bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1207: Molecular determinants of CXCR4 trafficking dictate the metastatic potential in breast cancer
Authors: Fruhwirth Gilbert O. , Brock Adrian , Keppler Melanie , Khan Abid , Giamperi Silvia , Sahai Erik , Gillet Cheryl , Archibald Steve J. , Ameer-Beg Simon , Ng Tony 
Published: June 2012

Abstract
The G-protein-coupled CXC chemokine receptor 4 (CXCR4) was shown to be a major determinant in organ-specific metastasis for various cancers. The C-terminus of the receptor contains phosphorylation/ubiquitination sites and residues that interact with adaptor proteins which couple to the endocytosis machinery. Post-endocytic events that lead to a decision between degradation and recycling are hitherto poorly understood.
We used fluorescently tagged receptor molecules stably expressed in breast cancer cells to establish that mutations in the protein kinase C (PKC) site of CXCR4 affect not only the cellular equilibrium between ESCRT-mediated degradation and recycling pathways but also the invasive properties. Importantly, the obtained in vitro results excellently translate to a murine model of breast cancer, in which we found that mutation of the PKC motif influences the metastatic potential. Furthermore, by using fluorescence lifetime imaging (FLIM) to measure direct protein-protein interactions via Förster resonance energy transfer (FRET) we show for the first time that ligand-dependent dimerization of CXCR4 receptors is a crucial mechanistic step in the above processes.
Our findings reveal a new mechanism whereby the penetrance of a mutated receptor that exhibits resistance to its desensitization and confers an enhanced cancer migratory phenotype, is reduced through the dimerization with its wildtype counterpart.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1207. doi:10.1158/1538-7445.AM2011-1207
Abstract 121: Identification of tumor suppressive microRNAs in maxillary sinus squamous cell carcinoma based on microRNA expression signature
Authors: Hanazawa Toyoyuki , Nohata Nijiro , Kikkawa Naoko , Mutallip Muradil , Katayama Akihiro , Harabuchi Yasuaki , Okamoto Yoshitaka , Seki Naohiko 
Published: June 2012

Abstract
Maxillary sinus squamous cell carcinoma (MSSCC) comprises 2-3% of all cancers of head and neck tumor and the annual incidence rate is 0.5-1.0 per 100,000 populations. After introduction of multimodality treatment comprising radiation therapy along with concomitant intra-arterial chemotherapy, rates of local control was improved. However the prognosis of advanced MSSCC is still worse. The 5-years survival rate of T4 tumors is 50% around. Local recurrence is the most common cause of treatment failure and death. Greater understanding of the molecular oncogenic pathways in MSSCC could help improve diagnosis, therapy, and prevention of the disease.
MicroRNAs (miRNAs), non-coding RNA 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. The expression signature of cancer related miRNAs could contribute as useful biomarkers for diagnosis and improvement of prognosis for MSSCC.
No studies have been carried out for the purpose of identifying specific miRNA alterations in MSSCC. In this study, we performed the miRNA expression signature specific to MSSCC by evaluating 749 mature miRNAs expressions in 5 matched pairs of MSSCC tissues and normal maxillary sinus epithelium. A subset of 9 miRNAs was significantly down-regulated in our signature. Gain-of-function analysis revealed that miR-874 was significantly inhibited cell proliferation, suggesting miR-874 has a tumor suppressive function in MSSCC. We are continuing a search of target genes of miR-874 by using genome-wide gene expression analysis.
