bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 906: PATZ1 promotes migration and invasion of thyroid cancer cells through upregulation of the activity of plasminogen activator and matrix metalloproteinases
Authors: Iesato Asumi , Nakamura Teruo , Uehara Tsuyoshi , Izumi Hiroto , Ito Ken-ichi 
Published: July 2017

Abstract
Background: PATZ1, a transcription regulator, has been reported to function as oncogene or tumor suppressor in several human malignant neoplasms. The aim of the study was to examine involvement of PATZ1 in carcinogenesis and progression of thyroid cancer.
Materials and methods: PATZ1 expression in 165 clinical thyroid specimens obtained from 87 patients were evaluated by IHC. We examined the function of PATZ1 using an immortalized normal thyroid follicular epithelial cell line (Nthy-ori 3-1), and four thyroid cancer cell lines; TPC-1 (papillary cancer), FTC-133 (follicular cancer), FRO and ACT-1 (anaplastic cancer). Knockdown of PATZ1 in Nthy-ori 3-1 and thyroid cancer cell lines was performed with siRNA-PATZ1, and overexpression of PATZ1 in thyroid cancer cell lines was performed with pcDNA3-FLAG-PATZ1.
Results: In the IHC analysis of clinical specimens, nuclear PATZ1 expression in anaplastic carcinoma was significantly less frequently than that in normal thyroid tissue or well-differentiated carcinoma (Table 1). Knockdown of PATZ1 in Nthy-ori 3-1 and differentiated thyroid cancer cell lines (TPC-1, FTC-133) induced morphological change of the cells and significant increase of cell proliferation and migration as well as moderate increase of invasion. Furthermore, the expression of u-PA, MMP2 and MMP11 was increased by inhibition of PATZ1 in TPC-1 and FTC-133. On the other hand, overexpression of PATZ1 in anaplastic cancer cell lines (FRO and ACT-1) decreased proliferation and migration of the cells along with the decreased expression of u-PA, MMP2, MMP9 and MMP11.
Conclusion: Our study suggests that PATZ1 might play an important role as a tumor suppressor in thyroid follicular epithelial cells and might be involved in progression of thyroid cancer.
Expression of nuclear PATZ1 in thyroid tumortypeNormal thyroid/ goiter (N=68)Follicular adenoma (N=5)Papillary cancer (N=39)Follicular cancer (N=8 )Poorly differentiated cancer (N=12)Anaplastic cancer (N=28)Medullary cancer (N=5)positive (%)68(100%)4(80.0%)35(89.7%)5(62.5%)7(58.3%)3(10.7%)4(80.0%)negative (%)0(0%)1(20.0%)4(10.3%)3(37.5%)5(41.7%)25(89.3%)1(20.0%)
Citation Format: Asumi Iesato, Teruo Nakamura, Tsuyoshi Uehara, Hiroto Izumi, Ken-ichi Ito. PATZ1 promotes migration and invasion of thyroid cancer cells through upregulation of the activity of plasminogen activator and matrix metalloproteinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 906. doi:10.1158/1538-7445.AM2017-906
Abstract 91: Molecular insight into drug resistance in acute myeloid leukemia: An in-silico and in-vitro approach
Authors: Desai Urja , Mirza Sheefa , Parikh Sonia , Rawal Rakesh 
Published: July 2017

