bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1674: Tripartite motif containing 28 (TRIM28) promotes breast cancer metastasis by stabilizing TWIST1 protein
Authors: Wei Chunli , Cheng Jingliang , Chen Hanchun , Zhang Dianzheng , Fu Junjiang 
Published: July 2016

Abstract
Regulation of gene expression by TRIM28 is not only by transcriptional repression but also by post-translational regulation. Here we report that TRIM28 promotes breast cancer cell metastasis through TRIM28-TWIST1-EMT pathway. We find that TRIM28 is highly expressed in metastatic cancer cell lines and advanced breast cancer tissues. The expression of TRIM28 and TWIST1 is positively correlated with most of the invasive breast carcinomas. Notably, we find that overexpression of TRIM28 upregulates TWIST1 protein, whereas TRIM28 depletion downregulates TWIST1 protein, indicating that TWIST1 upregulation likely occurs at post-transcriptional level, not at transcriptional level. Overexpression of TRIM28 in BT549 breast cancer cell line promotes cell migration and invasion functionally; conversely, knockdown of TRIM28 reduces TWIST1 protein level, up-regulates E-cadherin and down-regulates N-cadherin, and consequently inhibits cell migration and invasion. Furthermore, Immunoprecipitation and GST pull down reveal that TRIM28 interacts with TWIST1 directly, thereby preventing from proteasomal degradation. Moreover, TWIST1 degradation rate is reduced after cycloheximide blocking protein synthesis through the depletion of TRIM28 in BT549 cells. Taken together, our findings suggest that TRIM28 functionally stabilizes TWIST1 protein, reveals a novel mechanism, and provides an effective therapeutic strategy to target TRIM28 in breast cancer treatments.
Citation Format: Chunli Wei, Jingliang Cheng, Hanchun Chen, Dianzheng Zhang, Junjiang Fu. Tripartite motif containing 28 (TRIM28) promotes breast cancer metastasis by stabilizing TWIST1 protein. [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 1674.
Abstract 1677: CLCA2 interaction with EVA1 promotes mammary epithelial differentiation
Authors: Ramena Grace N.T. , Yin Yufang , Yu Yang , Walia Vijay , Elble Randolph C. 
Published: July 2016

Abstract
CLCA2 is a p53-, p63-inducible transmembrane protein that is frequently downregulated in breast cancer. It is induced during differentiation of human mammary epithelial cells, and its knockdown causes epithelial-to-mesenchymal transition (EMT). To determine how CLCA2 promotes epithelial differentiation, we searched for interactors using membrane dihybrid screening. We discovered a strong interaction with the cell junctional protein EVA1 (Epithelial V-like Antigen 1) and confirmed it by co-immunoprecipitation. Like CLCA2, EVA1 is a type I transmembrane protein that is regulated by p53 and p63. It is thought to mediate homophilic cell-cell adhesion in diverse epithelial tissues. We found that EVA1 is frequently downregulated in breast tumors and breast cancer cell lines, especially those of mesenchymal phenotype. Moreover, knockdown of EVA1 in immortalized HMEC caused EMT, implying that EVA1 is essential for epithelial differentiation. Both EVA1 and CLCA2 co-localized with E-cadherin at cell-cell junctions. The interacting domains were delimited by deletion analysis, revealing the site of interaction to be the transmembrane segment (TMS). The TMS primary sequence of CLCA2 was found to be conserved throughout mammals. Moreover, competitive inhibition of the interaction by ectopic expression of the TMS caused partial EMT, suggesting that the interaction is important for differentiation. A screen for other junctional interactors revealed that CLCA2 was involved in two different complexes, one with EVA1 and ZO-1, the other with beta catenin. Overexpression of CLCA2 caused downregulation of beta catenin and beta catenin-activated genes. Thus, CLCA2 links a junctional adhesion molecule to cytosolic signaling proteins that modulate proliferation and differentiation. These results may explain how attenuation of CLCA2 causes EMT and why CLCA2 and EVA1 are frequently downregulated in metastatic breast cancer cell lines.
Citation Format: Grace N.T. Ramena, Yufang Yin, Yang Yu, Vijay Walia, Randolph C. Elble. CLCA2 interaction with EVA1 promotes mammary epithelial differentiation. [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 1677.
Abstract 1679: Notch4 mediates mesenchymal-epithelial-like transition in melanoma
Authors: BonyadiRad Ehsan , Hammerlindl Heinz , Ravindran Menon Dinoop , Hafner Christine , Herlyn Meenhard , Schaider Helmut 
Published: July 2016

