bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1617: RUNX3 inhibits metastasis and angiogenesis in colorectal cancer
Authors: Kim Bo Ram , Kim Jung Lim , Na Yoo Jin , Park Seong Hye , Lee Sun Il , Kang Sanghee , Joung Sung Yup , Lee Suk Young , Kim Hong-Jun , Lee Dae-Hee , Min Byung-Wook , Oh Sang Cheul 
Published: July 2016

Abstract
Recent studies proved that an inactivation of RUNX3 (runt-related transcription factor-3) expression is highly associated with lymph node metastasis and poor prognosis in various cancer types. However, the mechanism of RUNX3-mediated suppression of tumor metastasis remains unclear. Herein, we aimed to clarify the effect of RUNX3 on metastasis and angiogenesis in colorectal cancer (CRC). First, we found that the reduction of expression of RUNX3 in CRC tissues when compared with tumor adjacent normal colon tissues, as indicated by reduced RUNX3 staining, was significantly correlated with TNM stage. Second, we demonstrated that RUNX3 overexpression inhibited CRC cell migration and invasion resulting from the elevated upregulation of matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9) expression. In contrast, the knockdown of RUNX3 reduced the inhibition of migration and invasion of CRC cells. Last, Vascular endothelial growth factor(VEGF) is an inducer of angiogenesis and lymphangiogenesis. We found that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation in CRC cells. Taken together, our data demonstrated that RUNX3 may provide insights into the development of RUNX3 for CRC metastasis diagnostics and therapeutics.
Citation Format: Bo Ram Kim, Jung Lim Kim, Yoo Jin Na, Seong Hye Park, Sun Il Lee, Sanghee Kang, Sung Yup Joung, Suk Young Lee, Hong-Jun Kim, Dae-Hee Lee, Byung-Wook Min, Sang Cheul Oh. RUNX3 inhibits metastasis and angiogenesis 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 1617.
Abstract 1626: Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis
Authors: Mukherjee Debarati , Lu Heng , Yu Lin , Lahiri Satadru K. , Li Tianshu , Zhao Jihe 
Published: July 2016

Abstract
Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turns induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
Citation Format: Debarati Mukherjee, Heng Lu, Lin Yu, Satadru K. Lahiri, Tianshu Li, Jihe Zhao. Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis. [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 1626.
Abstract 1634: The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity
Authors: Sizemore Steven T. , Xia Fen , Chakravarti Arnab 
Published: July 2016

Abstract
Soft tissue sarcomas (STS) are a heterogeneous group of tumors originating from mesodermal tissues such as skeletal muscle, adipose, and fibrous tissue. The propensity of STS to metastasize, particularly to the lung which occurs in approximately 20% of all cases, is the major source of mortality associated with this disease. Currently, themolecular mechanisms that drive STS metastasis are poorly understood greatly limiting our ability to determine which STS will metastasize and impeding the development of targeted therapies for the treatment of STS metastases. In this study we utilized analysis of publicly available gene expression data to identify loss of PPP2R1B expression as a strong prognosticator of STS metastasis. In vitro analyses using SW872 liposarcoma (LPS) and HT1080 fibrosarcoma cell lines determined that PPP2R1B plays an essential role in the dephosphorylation and inactivation of RALA, a major downstream effector of the Ras pathway. RALA was found to be essential for invasion of STS cells in modified Boyden chamber assays as knockdown of RALA by either siRNA or shRNA significantly decreased invasion through matrigel. Analysis of publicly available gene expression data revealed that RALA expression correlated with more aggressive LPS subtypes and was prognostic of LPS metastasis. Furthermore, we identify the transmembrane matrix metalloprotease MMP14 (MT1-MMP) as a key downstream effector of RALA mediated invasion in STS. Stable knockdown of RALA in SW872 and HT1080 cells resulted in significant mislocalization of MMP14 and reduced MMP14 enzymatic activity. MMP14 expression was also significantly prognostic of metastasis in a publically available LPS cohort. Finally, we demonstrate that a three gene signature comprised of PPP2R1B, RALA, and MMP14 can retrospectively stratify LPS patients into groups of low, moderate, or high risk for metastatic recurrence. To the best of our knowledge this is the first demonstration of a vital role for PPP2R1A and RALA in STS invasion and metastasis and these data demonstrate a novel role for RALA in the localization and activity of MMP14. In conclusion, we have identified the PPP2R1B-RALA-MMP14 axis as driver of STS metastasis with potential clinical value as both a prognostic marker and therapeutic target.
Citation Format: Steven T. Sizemore, Fen Xia, Arnab Chakravarti. The RALA pathway drives invasion and metastasis of soft tissue sarcomas by regulating MMP14 localization and activity. [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 1634.
Abstract 1636: The role of the ROR receptors in ovarian cancer progression and chemoresistance
Authors: Henry Claire E. , Llamosas Estelle , Hacker Neville F. , Heinzelmann-Schwarz Viola , Ford Caroline E. 
Published: July 2016