Abstract
INTRODUCTION:
Drug resistance of leukemic stem cells is a surmountable obstacle to effective chemotherapy in acute myeloid leukemia (AML). P-glycoprotein (Pgp) and FLT3 undoubtedly contribute to worse prognosis and mechanisms of these proteins lead to shorter survival and chemotherapy resistance. Due to heterogeneity of stem cells in AML, outcome of patients with a normal karyotype is highly challenging and changes in drug resistance genes likely to be identified which will contribute to a better understanding of the disease biology, eventually leading to the development of alternative therapeutic approaches regarding drug resistance in AML.
METHODOLOGY:
Blood and Bone-marrow samples were collected from newly diagnosed adult AML patients with normal karyotype. Gene expression analysis of MDR genes like Pgp, MRP1, BCRP and LRP was done by qRT-PCR in FLT3-ITD+/- and CD34+/- subgroups. Higher expression of Pgp amongst all MDR genes instigated to undertake in-silico analysis of Pgp with natural compound library using YASARA. MTT assay was used to find out IC50 value of natural compounds shortlisted from in-silico analysis and used alone or with cytarabine on THP-1 cell line and in primary AML stem cells. Pgp inhibitory activity of natural compounds was assessed by fluorimetric MDR assay.
RESULTS:
A significant upregulation of Pgp expression was observed in FLT3-ITD+, CD34+ group after cytarabine exposure during their induction (7+3) therapy. Docking analysis revealed curcumin, hesperidin and silymarin having better binding affinity with Pgp as compared to its known inhibitor Verapamil. Furthermore, these selected compounds were used in-vitro, and results of MTT assay suggested 6.1µM, 40.73µM, 63.09µM and 54.95µM IC50 values of cytarabine, curcumin, hesperidin and silymarin respectively in THP-1 cell line. Combination index (CI) analysis revealed that curcumin (25µM), hesperidin (30µM) and silymarin (35µM) having synergistic effect with cytarabine and decreased IC50 value of cytarabine (1µM). In addition to this, Silymarin at 250nM and 500nM concentration showed equivalent inhibition of Pgp as compared to control Verapamil.
CONCLUSION:
A combination of in-silico and in-vitro screening revealed Curcumin, Hesperidin and Silibinin can be used as MDR modulators as well as chemosensitizer to reduce the cytotoxicity profile and drug resistance in AML.
Citation Format: Urja Desai, Sheefa Mirza, Sonia Parikh, Rakesh Rawal. Molecular insight into drug resistance in acute myeloid leukemia: An in-silico and in-vitro approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 91. doi:10.1158/1538-7445.AM2017-91
Abstract 911: Destabilizing β-catenin and Ras could be an ideal therapy for treating metastatic colorectal cancer
Authors: Cho Yong-Hee , Yoon Jeong-Soo , Choi Kang-Yell 
Published: July 2017

Abstract
INTRODUCTION Aberrant activations of Wnt/β-catenin and Ras signaling pathways by APC (90%) and K-Ras (40-50%) mutations are closely interacted and accelerate CRC tumorigenesis. Protein level of β-catenin as well as Ras is increased by APC loss via inhibiting GSK3B-mediated poly-ubiquitination dependent Ras degradation through recruitment of β-TrCP E3 linker. Moreover, additional K-Ras mutation results in the liver metastasis by secondary activation of the Wnt/β-catenin signaling pathways via Ras-ERK and -AKT pathways in addition to the initial activation by APC loss. Consequently, both β-catenin and Ras were highly increased in human CRC patient tissues, especially in metastatic tumor.
EXPERIMENT PROCEDURES To investigate the synergistic effects of aberrant Wnt/β-catenin and Ras signaling pathways on tumor development to metastasis, we established the APCMin/+/K-RasG12DLA2 compound mouse that harbor APC and K-Ras mutations in animal model. We also analyzed Ras protein level using human CRC patient tissues of normal mucosa and adenocarcinoma (N=24) and metastatic adenocarcinoma (N=26) and tumor budding (N=10). To recapitulate the metastatic tumor environment which have enriched receptor tyrosine kinases (RTKs), we maintained and experimented with EGF (20ng/ml) in every in vitro studies.
RESULTS We observed that both β-catenin and Ras were increased in adenocarcinoma and metastatic adenocarcinoma of human CRC compared with normal mucosa. Interestingly, both β-catenin and Ras were most significantly increased in tumor budding regions which histopathologically represent epithelial mesenchymal transition (EMT). In murine model, the EMT phenomenon was effectively induced and invasion of small intestinal tumors were occurred in APCMin/+/K-RasG12DLA2 with increased level of β-catenin and Ras compared with APCMin/+. However, EMT phenomenon and its following events such as migration and invasion of CRC cells induced by APC and K-Ras mutations were abolished by destabilization of β-catenin and Ras.
CONCLUSION Our results show that destabilizing β-catenin and Ras could be effective therapeutic targets for inhibiting metastasis in the early stage of CRC development
Citation Format: Yong-Hee Cho, Jeong-Soo Yoon, Kang-Yell Choi. Destabilizing β-catenin and Ras could be an ideal therapy for treating metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2017-911
Abstract 912: ADAM9-plectin interaction involved in prostate cancer malignancy progression
Authors: Liu Che-Ming , Hsieh Chia-Ling , Sung Shian-Ying 
Published: July 2017

