bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1222: p53 downregulates CRKL proto-oncogene protein through miR-200 family
Authors: Sasaki Yasushi , Tamura Miyuki , Kobashi Kenta , Takeda Kousuke , Nakagaki Takafumi , Idogawa Masashi , Tokino Takashi 
Published: August 2015

Abstract
The downregulation of the miR-200 family has been involved in the progression and metastasis of human cancers. The miR-200 family includes two clusters: miR-200b, miR-200a and miR-429 (miR-200b-200a-429) located on chromosome 1; and miR-200c and miR-141 (miR-200c-141) located on chromosome 12. We identified response elements located around both clusters that are responsive to p53 family. Based on the similarity of their seed sequences, miR-200b, miR-200c and miR-429 have identical seed sequences, whereas the seed sequence of miR-141 and miR-200a is similar, but not identical, suggesting that miR-200b, miR-200c and miR-429 share similar mRNAs target. Here, in silico miRNA target prediction identified the v-crk sarcoma virus CT10 oncogene homolog-like (CRKL) as a potential target for miR-200b, miR-200c and miR-429 (miR-200b/200c/429). miR-200b/200c/429 inhibits the expression of CRKL mRNA and protein by directly targeting its 3′-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells with introduction of wild-type p53 and TAp63γ. Oncomine database shows that CRKL levels are significantly overexpressed in multiple cancer types compared with the corresponding normal tissues. We also found that CRKL was overexpressed in primary breast cancer tissues harboring mutant p53 genes. Our results indicate that miR-200b/200c/429, a p53-inducible miRNA, is a negative regulator of the CRKL oncoprotein and suggest a new p53-miR-200-CRKL pathway in carcinogenesis.
Citation Format: Yasushi Sasaki, Miyuki Tamura, Kenta Kobashi, Kousuke Takeda, Takafumi Nakagaki, Masashi Idogawa, Takashi Tokino. p53 downregulates CRKL proto-oncogene protein through miR-200 family. [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 1222. doi:10.1158/1538-7445.AM2015-1222
Abstract 1224: Identification of novel p53 targets by RNA sequencing in mice liver tissues
Authors: Koguchi Tomoyuki , Tanikawa Chizu , Kojima Yoshiyuki , Nakagawa Hidewaki , Nakamura Yusuke , Matsuda Koichi 
Published: August 2015

Abstract
In response to various type of cellular stress such as X-ray irradiation, ultraviolet exposure, and oxidative stress, the p53 protein is activated and regulates its target genes that induce cell cycle arrest, senescence, DNA repair, and apoptosis. Inactivation of the p53 gene is the most common alterations observed in human cancers. Therefore, identification of p53-target genes would help us to understand molecular carcinogenesis. However, an entire picture of the p53 signaling pathway has not been disclosed yet.
To elucidate the mechanism whereby p53 suppress tumor development, we purified RNA of 19 organs from p53+/+ or p53-/- mice with or without 10 Gy of X-ray irradiation. RNA sequence analysis of 228 tissues provided expression profile of 23813 genes. Then we screened genes which satisfy the following criteria at least one organ; median FPKM value after radiation in p53WT mice is more than two-fold higher than that of those in other groups with p-value of 0.05 by t-test; median FPKM value after radiation in p53WT mice is more than one. Among 119 previously identified p53 targets with functional p53 binding motifs, 70 targets were induced by DNA damage in at least one mice tissues.
Then we selected 16 candidates those were induced in mice liver. Quantitative PCR analysis using HepG2 human hepatocellular carcinoma cells revealed that four genes were induced by adriamycin treatment in a p53-dependent manner. Through these screening, here we identified p53-dependent inositol phosphate converting enzyme (PICE) as a direct target of p53. p53 induced PICE protein and mRNA in both human and mice. In addition we identified p53 binding sequence within its promoter region and exon 7 of the PICE gene. p53 also increased an inositol isomer synthesis in response to DNA damage. Our findings revealed the novel role of p53 in inositol phosphate metabolism.
Citation Format: Tomoyuki Koguchi, Chizu Tanikawa, Yoshiyuki Kojima, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Identification of novel p53 targets by RNA sequencing in mice liver tissues. [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 1224. doi:10.1158/1538-7445.AM2015-1224
Abstract 1225: Proteome-wide analysis of gain-of-function mutant p53 targets in breast cancer implicates PARP, PCNA and MCM4 as oncogenic drivers
Authors: Polotskaia Alla , Xiao Gu , Reynoso Katherine , Martin Che , Qiu Wei-Gang , Hendrickson Ronald , Bargonetti Jill 
Published: August 2015