Abstract
BACKGROUND: Despite recent advances in our understanding of the underlying genetic profile of distinct subtypes of ovarian cancer, overall survival remains poor. This is partly due to the absence of available targeted therapies, widespread metastatic disease at diagnosis, and the development of resistance to chemotherapy in the majority of patients. Patients with a more mesenchymal gene signature have a shorter overall survival, and are more likely to recur and develop chemoresistance. These patients also have upregulated Wnt signalling, a key developmental pathway associated with metastasis, epithelial to mesenchymal transition (EMT) and chemoresistance.
AIM: To investigate the role of the novel Wnt receptors ROR1 and ROR2 in ovarian cancer progression and chemoresistance, to determine their feasibility as therapeutic targets.
METHOD: Expression of ROR1 and ROR2 was measured in patient tumour (primary and metastatic) samples and ascites fluid taken at multiple time points during disease progression. In addition, the A2780 and cisplatin resistant A2780-cis cell lines were used as a model of ovarian cancer chemoresistance. Profiling of EMT and Wnt genes was undertaken alongside cell proliferation, adhesion, migration, invasion and viability assays after modulation of ROR1 and ROR2.
RESULTS: Expression of ROR1 and ROR2 is increased in ovarian cancer patients compared to benign fallopian tube and ovarian surface epithelium. High ROR1 expression is associated with type I epithelial ovarian cancer, and high ROR2 expression with aggressive type II epithelial ovarian cancer. Expression of each receptor fluctuates in paired metastatic samples compared to primary tumours, depending on the site of metastasis and recurrence time. Both receptors are increased in a model of cisplatin resistant ovarian cancer, and when silenced, cell migration and invasion is significantly inhibited. Silencing ROR1 and ROR2 also sensitizes resistant cells to cisplatin, and is associated with a shift away from a mesenchymal phenotype.
CONCLUSION: Upregulation of ROR1 and ROR2 drives migration, invasion and chemoresistance through regulating EMT via β-catenin independent Wnt signalling. As cell surface regulators of β-catenin independent Wnt signalling, the ROR receptors represent potential therapeutic targets for chemoresistant cancers.
Citation Format: Claire E. Henry, Estelle Llamosas, Neville F. Hacker, Viola Heinzelmann-Schwarz, Caroline E. Ford. The role of the ROR receptors in ovarian cancer progression and chemoresistance. [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 1636.
Abstract 1644: NF-κB inhibitor DMAPT blocks non-homologous end-joining repair of radiation-induced DSBs in NSCLC
Authors: Deraska Peter V. , O’Leary Colin , Lazaro Jean-Bernard , Sweeney Christopher J. , D’Andrea Alan D. , Kozono David 
Published: July 2016

Abstract
Background: Despite optimal multimodality therapy, non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the United States. A common limitation is our inability to provide sufficient radiotherapy (RT) to eradicate tumor due to risk of toxicities in surrounding tissues. There is thus an unmet need for radiosensitizers that can improve the therapeutic index. Dimethylaminoparthenolide (DMAPT), an orally bioavailable small molecule NF-κB inhibitor, inhibits repair of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) and increases control of subcutaneous mouse NSCLC xenografts. While our prior work focused on inhibition of homologous recombination as a mechanism for radiosensitization, we sought to characterize the effect of DMAPT on a second major DSB repair pathway, non-homologous end-joining (NHEJ).
Methods: NHEJ was assessed in NSCLC lines using the pEJ reporter and flow cytometry. The NF-κB super repressor (IκBαS32A,S36A) was used as a control. Immunofluorescence and Western blotting were used to assess NHEJ biomarkers including 53BP1, DNA-PKS2056, Ku70/80 and XRCC4. Cell fractionation was performed to assess Ku chromatin binding. Quantitative RT-PCR was performed to assess gene transcription. Ku complexes were purified to identify binding partners.
Results: NSCLC cells treated with IR-sensitizing doses of DMAPT (5-15 μM) or the NF-κB super repressor showed significant decreases in NHEJ. DMAPT increased the persistence of 53BP1 foci, indicating a failure to complete NHEJ. Regardless of exogenous DNA damage, there was reduced Ku70 chromatin binding following DMAPT treatment. DMAPT-treated cells produced fewer distinct IR-induced DNA-PKS2056 foci. Further, there was decreased IR-induced XRCC4 chromatin recruitment, suggesting that repair was impaired prior to ligation. There was no change in Ku70/80 transcription following DMAPT and/or IR. However, Western blotting of purified Ku complexes showed that DMAPT treatment decreased Ku association with RNA binding partners including RPL19. We also observed decreased recruitment of DNA-PKcs to the Ku complex, suggesting decreased Ku affinity for DSBs.
Conclusions: These results indicate that DMAPT radiosensitizes NSCLC by perturbing the binding affinity of Ku to RNA, DNA and its complex binding partners, thus blocking NHEJ. Further mechanistic investigation and analysis of NHEJ biomarkers in vivo is needed to identify the precise mechanism.
Citation Format: Peter V. Deraska, Colin O’Leary, Jean-Bernard Lazaro, Christopher J. Sweeney, Alan D. D’Andrea, David Kozono. NF-κB inhibitor DMAPT blocks non-homologous end-joining repair of radiation-induced DSBs in NSCLC. [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 1644.
Abstract 1657: Mapping mechanisms of radiotherapy resistance in prostate cancer
Authors: Bruens Serena T. , Milanese Chiara , Verkaik Nicole , Mastroberardino Pier , Gyenis Akos , Chang Jiang , Derks Kasper , Wiemer Erik , van Gent Dik , van Weerden Wytske , Jenster Guido , Hoeijmakers Jan , Pothof Joris 
Published: July 2016