The identification of tumor suppressive miRNAs and their target genes could provide new insights into potential mechanism of MSSCC carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 121. doi:10.1158/1538-7445.AM2011-121
Abstract 1216: The Fn14 receptor is highly expressed in NSCLC tumors and in NSCLC cell lines harboring EGFR-activating mutations
Authors: Tran Nhan L. , Asrani Kaushal , Jameson Nathan , Inge Landon , Cheng Emily , Hostetter Galen , Weiss Glen , Tuncali Serdar , Bremner Ross , Winkles Jeffrey A. 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer deaths in the USA and worldwide and ∼85% of these cancers are of the non-small cell lung cancer (NSCLC) subtype. Approximately 10-15% of the NSCLC patients in the USA and 30-50% of these patients in Asia have tumors harboring somatic mutations in the epidermal growth factor receptor (EGFR) that cause constitutive activation of this receptor. These patients have the best clinical response to the small molecule EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Here we report that the TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) is frequently overexpressed in NSCLC tumors. We have also found that NSCLC cell lines that contain the same EGFR activating mutations found in patients express high levels of Fn14. Erlotinib treatment of these cells decreases Fn14 levels; therefore, EGFR signaling is indeed triggering Fn14 gene expression in these cell lines. Consistent with this proposal, when EGFR activation mutant receptors (L858R, ΔL747-E749, and D770-N771 insertion) were expressed in rat RL65 lung epithelial cells Fn14 expression was induced. In contrast, RL65 cells expressing a kinase-deficient EGFR receptor (D837A) did not show an increase in Fn14 expression. Since some NSCLC tumors with EGFR activating mutations acquire an additional EGFR mutation (T790M) that promotes TKI resistance, we examined Fn14 levels in a cell line containing both types of mutations. The Fn14 receptor was expressed at high levels in these cells. Finally, we found that shRNA-mediated Fn14 knockdown reduces NSCLC cell migration. Together, these data indicate that EGFR activation in NSCLC cells increases Fn14 gene expression and that Fn14 levels remain elevated in drug resistant cells. Furthermore, Fn14 may play a role in NSCLC cell motility. We propose that Fn14 may be a good biomarker for selection of NSCLC patients most likely to benefit from EGFR TKIs. It may also be a therapeutic target for NSCLC patients; in particular, for those patients with EGFR-driven tumors who have either primary or acquired resistance to EGFR tyrosine kinase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2011-1216
Abstract 122: Downregulated miR-375 in tongue cancer and its putative role as a tumor suppressor microRNA
Authors: Jung Hyun Min , Patel Rushi S. , Cheng Jin Q. , Chan Edward K.L. 
Published: June 2012

Abstract
MicroRNAs are approximately 22-nt RNAs involved in posttranscriptional regulation of target gene expression. Oral cancers are ranked as the sixth most prevalent cancer worldwide, with squamous cell carcinoma accounting for the most common type (83% – 90%). Evolution and progression of oral cancers is thought to result from the accumulation of genetic alterations in molecular pathways. In order to identify aberrantly expressed miRNAs in oral squamous cell carcinomas (OSCCs), miRNA microarray was performed using 3 healthy controls and 17 OSCC tissue samples all derived from human tongue. Clustering expression patterns of miRNAs in the 17 OSCC samples using Pearson correlation coefficient demonstrated TNM stage-dependent miRNA expression pattern in OSCC. In the expression profile, 134 miRNAs (105 upregulated miRNAs and 29 downregulated miRNAs) were identified to be aberrantly expressed in OSCCs (p &lt; 0.05). The expression of miRNAs was validated by quantitative RT-PCR. MiR-375, the most underexpressed miRNA, was 7.2-fold (p=0.004) downregulated in OSCC samples compared to 5 healthy tongue samples. When compared to the control tongue samples, 88% (15/17) of OSCC samples showed lower miR-375 levels. Furthermore, the expression of miR-375 was inversely proportional to the TNM stage score (stage 2: 32.7-fold, p=0.008; stage 4: 38.4-fold, p=0.002). MTS assay showed that transfected miR-375 mimic inhibited cell proliferation of human oral cancer cell line CAL 27 in dose dependent manner. YWHAZ (14-3-3ζ), PDK1, JAK2, and ELAVL4 (HuD) were reported as miR-375 targets in other cancers. These 4 putative miR-375 targets were examined in CAL 27 cells. JAK2 and ELAVL4 were barely detectable in CAL 27 and thus not significantly regulated by miR-375. In contrast, YWHAZ and PDK1 were repressed both at the mRNA (54% and 19%, respectively) and protein levels (∼30% for both) after transfection of miR-375 mimic into CAL 27 cells. Since both YWHAZ and PDK1 genes are known to play important roles in proliferation and possibly in apoptosis, miR-375 may be the gatekeeper for the balance of the two cellular processes. The absence of miR-375 expression and its inhibitory role in oral cancer cells implicates miR-375 as a tumor suppressor miRNA.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 122. doi:10.1158/1538-7445.AM2011-122