Abstract
In melanoma Notch signaling is a well-established oncogenic factor and presumably driver of disease progression. Here we report that overexpression of the constitutively active intracellular domain of Notch4 (N4ICD) directs a mesenchymal-epithelial-like transition that results in an epithelial, low migratory, invasive and proliferative phenotype with decreased tumorigenicity in-vivo. Investigating the expression profile of 50 EMT markers in N4ICD overexpressing cells revealed an epithelial-like gene signature with major EMT markers, including Vimentin, MMP2, Snail1, Snail2 and Twist1, significantly decreased and several epithelial markers, including E-cadherin, Desmoplakin and Occludin significantly increased. N4ICD suppresses the expression of Snail2 and Twist1 in a non-canonical fashion by inducing transcription factors Hey-1 and Hey-2 which directly bind to promoter regions of Snail2 and Twist1 as determined by EMSA and luciferase assays. N4ICD overexpression also results in increased beta-catenin protein levels exclusively limited to the cytoplasm. Immunohistochemical stainings of primary melanomas and subcutaneous metastasis showed a correlation between Notch4, E-cadherin and beta-catenin expression. Our results demonstrate that overexpression of Notch4 ICD results in the emergence of an epithelial-like phenotype with increased E-cadherin and cytoplasmic beta catenin potentially steering the reformation of adherens junctions. This indicates that Notch4 supports a mesenchymal-epithelial-like transition trapping cancer cells in a low proliferative, invasive and migratory epithelial state, suggesting Notch4 to be a tumor suppressor in melanoma.
Citation Format: Ehsan BonyadiRad, Heinz Hammerlindl, Dinoop Ravindran Menon, Christine Hafner, Meenhard Herlyn, Helmut Schaider. Notch4 mediates mesenchymal-epithelial-like transition in melanoma. [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 1679.
Abstract 1681: DUOX1 expression in lung cancer disrupts pro-oncogenic activation mechanisms and localization of Src and EGFR
Authors: Little Andrew C. , Danyal Karamatullah , Bauer Robert A. , Heppner David E. , Hristova Milena , Dustin Christopher , Habibovic Aida , van der Vliet. Albert 
Published: July 2016