Abstract
Cancer cells that acquire radio-resistance are major problem for treatment outcome. We aimed at identifying mechanisms and networks that control ionizing radiation (IR)-resistance in prostate cancer cells. To this end, we applied to cancer cell lines an identical radiotherapy regiment as performed in the clinic, i.e. a total dose of 78 Gy in steps of 2 Gy per day for 5 consecutive days followed by 2 days rest. We observed that radio-resistance occurs early during treatment as seen in colony survival assays in which 100% of cells that can form colonies are resistant up to 8 Gy. Remarkably, a two-week period of culturing without radiotherapy completely sensitized these resistant cancer cell lines, indicating that resistance is not acquired by permanent mutations or chromosomal rearrangements. Currently, we are characterizing these extreme resistant cancer cell cultures by comparing these to their sensitive parental cancer cell lines and the two-week re-sensitized cancer cell lines. We observe changes in DNA repair pathway utilization, DNA damage checkpoint activation and energy metabolism parameters, but not in PI3-kinase signalling and cancer stem cell markers. We also performed genome-wide gene expression analysis by next generation sequencing and isolated gene signatures that correlate with resistance. Based on our results we applied inhibitors to sensitize these IR-resistant cells. Notably, application of single inhibitors did not lead to sensitivity. Combinations of small molecule inhibitors however, were able to sensitize these cancer cell lines, indicating that IR-resistance is a multi-factorial process. In summary, mapping gene networks and mechanisms will uncover new pathways associated with IR-resistance.
Citation Format: Serena T. Bruens, Chiara Milanese, Nicole Verkaik, Pier Mastroberardino, Akos Gyenis, Jiang Chang, Kasper Derks, Erik Wiemer, Dik van Gent, Wytske van Weerden, Guido Jenster, Jan Hoeijmakers, Joris Pothof. Mapping mechanisms of radiotherapy resistance in prostate 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 1657.
Abstract 1686: Glypican-3 (GPC3) induces a mesenchymal-epithelial transition in human breast cancer cells lines
Authors: Castillo Lilian F. , Tascon Rocio , Joffe Elisa Bal de Kier , Peters Giselle 
Published: July 2016

Abstract
Glypicans constitute a family of heparan sulphate proteoglycans which are linked to the extracellular surface of the plasma membrane through a glycosylphosphatidylinositol anchor. Since GPC3 has been linked to cancer, herein we generated and characterized a pre-clinical human breast cancer cell model to evaluate the role of GPC3 in human mammary tumor progression. GPC3 expression was blocked in MCF-7 cells (poorly-metastatic, GPC3 +) by siRNA (generating MCF-7-shGPC3 sublines), while it was overexpressed in MDA-MB231cells (metastatic, GPC3 -) by viral infection (producing MDA-MB231-GPC3 sublines).
We performed in vitro and in vivo characterization of this model. GPC3 silenced MCF-7 cells acquired F-actin stress fibers, enhanced their clonogenic ability (Colony number 130 -shGPC3 vs. 37 -sh Negative Control (NC)) as well as their migration (Wound coverage (%): 15 -shGPC3 vs. 2 -shNC), were less susceptible to cell death induction (Cell death (%): 21.6 -shGPC3 vs. 34 -shNC), diminished the expression of the epithelial marker E-Cadherin while acquired the mesenchymal marker N-Cadherin, and were more invasive and metastatic in vivo. These cells exhibited an upregulation of the EMT-transcription factor ZEB1, and the canonical Wnt/beta-Catenin signaling pathway was activated.
GPC3 overexpressing MDA-MB231 cells misplaced their fibroblast-like appearance as well as their F-actin stress fibers, repressed their clonogenicity (Colony number: 8 -GPC3 vs. 40 -vector) and migratory capacity (Wound coverage (%): 10 -GPC3 vs. 90 -vector), were more sensitive to death in starving condition (Cell death (%) 30 -GPC3 vs. 6.5 -vector), got the ability to form E-Cadherin dependent-spheroids, reexpressed E-Cadherin in cell-cell junctions and downregulated the mesenchymal markers N-Cadherin and vimentin, while were less invasive and metastatic in vivo. The expression of the E-Cadherin repressor ZEB1 was diminished, as well as the activity of the canonical Wnt/beta-Catenin signaling pathway. However, when canonical Wnt signaling was activated by LiCl, the expression of E-Cadherin did not change.
In summary, we present in vitro and in vivo experimental evidence supporting the hypothesis that GPC3 has a protective role of human breast cancer progression by inducing mesenchymal-epithelial transition (MET). The canonical Wnt/beta-Catenin signaling inhibition would not be required for MET process induced by GPC3.
Citation Format: Lilian F. Castillo, Rocio Tascon, Elisa Bal de Kier Joffe, Giselle Peters. Glypican-3 (GPC3) induces a mesenchymal-epithelial transition in human breast cancer cells lines. [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 1686.
Abstract 1703: Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial cancer
Authors: Inoue Kayo , Tsubamoto Hiroshi , Shibahara Hiroaki , Tamura Kazuo 
Published: July 2016