Abstract 1220: Enigma blocks Cbl-c-mediated RET ubiquitination and degradation
Authors: Kales Stephen C. , Lipkowitz Stanley 
Published: June 2012

Abstract
RET (rearranged during transfection) is an RTK that is activated by glial cell-derived neurotrophic factors (GDNF) and is critical to neuronal and kidney development. RET mutations causing loss of function are associated with Hirschsprung's disease, while gain of function mutations are associated with thyroid carcinomas and mutiple endocrine neoplasias (MEN2A&B). Cbl proteins are a family of ubiquitin protein ligases that mediate RTK degradation and thereby serve as negative regulators of RTK signaling. Cbl-c (a.k.a. Cbl-3), the most recently identified of the human Cbl proteins, is restricted to epithelial cells and most resembles the Cbl proteins found in lower organisms. Cbl-c can ubiquitinate and downregulate RTKs including activated RET and EGFR. Through yeast two-hybrid screening, we identified the LIM protein Enigma (a.k.a. PDLIM7) as a Cbl-c interacting protein. Enigma is an adapter protein for kinase anchoring to the cytoskeleton and is required for the mitogenic signaling of the RET/PTC2 oncogene. The interaction was confirmed in mammalian cells through co-immunoprecipitation of transfected and endogenous Cbl-c and Enigma. Enigma did not co-immunoprecipitate with c-Cbl or Cbl-b indicating that this interaction is specific to Cbl-c. Cbl-c can ubiquitinate and downregulate an activated form of RET, RET-MEN2A and we show that Enigma prevents Cbl-c-mediated RET ubiquitination and downregulation. This effect is specific to RET as EGFR ubiquitination was unaffected by the presence of Enigma. An Enigma mutant, lacking the RET binding site, does not block Cbl-c recruitment and subsequent ubiquitination and downregulation of RET. Our data suggest that Enigma blocks Cbl-c binding to the RET receptor and prevents its ubiquitination. This is further supported by microscopy data which demonstrates maintained surface expression of RET in the presence of Enigma. Together these data demonstrate a novel interaction between a positive and negative regulator or RET signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1220. doi:10.1158/1538-7445.AM2011-1220
Abstract 1225: α-Catulin promotes tumor growth by preventing cellular senescence
Authors: Chen Yuh-Ling , Fan Li-Ching , Liang Chen-Hsien , Tsai Yao-Tsung , Hsu Keng-Fu , Hong Tse-Ming 
Published: June 2012

Abstract
Cellular senescence is a proven tumor-suppressive strategy that forces transformed cancer cells to re-enter irreversible cell-cycle arrest. Triggering the senescence of tumor cells may contribute to successful cancer therapy. α-Catulin, an α-catenin-related protein, is reported to have tumorigenic potential because it regulates the NF-κB pathway, but little is known about its clinical relevance and the mechanism through which it regulates cancer progression. Here, we provide evidence that the expression of α-catulin is upregulated in most human cancer cells and clinical oral cancer tissues and positively correlated with tumor size (P = 0.001) and cancer stage (P = 0.004) of OSCC. α-Catulin knockdown in the OC2 and A549 cancer cell lines dramatically decreased cell proliferation and contributed to cellular senescence, and inhibited OC2 xenograft growth. Mechanistic dissection showed that α-catulin depletion strongly induced the DNA damage response (DDR) via a p53/p21-dependent pathway in A549 cells, but a p53/p21-independent pathway in OC2 cells carrying mutant p53. Global gene expression analysis revealed that α-catulin knockdown altered several crucial genes related to mitotic chromosome condensation, DDR, and DNA repair systems, which suggests that its depletion-induced cellular senescence might be caused by chromosome condensation failures, severe DNA damage, and impaired DNA repair ability. Our study provides evidence that α-catulin promotes tumor growth by preventing cellular senescence and suggests that downregulating α-catulin may be a promising therapeutic approach for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1225. doi:10.1158/1538-7445.AM2011-1225
Abstract 1226: p53 signaling pathway acts as rescue mechanism to β1 integrin silencing in head and neck cancer cell line
Authors: Kim Mi Ra , Chang Hyo Won , Kim Hyo Jung , Moon So Young , Lee Myung Jin , Han MyungWoul , Kim Seong Who , Kim Sang Yoon 
Published: June 2012

Abstract
β1 integrin's aberrant expression has implicated a cancer progression and resistance to cytotoxic therapy. Moreover, cancer cells gained epithelial mesenchymal transition (EMT) features were more resistant to the detachment-induced cell death. In this regard, we investigated the mechanism by which β1-Integrin governs cell viability and verified whether the signaling pathway is associated with EMT features.