Abstract
Non-small cell lung cancer (NSCLC) remains to be one of the leading causes of cancer-related mortalities worldwide. The NADPH oxidase homolog, Dual Oxidase 1 (DUOX1), is an H2O2 producing enzyme located in the airway epithelium with key roles in mucosal host defense and wound repair mechanisms. Recent studies indicate that DUOX1 is epigenetically silenced in many forms of NSCLC via hypermethylation of its promoter. We previously demonstrated that DUOX1 silencing in lung cancer cells is associated with epithelial-to-mesenchymal transition (EMT), a key feature of tumor invasiveness and metastasis, and that RNAi-mediated DUOX1 suppression can promote EMT, but the mechanism(s) by which DUOX1 silencing promotes these outcomes are not understood. Previous findings indicate that DUOX1-dependent epithelial host defense pathways are mediated by redox-dependent activation of epithelial signaling via the non-receptor tyrosine kinase, Src, and the receptor tyrosine kinase, EGFR. We therefore hypothesized that loss of DUOX1 in lung cancer may be associated with aberrant regulation of Src and/or EGFR, tyrosine kinases that are frequently overexpressed and activated in lung cancer and strongly contribute to tumor growth and survival. Furthermore, nuclear Src/EGFR localization and phosphorylation of EGFR-Y1101 in lung cancers was recently associated with metastatic cell behavior and poor clinical outcome. Preliminary findings in alveolar lung cancer A549 cells, which possesses some EMT-like features, indicate that DUOX1 overexpression redistributes Src localization to the plasma membrane and decreases its nuclear accumulation. Moreover, DUOX1 overexpression in A549 cells also suppressed EGF-stimulated EGFR internalization and nuclear translocation, in association with reduced EGFR phosphorylation on its Src target, Y1101. Conversely, RNAi-mediated silencing of DUOX1 in the epithelial cancer cell line H292 (which has retained DUOX1 expression) promoted EGF-mediated EGFR nuclear translocation and Y1101 phosphorylation. Further mechanistic studies will be performed to elucidate the molecular mechanisms by which DUOX1 is able to alter these events. Collectively, our findings indicate that DUOX1 silencing in lung cancer may contribute to EMT and/or tumor invasiveness by altering Src/EGFR localization and activation mechanisms.
Citation Format: Andrew C. Little, Karamatullah Danyal, Robert A. Bauer, David E. Heppner, Milena Hristova, Christopher Dustin, Aida Habibovic, Albert van der Vliet. DUOX1 expression in lung cancer disrupts pro-oncogenic activation mechanisms and localization of Src and EGFR. [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 1681.
Abstract 1683: Dual role of semaphorin5A in maintaining epithelial and mesenchymal phenotype in metastatic pancreatic cancer
Authors: Saxena Sugandha , Purohit Abhilasha , Varney Michelle , Batra Surinder K. , Singh Rakesh K. 
Published: July 2016

Abstract
Pancreatic cancer (PC) is a highly aggressive disease and in general has metastasized to distant organs by the time of its clinical diagnosis. Poor five-year survival rate of 7% with an average survival time of 5-8 months highlight the gravity of the situation and necessitate a better understanding of the molecules and mechanisms that lead to metastatic dissemination in PC. One of the key processes that lead to metastasis is the gain of cellular migration ability. Previous reports from our laboratory have identified semaphorin5A (SEMA5A), an axon guidance cue molecule regulating cellular migration, as a putative cell adhesion molecule which is involved in organ-specific homing during PC metastasis. Also, differential expression of SEMA5A was observed in cells derived from metastatic sites in comparison to those arising from primary tumors. On the basis of the these findings, we hypothesize that SEMA5A regulates epithelial to mesenchymal changes necessary to drive cellular migration and further leads to establishment of these cells at secondary sites. We utilized various cellular models such as the L3.3 and L3.6pl cell lines with different metastatic potential, cell lines derived from metastatic sites (Capan-1 and CD18/HPAF) with stable knock down of SEMA5A, and cell lines derived from primary tumors (Panc1) with overexpression of SEMA5A. We evaluated epithelial and mesenchymal markers, in vitro cellular migration and the metastatic potential of these cells. We observed down regulation of E-cadherin expression and re-localization of beta-catenin from the membrane to the nucleus in SEMA5A knockdown cells. Similarly, overexpression of SEMA5A in Panc1 cells resulted in higher E-cadherin expression. We also observed higher SEMA5A and E-cadherin expression in the highly metastatic L3.6pl cells in comparison with L3.3 cells. Furthermore, knock-down SEMA5A in Capan-1 cells resulted in enhanced in vitro cellular migration and higher metastasis when control or SEMA5A knockdown cells were orthotopically implanted in nude mice. Our observations suggest that SEMA5A plays a bi-functional role in mediating epithelial to mesenchymal transition at primary site while regulating mesenchymal to epithelial transition and establishment at secondary sites.
Citation Format: Sugandha Saxena, Abhilasha Purohit, Michelle Varney, Surinder K. Batra, Rakesh K. Singh. Dual role of semaphorin5A in maintaining epithelial and mesenchymal phenotype in metastatic pancreatic 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 1683.
Abstract 1684: Mesothelin regulates epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells
Authors: He Xiaoqing , Wang Liying , Despeaux Emily , Rojanasakul Yon 
Published: July 2016

