bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3072: miR-551b amplification regulates STAT3 expression and resistance to anoikis of ovarian cancer cells
Authors: Chaluvally Raghavan Pradeep , Pradeep Sunila , Lu Yiling , Sood Anil , Mills Gordon 
Published: August 2015

Abstract
Background and Hypothesis: The 3q26.2 locus is highly amplified in high grade serous ovarian cancer (HGSOC). Recently we identified two microRNAs, miR569 and miR551b are located in the 3q26 amplicon are highly expressed in the HGSOC due to the 3q26.2 amplification. However, the potential role of microRNAs amplified at 3q26 amplicon and their functions in tumorigenesis have not been well studied. In this study we have identified the mechanism how miR551b promote the tumor growth and metastasis of ovarian cancer cells.
Methods and Results: High-resolution SNP-based copy number analysis of 533 high-grade serous ovarian cancer samples demonstrated that miR551b is highly amplified in ∼35% of HGSOC patients’ samples. Quantitative real-time PCR (qRT-PCR) analysis of ovarian cancer samples demonstrated a marked increase in the level of mature miR551b in tumors with the 3q26.2 amplicon, relative to the non-amplified tumor samples as a consequence of the 3q26.2 amplicon. Of note, miR551b is expressed highly in the metastatic tumors than the primary tumors of ovary. Our reverse phase protein array (RPPA) demonstrated that enforced expression of miR551b increased the expression c-KIT, STAT3 and PCNA proteins. Importantly miR551b expression activated the ERK signaling pathway and inhibited the expression of BIM protein. Strikingly, the expression of miR551b induced the survival and proliferation of ovarian surface epithelial cells detached from extracellular matrix. Knock down of STAT3 using target specific siRNA abrogate the miR551b mediated c-KIT and PCNA expression and abolished the resistance to anoikis.
Summary: Our results posit that copy number alterations (CNAs) of miR551b primarily regulate the increased levels of mature miR551b. Mechanistic studies revealed that miR-551b regulate the expression of important oncogenes such as STAT3 and c-KIT, in turn causes resistance to anoikis. Resistance to anoikis is the key mechanism enhances the survival and metastasis of ovarian cancer cells in the peritoneal cavity. Of note our results demonstrates that miR-551b regulate c-Kit expression in STAT3 dependent manner. In conclusion, our results propose that the STAT3 expression induced by miR551b is the key mechanism regulates survival and metastasis of HGSOC cells.
Citation Format: Pradeep Chaluvally Raghavan, Sunila Pradeep, Yiling Lu, Anil Sood, Gordon Mills. miR-551b amplification regulates STAT3 expression and resistance to anoikis of ovarian cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3072. doi:10.1158/1538-7445.AM2015-3072
Abstract 3075: miRNA-10a* enhances invasiveness via suppression of HDAC5 in lung cancer
Authors: Hsu Pin-Yen , Ho Bing-Ching , Cheng Chiou-Ling , Chen Hsuan-Yu , Yu Sung-Liang , Huang Guan-Tarn 
Published: August 2015

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Metastasis, the spread process of cancer cells from a primary tumor to seed secondary tumors in distant sites, is one of the big challenges in cancer treatment today. For most patients, when the cancer is detected, metastasis has already occurred. The growing evidences implied that miRNAs play an important role in developmental lineage and different states of cancers as well as cancer invasion. In this study, we would like to establish a metastasis-based prognostic miRNA signature. First, 16 lung adenocarcinoma cells were divided into the high or low-invasive group. The miRNAs whose expression correlated with invasion were identified. Next, we investigated whether the expressions of identified miRNAs are correlated to patients’ survival. Quantitative RT-PCR results showed that the expression of miR-10a* is significantly correlated to the five-year survival in 98 lung adenocarcinoma patients. The inhibition of miR-10a* attenuated the invasion abilities of the highly invasive lung cancer cells. Moreover, we investigated the underlying regulation of miR-10a*. We found that miR-10a* negatively regulated Histone deacetylase 5 (HDAC5) was assayed by Western Blot, RT-PCR and luciferase reporter assay. These evidences suggested that HDAC5 is a direct target of miR-10a*. Besides, inhibition of HDAC5 promoted invasive ability. RNAs derived from two paired groups (pre-miR-10a* and pre-NC; sh-HDAC5 and sh-LacZ) were assayed by microarray and pathway analysis. The analysis result of MetaCore implied that miR-10a* trigger TGF-beta signalings. RT-PCR and Western Blot were utilized to validate the differentially altered expression of certain genes in miR-10a*-mediated pathways. The rescue effect of HDAC5 expression on miR-10a*-mediated phenotypic changes is also evaluated to elucidate the importance of HDAC5 in miR-10a*-mediated invasive ability. Our findings indicated that miR-10a* may play an oncogenic miRNA role in lung cancer.
