bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3075: MUC4 mucin as a potential tumor suppressor in colon cancer
Authors: Das Srustidhar , Ponnusamy Moorthy Palanimuthu , Johansson Sonny L. , Senapati Shantibhusan , Pandey Poomy , Roy Hemant K. , Batra Surinder K. 
Published: February 2011

Abstract
MUC4 is a heterodimeric large transmembrane mucin expressed by several normal epithelial tissues like testis, lungs and colon and is aberrantly over expressed by most human adenocarcinomas. MUC4 has been strongly implicated to play the role of an oncogene in the progression and metastasis of pancreatic, breast and ovarian cancers. On the other hand, previous reports indicating the loss of MUC4 expression in the progression of colon cancer was starkly in contrast to the role it plays in other cancers. Based on the previous studies, we hypothesized that loss of MUC4 as the tumor progresses might act as a prognostic indicator and MUC4 might act as a potential tumor suppressor in the colon cancer. In the present study, our aim was to investigate the functional significance of MUC4 in colon cancer progression. We performed immunohistochemistry on a tissue microarray comparing the expression levels of MUC4 among normal colon, adenoma, adenocarcinoma and metastatic adenocarcinoma. MUC4 immunoreactivity was highest in the normal colon tissue and significantly higher than tubular adenoma, non-metastatic and metastatic adenocarcinoma (p&lt;0.03) which confirmed the earlier findings. To evaluate the functional significance of MUC4, we stably over expressed MUC4 cDNA in HCT-15, a MUC4 non-expressing colon cancer cell line. Interestingly, the in vitro (growth kinetics, motility, invasion, colony forming) and in vivo (xenograft in nude mice) functional studies strongly support the role of MUC4 as a tumor suppressor in colon cancer. Further, mechanistic studies indicated that ectopic expression of MUC4 led to decreased activity of key intracellular signaling molecules like FAK, AKT and ERK. By regulating the levels of p-AKT, MUC4 expression led to growth arrest in S-phase which was mediated by the upregulation of cip/kip family of CDK inhibitors i.e. p21 and p27. Besides, overexpression of MUC4 led to a remarkable change from mesenchymal like (more triangular) phenotype to a more epithelioid (roundish) like phenotype confirmed by the phalloidin staining of the actin cytoskeleton. In conclusion, our results show for the first time the protective role MUC4 plays in colon cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3075.
Abstract 3077: LARP7: Potential novel tumor suppressor gene in gastric cancer
Authors: Cheng Yulan , Jin Zhe , Montgomery Elizabeth , Agarwal Rachana , Yang Jian , Hamilton James , Selaru Florin , Olaru Alexandru , David Stefan , Abraham John M. , Stephen Meltzer J. , Mori Yuriko 
Published: February 2011

Abstract
Gastric cancer is one of the most deadly of all human tumors. However, little is known about events leading to this deadly disease. We previously reported that the RNA binding protein gene, La ribonucleoprotein domain family, member 7 (LARP7) was frequently subjected to genetic aberration in gastric cancers. LARP7 stabilizes the noncoding 7sk small nuclear RNA (7sk), and both LARP7 and 7sk compose 7sk snRNP that negatively regulates the positive transcription elongation factor b (P-TEFb). Hyperactive P-TEFb has been associated with hyper-proliferation and de-differentiation in various tissues. Therefore, the functional loss of LARP7 may contribute to gastric tumorigenesis. In the current study, we evaluated the involvement of LARP7 in human gastric cancer by assessing the LARP7 expression in normal and cancerous gastric tissues as well as by LARP7 knockdown in normal gastric epithelial cells. Methods: LARP7 expression was assessed by real-time quantitative RT-PCR in 30 normal and 25 cancerous gastric tissues. LARP7 knockdown was performed by the specific siRNA transient transfection in an immortalized normal human gastric epithelial cell line, HFE-145. Results: LARP7 mRNA expression was significantly decreased in gastric cancers compare to normal tissues (34.5% reduction, p&lt;0.01). LARP7-targeting siRNA transfection in HFE-145 cells resulted in increased cell proliferation by 23% relative to the control siRNA transfection (p&lt;0.05; measured by WST assay). We also observed a 28% decrease in 7sk quantity in LARP7-targeting siRNA transfectant relative to control siRNA transfectant (p&lt;0.01). Conclusions: LARP7 downregulation is present in primary human gastric cancers and promotes 7sk downregulation as well as cell proliferation of normal gastric epithelial cells in vitro. Taken together, genetic aberrations that downregulate LARP7 may promote gastric tumorigenesis via p-TEFb deregulation. Further studies are warranted to explore the precise anti-tumor mechanisms of LARP7 and its potential role in the clinical care of patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3077.
Abstract 3081: Loss of Shoca-2 expression in colorectal cancer correlates with metastasis as Shoca-2 represses EGF-regulated STAT3 activation via recruitment of PP1beta
Authors: Loeffler Sébastien , Kovac Michal , Zuklys Saulius , Keller Marcel , Hess Daniel , Piscuoglio Salvatore , Terraciano Luigi , Heinimann Karl , Holländer Georg 
Published: February 2011