Cancer cell lines from head and neck cancer patients (AMC-HN3 and AMC-HN9) and well-known EMT cancer, MDA-MB231, were used in this study. To determine whether three cell lines reveal the epithelial EMT features, EMT markers such as Snail, vimentin, fibronectin and E-cadherin were evaluated by western blot analysis and immunofluroscence. To knockdown β1 integrin signal, β1 integrin small interfering RNA (siRNA) was transiently transfected into all cell lines. The cell viability was examined by looking at the results of propidium iodide staining, MTT assay, changes in the mitochondrial membrane potential and cell morphology.
MDA-MB231 and AMC-HN9 cells possessed EMT features whereas AMC-HN3 cells were not shown EMT phenotype. β1 integrin silencing cell increased the sub G1 from 1.0% to 29.8%, increased the percentage of cells losing their mitochondrial membrane potential from 5.3% to 65.9% as well as the number of fragmented mitochondria in AMC-HN3 cells. In contrast, MDA-MB231 cells showed more resistance to silencing of β1 integrin, lower cell death rate from 0.6% to 9.6% and less changes in the mitochondrial membrane potential from 4.34% to 34.51%. Interestingly, AMC-HN9 cells showed complete resistance to β1 integrin blocking even though FAK phosphorylation signaling was blocked in AMC-HN9 cells, same as AMC-HN3 cells, which is a different response from typical EMT featured cells. When AMC-HN9 cells were treated to inhibit β1 integrin and p53 separately, it showed no response to changes in the cellular morphology, viability and apoptosis-related signal pathway; however, when it was given the combined β1 integrin and p53, apoptosis occurred in the cell line.
In this study, acquisition of the EMT features in cancer cells presented resistance to the β1 integrin inhibition. In addition, the activation of p53-p21 signaling pathway provided resistance to detachment-induced apoptosis in head and neck cancer cell line with EMT features.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1226. doi:10.1158/1538-7445.AM2011-1226
Abstract 1227: Anti-oncogenic role of Peroxisome proliferator-activated receptor- β/Δ (Pparβ/Δ) involves regulation of viral Hras1 (v-Hras1)-induced senescence and endoplasmic reticulum (ER) stress in mouse primary keratinocytes
Authors: Zhu Bokai , Khozoie Combiz , Bility Moses , Blazanin Nicholas , Glick Adam B. , Gonzalez Frank J. , Peters Jeffrey M. 