Citation Format: Pin-Yen Hsu, Bing-Ching Ho, Chiou-Ling Cheng, Hsuan-Yu Chen, Sung-Liang Yu, Guan-Tarn Huang. miRNA-10a* enhances invasiveness via suppression of HDAC5 in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3075. doi:10.1158/1538-7445.AM2015-3075
Abstract 3082: miR-155-5p expression is associated with response to neoadjuvant paclitaxel treatment of locally advanced breast cancer
Authors: Straume Anne Hege , Birkeland Einar , Knappskog Stian , Lønning Per Eystein 
Published: August 2015

Abstract
Introduction
Resistance to chemotherapy remains a prominent obstacle to cure in cancer. We have previously shown that genetic defects in key pathways involved in processes like apoptosis, cell-cycle arrest and senescence may be involved in resistance to chemotherapy in vivo.
MicroRNAs (miRNAs) are known to be crucial regulators of gene expression, and to potentially affect the response to drugs, including chemotherapy. Here, we aimed to explore the potential role of miRNAs in mechanisms of breast cancer chemoresistance in-vivo, by analyzing miRNA expression in breast cancer patients with recorded responses to chemotherapy.
Patient materials and Methods
Breast tumour biopsies were collected before chemotherapy in a prospective clinical study, where patients were randomized to receive epirubicin or paclitaxel monotherapy (n = 223). Information about the response to therapy, as defined by the UICC criteria, in addition to long-term outcome, was available for all patients. The global miRNA expression levels were analyzed in 50 breast tumour biopsies by deep sequencing. The patients were selected based on their response to first-line chemotherapy. To verify the results obtained by miRNA sequencing, selected miRNAs were quantified in all patients by qPCR.
Results
No global miRNA patterns were observed when performing unsupervised clustering of miRNA sequencing data. Among samples from paclitaxel-treated patients, we identified three differentially expressed miRNAs between response groups; the expression of miR-155 was significantly lower (p = 0.005) in patients with poor response to paclitaxel, and the expression of both miR-181a and miR-181b were significantly higher (p = 0.003 and 0.012, respectively) in patients with poor response to paclitaxel.
qPCR data validated the initial association identified between high miR-155-5p expression levels and response to paclitaxel treatment. Intriguingly though, high levels of miR-155 were also associated with a poor prognosis in the study population as a whole (p = 0.012), as well as with the presence of mutations in TP53 (p &lt; 0.001).
Conclusion
Here, we show that breast cancer patients responding to paclitaxel treatment have higher expression levels of miR-155-5p. Also, patients with elevated levels of miR-155-5p expression have a poor prognosis and a higher frequency of TP53 mutations.
Citation Format: Anne Hege Straume, Einar Birkeland, Stian Knappskog, Per Eystein Lønning. miR-155-5p expression is associated with response to neoadjuvant paclitaxel treatment of locally advanced breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3082. doi:10.1158/1538-7445.AM2015-3082
Abstract 3089: CDKN2A and p53 status predicts response to CDK4/6 inhibition in melanoma
Authors: Martin Claire A. , Kirby Laura , Wong Stephen , McArthur Grant A. , Sheppard Karen E. 
Published: August 2015

Abstract
The p16-CyclinD1-CDK4-RB pathway regulates G1-S cell cycle transition. This pathway is deregulated in 90% of melanomas, through amplification or increased expression of CDK4 or Cyclin D1 (CCND1), or reduced expression of the CDK inhibitor p16INK4A (CDKN2A).