Abstract
Gain-of-function mutant p53 (mtp53) changes the cancer cell transcriptome. However no analysis of mtp53-associated proteome diversity has been carried out. We coupled cell fractionation with stable isotope labeling with amino acids in cell culture (SILAC) and inducible knockdown of endogenous mtp53 to determine the mtp53 driven proteome. Using SILAC followed by tandem mass spectrometry (LC-MS/MS) we identified that R273H mtp53 expression in MDA-MB-468 breast cancer cells both up and down-regulated multiple proteins and metabolic pathways. We sequenced 73,154 peptide pairs that corresponded to 3010 proteins detected under reciprocal labeling conditions. Importantly the high impact regulated targets included the previously identified transcriptionally regulated mevalonate pathway proteins but also identified two new levels of mtp53 protein regulation for non-transcriptional targets. Interestingly, mtp53 depletion profoundly influenced poly (ADP-ribose) polymerase 1 (PARP1) localization, with increased cytoplasmic and decreased chromatin-associated PARP1. An enzymatic PARP shift occurred with high mtp53 expression resulting in increased poly-ADP-ribosylated proteins in the nucleus. Mtp53 increased the level of PCNA and MCM4 protein without changing the amount of pcna or mcm4 transcript. Pathway enrichment analysis ranked the DNA replication pathway above the cholesterol biosynthesis pathway as an R273H mtp53 activated proteomic target. Knowledge of the proteome diversity driven by mtp53 suggests DNA replication and repair pathways are major targets of mtp53 and highlights consideration of combination chemotherapeutic strategies targeting cholesterol biosynthesis and PARP inhibition.
Acknowledgements. This work was supported by a grant to JB from the Breast Cancer Research Foundation.
Citation Format: Alla Polotskaia, Gu Xiao, Katherine Reynoso, Che Martin, Wei-Gang Qiu, Ronald Hendrickson, Jill Bargonetti. Proteome-wide analysis of gain-of-function mutant p53 targets in breast cancer implicates PARP, PCNA and MCM4 as oncogenic drivers. [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 1225. doi:10.1158/1538-7445.AM2015-1225
Abstract 1229: E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis
Authors: Zhang Cen , Liu Juan , Wang Xiaolong , Young Ken H. , Hu Wenwei , Feng Zhaohui 
Published: August 2015

Abstract
Tumor suppressor p53 plays a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications. Ubiquitination is the most important post-translational modification for p53. TRIM32 is a protein of the tripartite motif (TRIM) family. The proteins of TRIM family have been reported to be involved in different biological processes, including cell growth, differentiation, development, muscular physiology, innate immune response and cancer. However, like the majority of TRIM family proteins, the biological function of TRIM32 is not well-understood. Here, we identified TRIM32 as a novel p53 target gene and E3 ubiquitin ligase for p53. In response to stress, including ionizing radiation (IR) and chemotherapeutic agents (e.g. etoposide and 5-fluorouracil), p53 protein binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 protein interacts with p53 protein and promotes p53 degradation through ubiquitination to negatively regulate p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. Thus, p53 and TRIM32 form a novel negative feedback loop in cells to regulate p53 protein levels and function. TRIM32 is frequently overexpressed in different types of human tumors, including lung, colorectal and liver cancers. TRIM32 overexpression promotes the oncogenic transformation of primary mouse embryonic fibroblasts in a largely p53-dependent manner. Furthermore, TRIM32 overexpression promotes tumorigenesis in mice through the down-regulation of p53 function. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 plays an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis.
Citation Format: Cen Zhang, Juan Liu, Xiaolong Wang, Ken H. Young, Wenwei Hu, Zhaohui Feng. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. [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 1229. doi:10.1158/1538-7445.AM2015-1229
Abstract 123: Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1
Authors: Nakanishi Yoshito , Akiyama Nukinori , Tsukaguchi Toshiyuki , Fujii Toshihiko , Satoh Yasuko , Mizuno Hideaki , Ishii Nobuya , Aoki Masahiro 
Published: August 2015