Abstract
Introduction: To identify a specific biomarker for malignant prostate cancer progression and therapeutic target, we had demonstrated the correlation of ADAM9 expression and cancer progression. The aim is to clarify the association of ADAM9 and interactive proteins in malignant phenotypic progression.
Methods: Knockdown of ADAM9 expression was conducted to explore its role in cell motility and metastasis activities. Pull-down assays were performed to identify the proteins that interact with ADAM9 during cancer cell migration. Proximity ligation assay (PLA) was carried out to validate the protein-protein interaction. Transmission electron microscope (TEM) analysis to confirm ADAM9 and plectin interaction. Protein degradation test was conducted to determine the regulation pathway.
Results: Our study demonstrated that ADAM9 play an important role in the regulation of prostate cancer migration, invasion and metastasis in the in vitro assay and xenograft animal models. The combination of ADAM9 pull-down assays and mass spectrum analysis demonstrated hemidesmosome components, plectin, ladinin, and cytoskeleton were pull-down with ADAM9. However, the key element of hemidesmosome, integrin α6β4, did not pull-down together. Both TEM and PLA confirmed the interaction of ADAM9 and plectin in the protrusion end of migrating cells. This interaction can be strengthened after knockdown integrin β4; and vice verse, knockdown of ADAM9 increased interaction of integrin β4 and plecin. These results indicated ADAM9 and integrin β4 compete for plectin binding. Furthermore, shADAM9 attenuated the degradation of integrin β4. Clinical evaluation of 96 patient samples in TMU demonstrated increased of ADAM9 and plectin interaction in tumor region when compared to the benign part of the same patient.
Conclusions: Our studies demonstrated that ADAM9 promotes cancer metastasis through alteration of hemidesmosome dynamic by enhancing of integrin β4 degradation. Therefore, these results indicated possible to use ADAM9-plectin interaction to predict prostate cancer malignancy progression.
Citation Format: Che-Ming Liu, Chia-Ling Hsieh, Shian-Ying Sung. ADAM9-plectin interaction involved in prostate cancer malignancy progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 912. doi:10.1158/1538-7445.AM2017-912
Abstract 917: CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages
Authors: Choi Jae-Il , Hur Jin , Lee Hwan , Nham Pniel , Chae Cheong-Whan , Choi Young-Eun , Kim Taewan , Lee Ga-Young , Baek Sung Hee , Kim Hyo-Soo 
Published: July 2017

Abstract
Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we examine the role of CD82/KAI1 (CD82 hereafter) in niche-mediated LT-HSC maintenance. We found that CD82 is expressed predominantly on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs). In Cd82-/- mice, LT-HSCs were selectively lost as they exited from quiescence and differentiated. Mechanistically, CD82-based TGF-b1/Smad3 signaling leads to induction of CDK inhibitors and cell-cycle inhibition. The CD82 binding partner DARC/CD234 is expressed on macrophages and stabilizes CD82 on LT-HSCs, promoting their quiescence. When DARC+ BM macrophages were ablated, the level of surface CD82 on LT-HSCs decreased, leading to cell-cycle entry, proliferation, and differentiation. A similar interaction appears to be relevant for human HSPCs. Thus, CD82 is a functional surface marker of LT-HSCs that maintains quiescence through interaction with DARC-expressing macrophages in the BM stem cell niche. Finally, we hope that further development of our study will allow us to improve leukemia treatment by awakening not only “good” stem cells to keep beneficial stem cell functions, but also “bad” stem cells (e.g. cancer stem cells) in order to increase the sensitivity to treatment and avoid relapse.
Citation Format: Jae-Il Choi, Jin Hur, Hwan Lee, Pniel Nham, Cheong-Whan Chae, Young-Eun Choi, Taewan Kim, Ga-Young Lee, Sung Hee Baek, Hyo-Soo Kim. CD82/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 917. doi:10.1158/1538-7445.AM2017-917
Abstract 918: Cdc42 is crucial for intestinal stem cells survival by regulating Wnt and YAP signaling
Authors: Zhang Xiao , Gao Nan 
Published: July 2017