To explore if CDK4 may be a viable target for the treatment of human melanoma we screened a panel of melanoma cell lines with the highly selective CDK4/6 inhibitor PD-0332991 (PD-991). A majority of cell lines were found to be sensitive to PD-991, although there was a distinct population of resistant cell lines. In sensitive melanoma cell lines, treatment with PD-991 resulted in loss of hyperphosphorylated RB and a concomitant G0/G1 cell cycle arrest. Treated cells displayed an enlarged flattened morphology and an increase in SA-β-galactosidase staining compared to vehicle controls, indicative of cellular senescence. RB-null cell lines were resistant to CDK4/6 inhibition, and did not display cell cycle arrest or senescence. Expression and mutational analysis was performed to identify additional genomic predictors of sensitivity and resistance. Loss of CDKN2A/p16 correlated with sensitivity to PD-991 (p&lt;0.02), and this was confirmed at the level of protein expression. Mutation of p53 and the corresponding low expression of p53 targets p21 and MDM2 correlated with resistance (p&lt;0.0001). There was no increase in p53 transcriptional targets or evidence of apoptosis in response to PD-991 treatment of sensitive cells, and senescence occurs in both p53 WT and mutant cells, indicating that this response does not require functional p53. However, in p53 WT cells, combination treatment with PD-991 and the p53 pathway activator Nutlin3a results in increased sensitivity to PD-991 compared to treatment with PD-991 alone. This additive effect is not observed in p53 mutant cells, suggesting there is a functional role for WT p53 in the response to PD-991.
Conclusions: These preliminary data identify RB, p16 and p53 as predictors of response to PD-991, and support further evaluation of CDK4/6 inhibitors in melanoma.
Citation Format: Claire A. Martin, Laura Kirby, Stephen Wong, Grant A. McArthur, Karen E. Sheppard. CDKN2A and p53 status predicts response to CDK4/6 inhibition in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3089. doi:10.1158/1538-7445.AM2015-3089
Abstract 3092: In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples
Authors: Sharma Geeta , Vogeti Subha , Grant Wendy , Wu Shuzhen , Dias Christa , Nomanbhoy Tyzoon , Wu Jiangyue , Aban Arwin 
Published: August 2015

Abstract
Palbociclib (PD0332991) is a cyclin dependent kinase 4 and 6 inhibitor being developed for treatment of breast cancer. In order to evaluate the kinome-wide impacts of Palbociclib in an in-vivo setting, nude mice inoculated with COLO-205 (human colon carcinoma) cells were administered Palbociclib at different doses (12.5, 75 and 150mg/kg once daily for 3 days. Tumors were collected at various time points after the final dose (1, 3, 6, 12, 24 & 48 hours), lysed and subjected to in-situ kinase profiling using the KinativTM technology. Tumor lysates were probed with an ATP acylphosphate desthiobiotin probe which covalently modifies lysine residues in the kinase active site. Samples are then denatured, trypsinized, and the probe-labeled peptides captured with streptavidin, eluted, and quantitated by targeted mass spectrometry. The presence of an inhibitor bound to the active site of a kinase prevents the probe binding, resulting in the loss of MS signal for peptides from that kinase. In addition, the upregulation or downregulation of kinase proteins can also result in changes in the MS signals in palbociclib versus vehicle-treated samples. A total of 180 kinases were quantified. As expected, direct targets of palbociclib were observed to be inhibited in this study (i.e., kinases inhibited by Palbociclib in Colo205 lysate), including CDK4 &6 as well as ERK5, JNK, CDK16 &17, PIK3C3 and PIP4K2C. The observed inhibition of these targets was both dose and time dependent. Significantly, the MS signals for additional kinases not observed to directly bind Palbociclib in Colo205 lysate were also strongly downregulated in this study. These include CDC2, AurA, AurB, PLK1 and MASTL; kinases critical for cell cycle progression. We hypothesize that the downregulation of these kinases was due to cell cycle arrest in G1 phase. Consistent with this hypothesis, the downregulation of these kinases corresponded well with the inhibition of phosphorylated (Ser780; pRb) as demonstrated by Western Blots of a part of tumor tissue used for the Kinome profiling. Taken together, these results highlight the utility of kinome wide profiling in tumor samples collected from xenograft mice to better understand both pharmacodynamics of target engagement as well as pathway effects elicited by compound treatment.