Abstract
Lung cancer and malignant mesothelioma are two of the most deadly forms of cancers. The prognosis of lung cancer and mesothelioma is poor due to limited treatment modalities and lack of understanding of the underlying disease mechanisms. Mesothelin (MLSN), a plasma membrane differentiation antigen, is expressed at a high level in several human cancers, including 70% of lung cancer and nearly all mesotheliomas. Recent studies have shown that plasma and/or pleural effusion MSLN may be used as a biomarker for certain cancers and malignant pleural mesothelioma. However, the role of MLSN in lung cancer and mesothelioma is relatively unknown. In this study, we found that MLSN plays an important role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung epithelial and mesothelial cells, which control their tumorigenicity. Firstly, MLSN was found to be highly upregulated in human non-small cell lung cancer tissues and in lung cancer and mesothelioma cells, as compared to normal tissues and non-tumorigenic lung epithelial and mesothelial cells. Secondly, knockdown of MLSN by RNA interference significantly reduced anchorage-independent cell growth, tumor sphere formation, and cell migration and invasion in vitro, as well as tumor formation in vivo. Thirdly, knockdown of MLSN attenuated cancer stem cell marker (ALDH) activity and several EMT markers in lung cancer and mesothelioma cell lines. These findings indicate the essential role of MLSN in EMT and malignant properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, our finding on the role of MLSN may provide new insights into the disease mechanisms and treatment strategies for aggressive lung cancer and mesothelioma.
Citation Format: Xiaoqing He, Liying Wang, Emily Despeaux, Yon Rojanasakul. Mesothelin regulates epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. [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 1684.
Abstract 1687: KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A
Authors: Kim Min-Young , Shin Jung-Young , Kim Jeong-Oh , Son Kyoung-Hwa , Kang Jin Hyoung 
Published: July 2016

Abstract
Background & Purpose
In recent, KIF5B-RET gene rearrangement has been discovered as a driver oncogene in non-small cell lung cancers. This fusion gene was demonstrated to be able to induce tumorigenesis in vivo mouse model. Hereby, we investigated how KIF5B-RET fusion gene affect tumor differentiation and which transcription factors and signaling pathway are activated.
Methods
We analyzed cell proliferative activity in transformed HEK293T cells with KIF5B-RET fusion gene (K4) and empty vector (V5) using CCK8 assay. We used light microscopy and H&E staining to observe morphological changes of transformed cells. We evaluated protein and mRNA expressions of four EMT markers (E-cadherin, N-cadherin, Snail, and Twist) and two transcription factors (FOXA2, p-STAT5A) using transcription factor PCR array, Western blot, RT-PCR, immunofluorescence staining.
Results
K4 cells showed decreased cell proliferative activity compared with V5 cells. V5 cells had spreading pattern alike mesenchymal phenotype when their density was lower. However, their morphology changed to epithelial phenotype as they were overgrown with higher density. On the other hands, K4 cells exhibited the island growing pattern similar to epithelial phenotype in lower density of tumor cells, but changed to mesenchymal phenotype as the density of tumor cells gradually increased. On H&E staining, the cytoplasm of K4 cells was much smaller than that of V5 cells. We observed that E-cadherin mRNA was down-regulated, but N-cadherin and Twist were up-regulated in K4 cells. Based on the results of repeated screening assay, we finally selected two transcription factors, FOXA2 and STAT5A, which were significantly overexpressed in K4 cells. In K4 cells, phosphorylated-STAT5A was increased and FOXA2 was decreased compared to V5 cells. In addition, the expression of E-cadherin was reduced, but p-GSK3β, p-AKT, and p-ERK were markedly increased in K4 cells. The pattern of immunofluorescence staining of V5 and K4 cells were similar to the protein expressions of E-cadherin and p-STAT5A in Western blot analysis.
Conclusion
Taken together, FOXA2 and E-cadherin are down-regulated and p-STAT5A is up-regulated in HEK-293T cells stably expressing the KIF5B-RET. Our data suggest that KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A.
Citation Format: Min-Young Kim, Jung-Young Shin, Jeong-Oh Kim, Kyoung-Hwa Son, Jin Hyoung Kang. KIF5B-RET fusion gene may induce EMT via the regulation of two transcription factors, FOXA2 and STAT5A. [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 1687.
Abstract 1699: Protumoral role of trans fatty acid in colorectal cancer
Authors: Ohmori Hitoshi , Kuwai Toshio , Kitadai Yasuhiko , Fujii Kiyomu , Fujiwara Rina , Nishiguchi Yukiko , Sasahira Tomonori , Kuniyasu Hiroki 
Published: July 2016