Abstract
Strictly defined architecture of intestinal epithelial cells and the gradient of signaling cues along the villus-crypt axis ensure the maintenance of adult intestinal stem cells, as well as proper regeneration and differentiation of all intestinal epithelial cell types. The Rho family small GTPase Cdc42 controls the polarized division of intestinal stem cells, and affects subsequent fate-determination of the progenitor cells. As we previously described in Cdc42 Villin-Cre knockout mice, loss of Paneth cells from crypt bottom and emergence of Goblet cell-like intermediate cells at the villus indicate possible compromise of the canonical Wnt signaling during Paneth cell differentiation. Here we further characterized the underlying molecular mechanism of Cdc42 regulating intestinal stem cell survival, proliferation, and differentiation. IHC of the intestinal tissue in Cdc42 Villin-Cre knockout mice suggests greatly reduced Olfm4 level in the stem cells, which are abnormally positioned in the crypts, along with a reduction of both transcription co-factors beta-Catenin and YAP. However, the Notch signaling, which is required for stem cells and the differentiation of absorptive linage, seems intact. The autonomous regulation of Cdc42 on Yap signaling is probably through its specific role in stabilizing cell-cell junction and actin filaments in the epithelium, both of which are known regulatory inputs of the Hippo-YAP pathway. Both Wnt/beta-Catenin and Yap signaling are required for the initiation and progression of colorectal cancer, and the regeneration of stem cells post radiation. Given that Cdc42 is overexpressed in multiple types of cancers, especially colorectal cancer, our finding that Cdc42 regulates both Wnt and YAP pathways in the homeostasis of adult intestinal tissue sheds new light on the molecular mechanism of its pathological involvement, and potential therapeutic target.
Citation Format: Xiao Zhang, Nan Gao. Cdc42 is crucial for intestinal stem cells survival by regulating Wnt and YAP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 918. doi:10.1158/1538-7445.AM2017-918
Abstract 926: Generation of a potential breast cancer stem cell model from induced pluripotent stem cells
Authors: Nair Neha , Calle Anna Sanchez , Zahra Maram Hussein , Oo Aung Ko Ko , Vaidyanath Arun , Masuda Shinobu , Kasai Tomonari , Seno Masaharu 
Published: July 2017

Abstract
The role of cancer stem cells (CSC) in the present scenario of breast cancer research is perceived as indispensable in the development and progression of the disease. The CSC niche maintains a heirarchy of heterogeneous cells, which facilitates the inception of the tumor until its invasion. Therefore, our study focuses on the development of an effective breast cancer stem cell model from mouse induced pluripotent stem cells (miPSCs).
Taking into consideration the intertumor heterogeneity of breast cancer, three human breast cancer cell lines, namely BT549, SKBR3 and T47D representing three major hormone subtypes were used to derive respective conditioned medium. The miPSCs were treated with these conditioned media separately for a period of one month following the protocol previously established by our laboratory. The resulting survived cells were subcutaneously and orthotopically transplanted into Balb/c nude mice. Within a short span of 15-20 days, both subcutaneous and orthotopic tumors were developed. Serial transplantations in to nude mice also generated malignant tumors with same vigor. Histopathological studies of these tumors confirmed a malignant infiltrating ductal carcinoma with apparent desmoplasia in orthotopic tumor and Her2 expression in comparison with subcutaneous ones, all of which confirmed us the conversion of miPSCs to CSCs. Presence of lung metastatic nodes further ascertained the invasiveness of this in vitro generated CSCs. Marked expression of prominent CSC markers namely CD44, Nanog, Sox2 and CD49f were observed in primary cells generated from these tumors. Tumor sphere formation assay further confirmed the presence of a good population of self renewing CSC population in the tumor tissues.
This study attempts to recapitulate human breast cancer disease in mice without any genetic manipulation, but by exploiting the tumor microenvironment in the form of conditioned medium. This should pave the way for the establishment of personalized therapy and a model to assess effective therapeutic interventions.
Citation Format: Neha Nair, Anna Sanchez Calle, Maram Hussein Zahra, Aung Ko Ko Oo, Arun Vaidyanath, Shinobu Masuda, Tomonari Kasai, Masaharu Seno. Generation of a potential breast cancer stem cell model from induced pluripotent stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 926. doi:10.1158/1538-7445.AM2017-926
Abstract 928: Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem cells
Authors: Fyala Amira S. , Sultan Ahmed S. 
Published: July 2017