Abstract
Objective: We sought to define in colorectal cancer (CRC) the function of Shoca-2 (a.k.a. SH2D4A), an until now uncharacterized SH2 domain-containing protein.
Methods: Tandem affinity purification, immunoprecipitation, site-specific mutagenesis, shRNA expression targeting and gene expression analysis were used to characterize binding partners of human Shoca-2 and identify the signaling pathway(s) where this adapter protein is involved. To assess Shoca-2 function on cell growth, colony formation assays and cell cycle analyses were carried out. CRC biopsies were analyzed by immunohistochemistry and molecular genetic methods for the presence of Shoca-2.
Results: Here we demonstrate that Shoca-2 forms a complex with EGFR and STAT3. In response to EGF signaling, a Shoca-2/STAT3 dimer dissociates from EGFR and recruits the serine/threonine phosphatase PP1beta to the complex. Consequently, STAT3 activity is repressed and the EGF signaling pathway ceases to be activated. A lack of Shoca-2 expression secondary to a genomic loss of the locus is frequently observed in metastatic colorectal cancer and correlates with an increase in phosphorylated STAT3 in these cells. Conversely, the ectopic expression of wild type Shoca-2 but not of a mutant form defective in its ability to bind to PP1beta suppresses STAT3-dependent tumor cell growth.
Conclusion: Our results identify Shoca-2 as a tumor suppressor that acts upon EGF stimulation as an adaptor protein to target STAT3 for dephosphorylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3081.
Abstract 3082: A paradoxical suppressive role for Src in urothelial carcinoma
Authors: Pollard Courtney , Thomas Shibu , Harding Michael A. , Theodorescu Dan 
Published: February 2011

Abstract
The most prevalent type of bladder cancer in western nations is urothelial carcinoma (UC). A significant number of patients with UC present with the muscle invasive form of the disease that is treated by radical cystectomy. Even with these treatments approximately 50% of these patients will develop metastases, resulting in essentially incurable disease. Thus, understanding the molecular basis of metastases in UC may prove useful in providing new therapeutic insights and targets. Src (v-Src sarcoma viral oncogene homolog) has been found to play pivotal oncogenic roles in a variety of in vitro and in vivo cancer models. Interestingly, when Src expression and activity was evaluated in a panel of bladder cancer cell lines and human bladder cancer tissue, it was shown that there was an inverse correlation between Src expression/activity and bladder tumor grade, suggesting that the Src oncogene might play a paradoxical suppressive role in UCs.
Herein, we show that that stable expression of constitutively active Src in a high grade bladder cancer cell line (UMUC3) corresponds to a decrease in in vitro monolayer growth (p = 0.05), Boyden Chamber migration (over a period of time where growth effects are inconsequential) (p &lt; 0.01) and a reduction of experimental lung metastases in nude mice (p &lt; 0.036). Supportive of this surprising finding that Src is a suppressor of various malignant phenotypes, we demonstrate that pharmacological inhibition of Src tyrosine kinase activity in the KU7 non invasive UC cells that have high Src expression and tyrosine kinase activity increases cellular proliferation and anchorage independent growth, compared to carrier treated controls. Interestingly, we show that stimulation of FGFR3, a tyrosine kinase receptor that has been associated with low grade and stage non- invasive bladder cancers with favorable prognoses, leads to induction of Src kinase activity in the KU7 cell line. Taken together, these data suggest direct evidence that Src acts paradoxically as a suppressor or aggressive urothelial cancer phenotypes and provide a possible explanation how FGFR3 activity may maintain a non aggressive tumor phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3082.
Abstract 3085: Overexpression of the NOTCH3 intracellular domain alters neuroendocrine phenotype in carcinoid tumor cells
Authors: Jaskula-Sztul Renata , Pisarnturakit Ponghtep , Kunnimalaiyaan Muthusamy , Chen Herbert 
Published: February 2011