Abstract
Trans fatty acids (TFAs) is a recent focus of health problems. TFA is a definitive risk factor for cardiovascular diseases and the death. TFA is also possible risk factor for Alzheimer's disease, obesity, diabetes, fatty liver, and ovulation infertility. Relation of TFA with carcinogenic risk is controversy; however, TFA is reported to increase the risk of breast cancer and prostate cancer. Elaidic acid (EA), a trans form of oleic acid, enhances cancer cell growth, invasion, and anti-apoptotic survival. By animal models, EA promotes tumor growth and metastasis to the lung, liver, and peritoneum. EA induces stemness in cancer cells through transactivation of EFGR via SRC from GPR40/120 as receptors in EA-integrated cholesterol raft. Activated EGFR relays the signals to activate canonical and non-canonical wnt pathway and to inactivate notch1 pathways. EA also increases miR-494, which inhibits cell differentiation through decrease of target genes. Continuous EA feeding with dosage alteration increased cancer cell stemness. EA diminishes the efficiency of 5-fluorouracil by increase of residual cancer stem cells. These findings suggest that TFA is a relevant cancer promoting factor. Decision of removal of TFA from foods by FDA might provide an impact to cancer clinics.
Citation Format: Hitoshi Ohmori, Toshio Kuwai, Yasuhiko Kitadai, Kiyomu Fujii, Rina Fujiwara, Yukiko Nishiguchi, Tomonori Sasahira, Hiroki Kuniyasu. Protumoral role of trans fatty acid 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 1699.
Abstract 1712: Intestinal stem cell integrity is preserved through modulation of endoplasmic reticulum stress by guanylyl cyclase C
Authors: Kraft Crystal , Lin Jieru , Snook Adam , Kim Gilbert , Waldman Scott 
Published: July 2016

Abstract
Intestinal stem cells (ISCs) are a long-lived, dynamic cell population at the base of intestinal crypts that adjust their molecular phenotypes as necessary to meet the maintenance and regenerative needs of the epithelium. The long-life, plasticity and proliferative potential of ISCs underlie the necessity for tight regulation, as these cells have been implicated as initiators of colorectal tumorigenesis. In that context, guanylyl cyclase C (GCC) and its effector, cGMP, regulate intestinal epithelial proliferation, differentiation, and susceptibility to intestinal insult and tumor formation. However, the specific role of this signaling axis in ISCs remains undefined. Here, utilizing transgenic mouse models and immunodetection techniques, we reveal that GCC mediates ligand-dependent cGMP signal transduction in ISCs. Further, the absence of GCC alters expression of key ISC markers, decreasing the active ISC marker Lgr5 and increasing the reserve ISC marker Bmi1. Endoplasmic reticulum (ER) stress, which is typically absent from ISCs and has been associated with inflammation and tumorigenesis, is elevated throughout the crypt base in the absence of GCC. Conversely, administration of cGMP or the chemical chaperone taurourdeoxycholic acid eliminates ER stress and restores the normal crypt ISC phenotype. Finally, ISCs exhibit an impaired regeneration response following irradiation in the absence of GCC, highlighting the importance of this signaling pathway in ISC survival and epithelial repair. Together, these observations suggest that GCC signaling modulates ER stress as part of the essential machinery defending the integrity of the ISC niche.
Citation Format: Crystal Kraft, Jieru Lin, Adam Snook, Gilbert Kim, Scott Waldman. Intestinal stem cell integrity is preserved through modulation of endoplasmic reticulum stress by guanylyl cyclase C. [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 1712.