Abstract
Manuka honey is well known for its anti-bacterial and wound healing properties but its anticancer role against cancer stem cells (CSC) in hepatocellular carcinoma (HCC) cell lines and the underlying molecular mechanisms remain uninvestigated. Recently, we identified a CSC subpopulation in HCC cell lines characterized by their CD133+ and CD90+ phenotype. The CD133+/ CD90+cells demonstrated a more aggressive phenotype than the CD133-/ CD90- counterpart and formed metastatic lesions in the lung of immunodeficient mice. In order to evaluate the effect of Manuka honey alone or in combined treatment with Metformin, a biguanide that has been widely used to treat type 2 diabetes, on cell viability and apoptosis induction in human HCC cell lines, isolated and identified CD133+/ CD90+subpopulation CSC were used. Cell viability was monitored using an MTT assay. In addition, apoptosis induction was labeled by Annexin V-fluorescein isothiocyanate/propidium iodide and measured using flow cytometry. Western blotting was used to examine the protein expression of p53, Bcl-2, Bax, Bcl-2-associated death promoter (Bad), Bcl-2 homologous antagonist/killer (Bak) and cleaved-caspases-3 and -9. The results of the present study revealed that Manuka honey alone or in combined treatment with Metformin suppressed the cell viability of CD133+/CD90+cells in a concentration-dependent manner and the maximum effect was detected in combined treatment after 24 h. In addition, Manuka honey alone or in combined treatment with Metformin induced a significant apoptosis in the tested cells. Furthermore, it was demonstrated that combined treatment increased the expression of proapoptotic proteins, including p53, Bax, Bad and Bak, while it decreased the protein level of antiapoptotic protein Bcl-2 compared to control, Manuka honey or Metformin alone. Furthermore, the combined treatment strongly inhibited stemness characteristics of CSC subpopulation, colony formation and dramatically inhibited CD133+/CD90+tumor growth in vivo. Our data demonstrated that combined treatment induced apoptosis in CD133+/CD90+ subpopulation through G1 arrest in the cell-cycle and regulating p53/Bcl-2/caspase-3 signaling pathway. In conclusion, our results suggested that Monuka honey alone or combined treatment with Metformin may be a potential treatment for apoptosis induction in CSC and may provide a novel therapeutic model for HCC.
Citation Format: Amira S. Fyala, Ahmed S. Sultan. Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 928. doi:10.1158/1538-7445.AM2017-928
Abstract 929: Dissecting heterogeneity and population dynamics in breast cancer stem cells
Authors: Brooks Michael D. , Wicha Max S. 
Published: July 2017

Abstract
The CSC hypothesis posits that there is a subset of tumors cells driving tumor growth and metastasis and that by targeting this population, tumors can be more efficiently eradicated. Recently it was shown that there are two types of CSCs in breast cancer, mesenchymal CSC’s characterized as CD44+/CD24- and an epithelial type marked by ALDH expression. The cellular plasticity of these CSC states may contribute to their metastatic capacity. However, little is known about the heterogeneity of these CSC populations or how they are regulated by the tumor microenvironment. To address these issues we have utilized Drop-Seq to generate single cell RNA-Seq data from thousands of cells across patient derived xenografts from various molecular subtypes of breast cancer. In order to monitor real-time state transitions between the determined cellular populations, we have also designed and constructed fluorescent reporter constructs for genes specific to critical cell populations and cancer stem cells. We used CRISPR/Cas9 to introduce these reporters into the native loci of the genes in order to recapitulate native gene expression patterns. Single cell transcriptomics will help to characterize the molecular heterogeneity of CSC populations. The addition of fluorescent reporters will help to elucidate the mechanisms that regulate breast CSC’s as well as their interaction with the tumor microenvironment and to identify potential therapeutic targets.
Citation Format: Michael D. Brooks, Max S. Wicha. Dissecting heterogeneity and population dynamics in breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 929. doi:10.1158/1538-7445.AM2017-929