Citation Format: Geeta Sharma, Subha Vogeti, Wendy Grant, Shuzhen Wu, Christa Dias, Tyzoon Nomanbhoy, Jiangyue Wu, Arwin Aban. In-situ Kinome wide profiling of Palbociclib treated COLO-205 human tumor xenograft samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3092. doi:10.1158/1538-7445.AM2015-3092
Abstract 31: WEE1 kinase inhibition enhances PI3K inhibitor response in p53 deficient gliomas
Authors: Wu Shaofang , Zheng Siyuan , Wang Shuzhen , Yung W.K.Alfred , Koul Dimpy 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is an aggressive brain tumor that is resistant to chemotherapy and radiation, and is almost always fatal. Oncogenic activation of the PI3K signaling pathway plays a pivotal role in the development of GBM and is a major molecular target for therapeutic development. However, clinical results of single-agent PI3K inhibitors have been modest to date. PI3K inhibitors have led to tumor stabilization and some disease responses; however, dramatic tumor regressions are not typical. Multiple recent reports have described mechanisms of resistance to PI3K inhibitors. The goal of the present study was to identify ways to improve the efficacy of PI3K inhibitor-based therapy by overcoming adaptive resistance. In this study we show that PI3K inhibitor BKM induces G2/M cell cycle arrest and inhibits GBM cell proliferation. We identified WEE1 as a putative treatment target of resistance to PI3K inhibition based on its potential function as a mitotic gatekeeper and its specific overexpression in GBM. WEE1 kinase is a key molecule in maintaining G2-cell-cycle checkpoint arrest for premitotic DNA repair. We show that that BKM treatment activates WEE1, which in turn phosphorylates CDC2 at Tyr15, inactivates CDC2 and inhibits CDC2 activity, leading to G2/M arrest in glioma initiating cells (GICs). We show that treatment with WEE1 inhibitor MK1775 inhibited BKM-induced Cdc2 Tyr15 phosphorylation, and forced GICs to enter into the mitotic phase of the cell cycle. Using a panel of GICs, we show that MK1775 synergizes with BKM to inhibit GBM cell proliferation. Further, MK1775 and BKM as a single agent alone partially blocks proliferation, however, combination of MK1775 and BKM induces apoptosis as evaluated by Annexin V positive cells, cleaved PARP and caspase 3, and TUNEL staining. This effect was observed specifically in p53 mutant cells. Finally we show that depletion of WEE1 by shRNAs synergizes with BKM to inhibit GBM cell proliferation and induce apoptosis. These results indicate that WEE1 inhibition potentiated the effectiveness of PI3K targeted inhibition in GBM, and suggest a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in p53 mutant GBM.
Citation Format: Shaofang Wu, Siyuan Zheng, Shuzhen Wang, W.K.Alfred Yung, Dimpy Koul. WEE1 kinase inhibition enhances PI3K inhibitor response in p53 deficient gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 31. doi:10.1158/1538-7445.AM2015-31
Abstract 3100: Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors
Authors: Lindamulage Indeewari K. , Vu Hai-Yen , Trivedi Dr. Piyush , Lee Dr. Hoyun 
Published: August 2015

Abstract
Agents targeting colchicine-binding site are recognized as valuable lead compounds in the development of new anticancer drugs. Although colchicine can effectively inhibit cell proliferation, its use as an anticancer agent has not been approved by FDA due to its inherent toxicity. To develop colchicine-binding site targeting agents with low or no toxicity, we have created and examined several chalcone derivatives, from which we have identified CTR-17 and CTR-20 as promising leads. We have examined their anti-proliferative activities using three human breast cancer cell lines (MDA-MB-468, MDA-MB-231 and MCF-7) and two matching non-cancer breast cell lines (184B5 and MCF10A). In addition, we also examined their efficacy using one leukemic cell line (K-562) and one cervical cell line (HeLa). Data from this study showed that CTR-17 and CTR-20 preferentially kill cancer cells 10-100 times over non-cancer cells. Data obtained from flow cytometry, confocal microscopy and Western blotting showed that CTR-17 and CTR-20 induced prolonged