plattner Rina 
Published: August 2014

Abstract
Despite 40 years of clinical trials, there has been little improvement in one-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for Abl kinases in melanoma progression. We demonstrate that Abl kinases (c-Abl, Arg) are activated in human melanoma cell lines, in primary melanomas (60%), and in a subset of benign nevi (33%). Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is required for melanoma cell proliferation, survival, matrigel-invasion and single-cell 3D invasion. Moreover, active c-Abl transcriptionally upregulates MMP-1, and using rescue approaches we show that c-Abl promotes invasion via a STAT3-MMP-1 pathway. Conversely, active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Paradoxically, c-Abl and Arg also increase expression of TIMP-1, a negative regulator of MMPs, both at the transcript and protein level via a STAT3-dependent pathway. In addition to negatively regulating MMPs, TIMPs also have anti-apoptotic functions, and high TIMP-1 expression is correlated with decreased survival and a poor clinical outcome in breast and colon cancer patients. Currently, we are in the process of testing whether c-Abl and Arg promote survival via induction of TIMP-1. Most importantly, we found that Abl kinases not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg with nilotinib dramatically inhibits lung colonization/metastasis in a mouse model using two different melanoma cell lines. Taken together, these data identify Abl kinases as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may useful in preventing metastasis in patients with melanomas harboring active Abl kinases.
Citation Format: Sourik S. Ganguly, Leann S. Fiore, Jonathan T. Sims, J Woodrow Friend, DivyaMani Srinivasan, Matthew Thacker, Michael L. Cibull, Wang Chi, Rina Plattner. c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion, proliferation, survival, and drive metastatic progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C51.
Abstract C54: Characterization of HGF-mediated EMT and its inhibition with novel HGF pathway inhibitors using transcriptomic analysis
Authors: Tuttle Kevin J. , Burton Jason , Johnson W Evan , Hansen Marc DH 
Published: August 2014

Abstract
The ability of cancer cells to detach from their neighbors, invade through local tissues, and establish distant metastases is a major contributor to cancer mortality. Epithelial-mesenchymal transition (EMT) describes a developmental process by which cells break cell-cell adhesions and gain motility. Interestingly, cells generated by EMT also bear stem cell properties and are more resistant to chemotherapeutics. EMT is triggered by a number of cellular signaling pathways, including via hepatocyte growth factor. Inappropriate signaling in epithelial tumors is thought to drive EMT, facilitating cancer metastasis. A common feature is the activation of a number of transcriptional programs. Here we report the results of transcriptomic studies that are designed to characterize transcriptional changes in cells undergoing EMT in response to HGF stimulation. MDCK cells, a normal epithelial cell line, were stimulated with HGF for different amounts of time under otherwise identical culture conditions. Since cell substrate composition affects the robustness of the HGF response, we performed this experiment on cells grown on different extracellular matrices in an attempt to better understand how cellular substrates provide context to HGF signaling. Triplicate samples of mRNA were generated from these cultures for transcriptomic sequencing and analysis. Each sample generated 20-40 million sequence reads that were assembled into known and de novo (novel) transcripts using Tuxedo Suite, allowing detection of differential transcript expression by cummeRbund and edgeR. Many of the differentially expressed genes correlated well to known cancer pathways. HGF signaling is widely accepted to play an important role in cancer progression and to be an important target for development of novel therapeutics. We previously identified a series of novel HGF pathway inhibitors using a phenotypic screening approach. Compounds were subjected to analysis of their structure-activity relationship, in vivo toxicity, and pharmacokinetic profiles. Compounds that block EMT without affecting proliferation were applied to MDCK cells prior to HGF stimulation and mRNA samples generated from these cultures. We report how these inhibitors alter the transcriptional response of MDCK cells to HGF stimulation, providing a molecular basis for how these inhibitors prevent EMT.
Citation Format: Kevin J. Tuttle, Jason Burton, W Evan Johnson, Marc DH Hansen. Characterization of HGF-mediated EMT and its inhibition with novel HGF pathway inhibitors using transcriptomic analysis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C54.
Abstract C55: Detachment of epithelial cells is driven by myosin-based contractility and RhoA
Authors: Hoj Jacob Peter , Fullmer Kendra , Davis John , Morrell David , Hansen MDH 
Published: August 2014

Abstract
Metastasis requires shedding and migration of individual cells from the tumor. In tumors of epithelial origin, cells often maintain strong cell-cell interactions that must be disassembled prior to cell detachment. Remodeling of cell-cell adhesions occurs during epithelial-mesenchymal transition (EMT), a developmental process where individual cells are triggered to detach and migrate to distant sites by developmental signaling programs. It is thought that inappropriate activation of EMT drives metastasis, particularly by allowing detachment and migration of cancer cells. While much is known about migration and invasion, how cell-cell junctions are detached remains poorly understood. Here we sought to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/ scatter factor-induced EMT. We find that HGF signaling actually increases cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion are not enough to drive epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role. Cell-substrate adhesion increases upon HGF stimulation and alterations in the pliability of the subtratum alter cells' ability to undergo scattering. Interestingly, scattering is impaired in cells expressing both active and inactive RhoA mutants. While this also indicates a role for important changes in cell-substrate adhesion during cell-cell detachment, RhoA also affects myosin-based contractility. We sought to examine how myosin-based contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely initiation of cell spreading and an inability to rupture cell-cell adhesions in response to HGF treatment. Interestingly, when cell spreading is induced by transient treatment of cells with blebbistatin, blebbistatin washout results in cellular events that closely resemble HGF-induced epithelial scattering. This suggests that global suppression and subsequent induction of myosin II activity may be sufficient to rupture cell-cell adhesions. Such experiments also suggest a role for RhoA, as blebbistatin-induced scattering is not fully completed in cells expressing a dominant-negative RhoA mutant. Taken together, these results suggest that cell-cell detachment is controlled by contractility, with a contribution by RhoA-mediated changes in cell adhesion.
Citation Format: Jacob Peter Hoj, Kendra Fullmer, John Davis, David Morrell, MDH Hansen. Detachment of epithelial cells is driven by myosin-based contractility and RhoA. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C55.