Abstract
Background: There are limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common antifungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancer, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC.
Patients and Methods: We reviewed cases of patients with serous endometrial intraepithelial carcinoma (SEIC) and patients who were diagnosed with EC with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites and who recurred at our institution from January 2005 to December 2013. We also reviewed cases with endometrioid adenocarcinoma grade 1 or 2 at FIGO stage IA with myometrial invasion and negative cytology of ascites without recurrence over 5 years after surgery during 2006 and 2007. Immunohistochemistry was performed on EC tumour samples including SEIC for sonic Hedgehog (sHh), glioma-associated oncogene homolog 1 (GLI1), Progesterone receptor (PR), and chemokine ligand 18 (CCL18). Furthermore, we examined the effects of itraconazole on human EC cell lines (Ishikawa and HEC-1A cells) using a modified methylthiazol tetrazolium (MTT) assay and a migration assay.
Results: SHh and GLI1 were expressed in SEIC and endometrioid adenocarcinoma. Immunohistochemical evaluation of sHh and GLI1 did not distinguish between recurrent and non-recurrent low-grade FIGO stage IA EC. The MTT assay revealed that itraconazole significantly inhibited the growth of Ishikawa and HEC-1A cells in a dose-dependent and time-dependent manner. However, migration was not significantly effected for either Ishikawa or HEC-1A cells. HEC-1A cells exhibited dose-dependent migration retardation.
Conclusion: Hedgehog signalling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC.
Citation Format: Kayo Inoue, Hiroshi Tsubamoto, Hiroaki Shibahara, Kazuo Tamura. Expression of Hedgehog signals and growth inhibition by itraconazole in endometrial 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 1703.
Abstract 1706: Evaluation of LGR5 protein expression in colon cancer stem cells
Authors: Fu Wei , Gonzalez Rachel , Yuan Kehu , Chen Caiwei , Wei Haitao , Lu Hsiangmin , Ren Qi , Logis Evelin , Kelly Sean , He Wei-Wu , Ma Donghui 
Published: July 2016

Abstract
Cancer stem cells are a subpopulation of cancer cells responsible for cancer initiation, development and metastasis. A number of studies demonstrated that Leucine-rich repeat containing G-protein-coupled receptor 5 (LGR5) can drive cancer development through triggering canonical Wnt signaling and its downstream gene expression. LGR5 is an important biomarker specifically expressed on colon cancer stem cells. In this study, we have successfully developed an LGR5 antibody with high specificity to detect endogenous LGR5 expression in different immunoassay application.
By screening multiple anti-LGR5 hybridoma clones, antibody generated by clone UMAB212 was proven to be highly specific on our high density protein microarray chip assay. Here our experimental data demonstrated that clone UMAB212 recognizes not only human LGR5 protein but also mouse LGR5 protein in both western blot and flow cytometry applications. No cross-reactivity was observed with the other two LGR family members, LGR4 and LGR6. Furthermore, this antibody also works great on immunohistochemistry application on FFPE tissue blocks. In summary, UMAB212 is great tool for us to study LGR5 protein in different immunoassay setting and it could also be a potential cancer diagnostic reagent.
Citation Format: Wei Fu, Rachel Gonzalez, Kehu Yuan, Caiwei Chen, Haitao Wei, Hsiangmin Lu, Qi Ren, Evelin Logis, Sean Kelly, Wei-Wu He, Donghui Ma. Evaluation of LGR5 protein expression in colon cancer stem 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 1706.