Published: June 2012

Abstract
Pparβ/Δ-null mice exhibit enhanced chemically-induced skin tumorigenesis compared to wild-type counterparts. Since an oncogenic mutation of Harvey sarcoma ras virus gene (v-Hras1) is a critical event in chemical carcinogenesis, the role of PPARβ/Δ in mouse primary keratinocytes infected with a retrovirus encoding viral Hras1 (v-Hras1) gene was examined. While v-Hras1 induced senescence in wild-type mouse primary keratinocytes, the level of v-Hras1-induced senescence was significantly reduced in Pparβ/Δ-null keratinocytes, which was due in part to decreased phospho-MEK and phospho-ERK during the early stage of v-Hras1 expression. In addition, while total v-Hras1 protein level was comparable between wild-type and Pparβ/Δ-null keratinocytes, the level of the GTP-bound form of v-Hras1 was significantly decreased in Pparβ/Δ-null keratinocytes from 4 day to 7 day post v-Hras1 infection. Surprisingly, the decreased activity of v-Hras1 did not lead to a decreased level of phospho-AKT in Pparβ/Δ-null keratinocytes. However, Pparβ/Δ-null keratinocytes were more dependent upon PI3K-AKT pathway for maintenance of proliferation and evasion of senescence. Differentially expressed genes between wild-type and Pparβ/Δ-null keratinocytes that are involved in the regulation of senescence were determined by cDNA microarray analysis. Differential expressions of both positive and negative regulators of RAS pathway were observed between wild-type and Pparβ/Δ-null keratinocytes following v-Hras1 infection. Notably, the mRNA encoding CDK inhibitor p27Kip1 was lower in Pparβ/Δ-null keratinocytes, In addition, Pparβ/Δ-null keratinocytes showed enhanced endoplasmic reticulum (ER) stress and unfolded protein response (UPR) post v-Hras1 infection, characterized by enhanced vacuolation and higher levels of major ER stress markers. However, the enhanced ER stress did not lead to apoptosis in Pparβ/Δ-null keratinocytes. These results suggest an anti-oncogenic role of PPARβ/Δ in v-Hras1-transformed mouse primary keratinocytes that involves both the promotion of anti-tumorigenic senescence and attenuation of pro-tumorigenic ER stress and UPR. (Supported by CA124533)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1227. doi:10.1158/1538-7445.AM2011-1227
Abstract 1230: Wnt5a-dependent induction of senescence suppresses epithelial ovarian cancer
Authors: Bitler Benjamin G. , Nicodemus Jasmine P. , Li Hua , Cai Qi , Soring Keri , Birrer Michael J. , Connolly Denise C. , Godwin Andrew K. , Cairns Paul , Wu Hong , Zhang Rugang 
Published: June 2012

Abstract
Epithelial Ovarian Cancer (EOC) remains the most lethal gynecological malignancy in US and is the fifth leading cause of cancer deaths among American women. Thus, there is an urgent need to understand the etiology of EOC to develop novel therapies for this disease. Wnt5a is classified as a non-canonical Wnt ligand. Here, we demonstrated that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOC compared with either normal ovarian surface epithelial cells (p=0.039) or fallopian tube epithelial cells (p&lt;0.001). Importantly, expression of Wnt5a in primary human EOC inversely correlates with tumor stage (p=0.003) but not tumor grade (p=0.086). Interestingly, Wnt5a expression is significantly lower in Type II high-grade serous EOC compared to Type I EOC that includes low-grade serous, mucinous, clear cell and endometrioid subtypes of EOC (p=0.005). In addition, we discovered that hypermethylation of promoter CpG island contributes to Wnt5a downregulation in human EOC cells. Significantly, restoration of Wnt5a expression in human EOC cells promoted senescence of EOC cells and resulted in a dramatic decrease in cell proliferation both in vitro and in vivo in an orthotopic model of EOC in the ovary of SCID mice. Mechanistically, Wnt5a inhibited canonical Wnt/beta-catenin signaling and resulted in the activation of senescence-promoting histone repressor A/PML pathway. In summary, we show that Wnt5a is often expressed at lower levels in primary human EOC and Wnt5a expression suppresses the growth of EOC cells by triggering senescence through antagonizing canonical Wnt signaling. Our data imply that the cell of origin between Type I and Type II EOC is different. These results also suggest that loss of Wnt5a expression is a putative marker of EOC and that non-canonical Wnt signaling is a potent target for developing novel EOC therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1230. doi:10.1158/1538-7445.AM2011-1230