Abstract
Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding fibroblast growth factor receptor (FGFR) family members. However, most fusion genes are not functionally well characterized, and the oncogenicity of some fusions as well as their potential sensitivity to targeted therapy are still unclear. In a previous study, we investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). The FGFR3-BAIAP2L1 fusion gene was identified in 4 bladder cancer patients and 2 lung cancer patients via screens involving PCR and a break-apart fluorescence in situ hybridization assay. The functional analysis of FGFR3-BAIAP2L1 transfectant in Rat-2 fibroblast cells (Rat-2_F3-B) indicated that FGFR3-BAIAP2L1 forms a dimer via the Bin-Amphiphysin-Rvs (BAR) BAIAP2L1 dimerization domain that constitutively activates its FGFR3 kinase activity. CH5183284/Debio 1347*, a selective FGFR inhibitor, effectively inhibits growth of Rat-2_F3-B both in vitro and in vivo, indicating that the FGFR3 kinase activity is critical for tumorigenic activity of this fusion. These results indicate a potential application of FGFR inhibitors to treat FGFR3-BAIAP2L1fusion gene positive patients.
In this study, we further elucidate the mechanism of tumorigenic potential of FGFR3-BAIAP2L1A by a comprehensive gene expression analysis of 4 cell lines (Rat-2_mock, Rat-2_FGFR3, Rat-2_F3-B, and Rat-2_BAIAP2L1) using RNA sequencing. We identified 143 up-regulated and 67 down-regulated genes specifically engaged by FGFR3-BAIAP2L1. Our gene signature analysis with this gene set revealed that FGFR3-BAIAP2L1 activates growth signals, such as the mitogen-activated protein kinase pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. Analysis by Western blot in xenograft tissues confirmed the activation and inactivation status of those pathways. These data suggest that a concurrent regulation of an oncogenic pathway and a tumor-suppressive pathway results in the tumorigenic potential of FGFR3-BAIAP2L1.
*CH5183284/Debio 1347 was discovered by Chugai Pharmaceutical Co., Ltd. and is being developed by Debiopharm International S.A. under an exclusive worldwide license.
Citation Format: Yoshito Nakanishi, Nukinori Akiyama, Toshiyuki Tsukaguchi, Toshihiko Fujii, Yasuko Satoh, Hideaki Mizuno, Nobuya Ishii, Masahiro Aoki. Mechanism of oncogenic signal activation by the novel fusion kinase FGFR3-BAIAP2L1. [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 123. doi:10.1158/1538-7445.AM2015-123
Abstract 1233: Impairment of TFF3 induces cellular apoptosis in prostate cancer cell lines and overexpression of TFF3 may be a prognostic biomarker in human prostate cancers
Authors: Kim So-Youn , Liu Ji-Ying , Chung Yeun-Jun 
Published: August 2015

Abstract
Background: Human trefoil factor 3(TFF3)/ Intestinal trefoil factor(ITF) is originally known well as an essential regulator for epithelial restitution in gastrointestinal tract and also suggested as a potential cancer marker in serum. Furthermore, the aberrant overexpression of TFF3 has been reported in various human cancers, majorly colorectal cancers, suggesting that TFF3 may play a critical role in tumor growth. However, its molecular signaling pathway remains unclear.
Objective: To clarify whether TFF3 is related to survival/anti-apoptotic cell signaling pathways, and to determine that tff3 could be a molecular marker in prostate cancers.
Design, Setting, and Participants: TFF3 gene was silenced by using siRNA in prostate cancer two kinds of cell lines, LNCap and PC3, following investigation of genes related to apoptosis and cell migration. The expression of TFF3 was analyzed by immunohistochemistry in 109 prostate cancer and 106 normal prostate tissues.
Results and Limitations: TFF3 silenced prostate cancer cell lines exhibited increased annexin V binding and the activation of caspase-9 and caspase-3 which are crucial for programmed cell death, consistent with an increased rate of apoptosis, reduced rate of proliferation and migration. In human prostate cancer tissue microarray, TFF3 was positive in 54.7% (49.1%, 2+; 5.6%, 1+) of cancer cases (59/108) and 2.8% (1.9%, 2+; 0.9%, 1+) of morphologically normal tissue cases (3/106), P&lt;0.0001.
Conclusions: The results suggest that TFF3 expression seems play a role in promoting cell survival and be a potential useful marker in prostate cancers. In these contexts, TFF3 in human prostate cancers deserves further investigation to exploit as a cancer marker and anticancer drug.
Citation Format: So-Youn Kim, Ji-Ying Liu, Yeun-Jun Chung. Impairment of TFF3 induces cellular apoptosis in prostate cancer cell lines and overexpression of TFF3 may be a prognostic biomarker in human prostate cancers. [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 1233. doi:10.1158/1538-7445.AM2015-1233
Abstract 1240: Boric acid inhibits cell proliferation through RB1 protein in head and neck cancer
Authors: Gunduz Esra , Hatipoglu Omer Faruk , Cigdem Sadık , Erdogan Kubra , Elitok Mustafa Semih , Grenman Reidar , Erdamar Husamettin , Gunduz Mehmet 
Published: August 2015