mitotic arrest prior to killing cancer cells by apoptosis. We also found that both CTR-17 and CTR-20 inhibit tubulin polymerisation and bind to purified tubulin fibers with a dissociation constant of 3.4±1.7 μM and 5.9±1.9 μM, respectively. CTR-17 competitively inhibits the binding of colchicine to tubulin with an inhibitory concentration of 8.67 μM, suggesting that CTR-17 binds to tubulin at a site close to the colchicine binding site. Molecular docking studies confirmed this binding which occurs via three hydrogen bonds and Van der Waals interactions. In our xenograft model of the human breast cancer cells, the treatment of mice with CTR-17 or CTR-20 (30 mg/kg) twice per week for 30 days effectively inhibits tumor growth. The combination of CTR compounds (15 mg/kg/week) and paclitaxel (5 mg/kg/week) increases paclitaxel's anti-tumor activity by 40-60%. Most importantly, both CTR-17 and CTR-20, when used alone or in combination with paclitaxel, showed no notable toxicity to vital organs (spleen, liver, kidney and lung). Therefore, the novel CTR-17 and CTR-20 chalcone derivatives possess substantial potential as safe and effective anticancer drugs.
This project was supported in part from the funds by the Northern Ontario Heritage Funds Corporation, Northern Cancer Foundation, and The City of Greater Sudbury Development Corporation. IKL is a recipient of the Ontario Trillium Scholarship.
Citation Format: Indeewari K. Lindamulage, Hai-Yen Vu, Dr. Piyush Trivedi, Dr. Hoyun Lee. Characterisation of novel chalcone derivatives, CTR compounds as tubulin polymerisation inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3100. doi:10.1158/1538-7445.AM2015-3100
Abstract 3108: MicroRNA-200B inhibits arsenic-transformed cell migration by targeting protein kinase Cα signaling pathway
Authors: Wang Zhishan , Humphries Brock , Yang Chengfeng 
Published: August 2015

Abstract
Arsenic is one of the most common environmental pollutants and long term exposure to arsenic is associated with increased risk of multiple types of cancer including lung cancer. Despite extensive studies, the mechanism of arsenic carcinogenicity has not been elucidated. MicroRNAs (miRNAs) are a large class of small non-coding RNAs and have been shown to play important roles in many fundamental processes of cancer. MiRNA-200b (miR-200b) is a member of miR-200 family, which contains 5 members. The miR-200 family has been shown to inhibit tumor cell migration; however, the underlying mechanisms are not clearly defined. We recently found that miR-200 expression is depleted in arsenic-transformed human bronchial epithelial cells, which are highly migratory and invasive. To further study the mechanism by which miR-200 inhibits tumor cell migration, we investigated the effects of stably expressing miR-200b on arsenic-transformed cell migration. We found that stably expressing miR-200b drastically inhibits arsenic-transformed cell migration. Wnt5b and protein kinase Cα (PKCα) are highly expressed in arsenic-transformed cells. Stably expressing miR-200b significantly down-regulated protein levels of both Wnt5b and PKCα. Combining bioinformatics screening and 3′UTR luciferase reporter assays, we identified PKCα but not Wnt5b as a new direct target of miR-200b. We also found that siRNA knocking down Wnt5b greatly reduces PKCα activation while inactivating PKCα drastically decreases Wnt5b level, revealing a positive feedback loop between Wnt5b and PKCα. Knocking down Wnt5b or PKCα phenocopy the effect of stably expressing miR-200b on cell migration. Moreover, enforced expression of PKCα impairs the inhibitory effect of miR-200b on cell migration. These findings not only reveal a novel mechanism showing that miR-200b inhibits tumor cell migration by targeting PKCα and Wnt5b-PKCα positive feedback loop, also suggest that deregulation of miR-200b, Wnt5b and PKCα plays an important role in arsenic carcinogenesis.
Citation Format: Zhishan Wang, Brock Humphries, Chengfeng Yang. MicroRNA-200B inhibits arsenic-transformed cell migration by targeting protein kinase Cα signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3108. doi:10.1158/1538-7445.AM2015-3108