Abstract
Boric acid is a very common chemical used in a wide variety of applications as well as in medicine. In this study, the usage of boric acid as a potential alternative cancer therapeutic was investigated by examining its effect in head and neck cancer cell line proliferation and tumor suppressor gene expression.
Head and neck cancer cell lines UT-SCC 6A, 6B, 9A, 16A, 16B, 24A, 54C, 74A, and 74B were treated with varying doses of boric acid, ranging from 200 ug/mL to 1800 ug/mL and XTT assay was used to measure the dose response. Subsequently, RNA was isolated from treated cells and was converted to cDNA to evaluate the expression of P53, RB1, ING1 and ING3 via Real-time PCR. Also protein was isolated from the same cell lines for Western Blot analysis.
Boric acid treatment caused a significant decrease in proliferation in all of the head and neck cancer cell lines investigated, including UT-SCC 6A, 6B, 9A, 16A, 16B, 24A, 54C, 74A, and 74B. Results from boric acid treatment and untreated controls were analyzed for statistical significance using Mann Whitney U test. The results approached statistical significance with p value of 0.05. After determining the effective doses, cell lines were treated with boric acid and gene expression of P53, RB, ING1 and ING3 were analyzed. All of the genes’ expression were increased in several of the cell lines examined. We couldn't detect the protein expression of ING1 and ING3. But we’ve detected the higher expression of Phospho (PP)-RB and Bax, lower expression of bcl2 protein.
In short, our results displayed similar results to prostate cancer reported in literature in terms of inhibition of proliferation. We’ve showed that boric acid has reduced levels of cell proliferation in head and neck cancer cell lines for the first time in our study. Also higher expression of PP-RB indicated that boric acid stopped cell cycle at G1. As a pro-apoptotic Bax expression was up-regulated and anti-apoptotic bcl2 was down-regulated in some of the cell lines showing that boric acid may lead the cells to apoptosis. In the light of these results, boric acid appears to be a candidate alternative therapeutic agent for cancer. Of course, further experiments are necessary in order to strengthen this conclusion.
Citation Format: Esra Gunduz, Omer Faruk Hatipoglu, Sadık Cigdem, Kubra Erdogan, Mustafa Semih Elitok, Reidar Grenman, Husamettin Erdamar, Mehmet Gunduz. Boric acid inhibits cell proliferation through RB1 protein in head and neck 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 1240. doi:10.1158/1538-7445.AM2015-1240
Abstract 1251: Expression of NADPH oxidase 5 (Nox5) modulates cellular morphology, proliferation and invasiveness of human melanoma UACC-257 cells
Authors: Antony Smitha , Wu Yongzhong , Jiang Guojian , Meitzler Jennifer L. , Liu Han , Juhasz Agnes , Lu Jiamo , Anver Miriam R. , Roy Krishnendu K. , Doroshow James H. 
Published: August 2015

Abstract
NADPH oxidase 5 (Nox5), one of the seven members of the NADPH oxidase gene family that generate reactive oxygen species (ROS), has been implicated in physiological and pathophysiological processes. Recently, we have reported substantial overexpression of Nox5 in several human cancers including those of prostate, ovary and melanomas; expression in most non-malignant tissues was weak to modest. Despite being upregulated in many human cancers and implicated in promoting cell proliferation, the molecular mechanisms regulated by Nox5 are poorly understood. In this study, the functional significance of Nox5 was assessed in human UACC-257 melanoma cells by generating stable Nox5-overexpressing clones and knockdown clones. Overexpression of Nox5 in UACC-257 cells resulted in enhanced cell growth, increased BrdU positive cells and decreased phosphatase activity. Additionally, these cells had increased normoxic Hif-1α expression and decreased p27Kip1 expression. Conversely, knockdown of endogenous Nox5 in UACC-257 cells resulted in decreased cell growth, decreased BrdU positive cells, decreased Hif-1α expression and increased p27Kip1 expression. Cadherin switch, loss of E-cadherin expression and upregulation of N-cadherin was observed in Nox5 overexpressing cells indicative of an invasive phenotype; conversely, an upregulation of E-cadherin expression in Nox5 knockdown cells was noted. Cell invasion assay through matrigel-coated membranes also demonstrated enhanced invasion by Nox5 overexpressing cells. Additionally, 3D cultures of Nox5 overexpressing cells exhibit an amoeboid morphology compared to that of the Nox5 knockdown cells that were mesenchymal, suggestive of an amoeboid - mesenchymal (AMT) transition. Strikingly, cells that overexpress Nox5 were able to proliferate in serum-free conditions for over a month. In summary, our findings suggest that Nox5 expression in human melanoma UACC-257 cells could contribute to cell proliferation, invasion, amoeboid morphology, and the ability to grow in the absence of serum or growth factors in part due to the generation of high local concentrations of extracellular ROS that modulate multiple signaling networks that regulate Hif-1α, p27Kip1, and the cadherin switch.
Citation Format: Smitha Antony, Yongzhong Wu, Guojian Jiang, Jennifer L. Meitzler, Han Liu, Agnes Juhasz, Jiamo Lu, Miriam R. Anver, Krishnendu K. Roy, James H. Doroshow. Expression of NADPH oxidase 5 (Nox5) modulates cellular morphology, proliferation and invasiveness of human melanoma UACC-257 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 1251. doi:10.1158/1538-7445.AM2015-1251
Abstract 1253: Selectivity of regulated IRE1 dependent decay of RNA controls pro-oncogenic signaling in glioblastoma
Authors: Chevet Eric 
Published: August 2015

Abstract
Glioblastoma multiforme (GBM) is the most lethal form of glioma with an overall survival at 5 years nearly null (&lt; 5%). Increasing evidences point towards the RNase activity of IRE1 as a central player in GBM development, particularly in cancer cell invasion and tumor vascularization. Indeed, IRE1 promotes XBP1 mRNA splicing, a well-described cytoprotective transcription factor that is required for cancer cell survival. Moreover, regulated IRE1 dependent decay of RNA (RIDD) leads to opposite effects on cell fate depending the ER stress intensity or duration and on the target RIDD substrates. Recent studies unraveled the presence of somatic mutations on the IRE1 gene in GBM that could play a driver role but without providing any functional information. Here, we have sequenced IRE1 exons in 23 human GBMs and identified a new somatic mutation on the IRE1 gene. Interestingly, using biochemical approaches and an orthotopic tumor graft mouse model we show that this variant displays an altered RIDD selectivity in particular towards the specific RIDD substrates already characterized in GBM (SPARC and PER1) and also miR-17, a previously described RIDD substrate whose expression has also a prognostic value in GBM. IRE1-dependent gene expression pattern alterations lead to major functional consequences in terms of tumor phenotype including (i) a magnified induction of the inflammatory and pro-angiogenic pathways based on transcriptome signatures and (ii) an increase of the aggressiveness/infiltration potential of U87 derived tumors in mice. This study provides the first evidence that RIDD substrates selectivity can be modulated and unravels the first mechanistic example of how a somatic mutation in the IRE gene can provide adaptive advantages to glioblastoma cells.
Note: This abstract was not presented at the meeting.
Citation Format: Eric Chevet. Selectivity of regulated IRE1 dependent decay of RNA controls pro-oncogenic signaling in glioblastoma. [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 1253. doi:10.1158/1538-7445.AM2015-1253