Abstract
Introduction: There are four mammalian Notch receptors (Notch1-4), which exhibit unique and overlapping expression pattern and act as oncogenes or tumor suppressor genes depending on the cell and context type. We previously reported that Notch1 pathway is minimally active in neuroendocrine (NE) tumors. Furthermore, induction of the Notch1 signaling pathway by over- expression or by pharmacological treatment with valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) suppresses hormone secretion. However, the role of other Notch isoforms is not clear in carcinoid. In this study, we analyzed the presence of Notch isoforms and their regulatory role on chromogranin A (CgA), a clinically important NE marker, and achaete-scute complex-like1 (ASCL1), a known downstream target of Notch.
Methods: Expression of four Notch isoforms was quantified by real time RT-PCR from parental BON cells (GI carcinoid) and VPA treated BON cells. pcDNA3.3 TOPO plasmid containing constitutively expressed human active portion of Notch3, NICD3, was transiently transfected into BON cells and the cell lysates were tested for the presence of NOTCH3. The levels of NE markers such as CgA and ASCL1 were analyzed by Western blot.
Results: Gene expression analysis showed that the parental BON cells had very minimal levels of Notch1-3. Notch4 expression was not detected. In VPA treated cells, the levels of Notch1, 2 and 3 were increased significantly. Overall, the Notch3 expression level was higher than Notch1 and 2 in VPA treated cells. Importantly, there was a 60-fold induction of Notch3 expression in VPA treated cells compared to parental untreated cells. VPA treatment also resulted in a 15-fold and 20-fold increase for Notch1 and Notch2 respectively whereas Notch4 was not detected in these cells. The constitutive expression of NICD3 in BON cells resulted in a reduction in ASCL1 and CgA.
Conclusions: Carcinoid tumor cells have a paucity of all Notch isoforms, including Notch3. For the first time, we demonstrate that Notch3 regulates the NE phenotype, and may play an important role in regulating carcinoid tumor progression. These findings warrant further investigation on targeting Notch3 for carcinoid cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3085.
Abstract 3086: Gain of chromosome 13 is a cause of CDK8 overexpression associated with colorectal adenoma to carcinoma progression
Authors: Carvalho Beatriz , Postma Cindy , Mongera Sandra , van Diemen Pien , Ylstra Bauke , Meijer Gerrit A. 
Published: February 2011

Abstract
Introduction: Colorectal adenomas are common precursors of colorectal cancer (CRC). About only 5% of adenomas progress to cancer and this progression is mostly associated with overall onset/increase of chromosomal instability. Gain of 13q is often implicated in this progression of adenoma to carcinoma (1). Until recently however no genes were identified to be the drivers of this amplicon. Recently, Firestein and collaborators (2) showed that cyclin 8 (CDK8), at 13q12.13, functions as an oncogene in CRC.
The aim of this study was to evaluate CDK8 gene dosage effects in colorectal adenoma to carcinoma progression.
Material and methods: Sixty seven colorectal tumours (34 adenomas and 28 carcinomas) were analysed by array CGH (5k BAC platform, including contig coverage of 13q) and by expression microarray (30k Compugen library). Integration of DNA copy number dosage and gene expression was performed using the Ace-it tool (3).
Results: In the tumours analysed we observed 13q copy number gain in 9% and 46% of adenomas and carcinomas, respectively. Integrating copy number and mRNA expression with the differential upregulation of genes between carcinomas and adenomas, provided us with a list of 43 genes. Within this list, CDK8 ranked 7th in significancy (p=0.003).
Conclusions: Copy number gain of 13q has a gene dosage effect on CDK8 mRNA expression, indicating a role of this gene in colorectal adenoma to carcinoma progression.
(1) Hermsen M, Postma C, Baak J, Weiss M, Rapallo A, Sciutto A, Roemen G, Arends JW, Williams R, Giaretti W, De Goeij A, Meijer G. Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. Gastroenterology 2002 Oct;123(4):1109-19.
(2) Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, Ogino S, Chheda MG, Tamayo P, Finn S, Shrestha Y, Boehm JS, Jain S, Bojarski E, Mermel C, Barretina J, Chan JA, Baselga J, Tabernero J, Root DE, Fuchs CS, Loda M, Shivdasani RA, Meyerson M, Hahn WC. CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 2008 Sep 25;455(7212):547-51.
(3) van Wieringen WN, Belien JA, Vosse SJ, Achame EM, Ylstra B. ACE-it: a tool for genome-wide integration of gene dosage and RNA expression data. Bioinformatics. 2006 Aug 1;22(15):1919-20.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3086.
Abstract 3088: Mammalian sterile-20 like kinase 1(Mst1) upregulates cyclin D1 to promote hepatocellular carcinoma cell growth
Authors: Ng Yuen Keng , Lui Vivian Wai Yan , Cheng Alfred Sze Lok , Chen George Gong , Lai Paul Bo-san 
Published: February 2011

Abstract
Although hepatocellular carcinoma (HCC) is highly related to the chronic infection of hepatitis B or C viruses, the progression of the malignancies is caused by the increased proliferation of the HCC cells. The proliferation of tumor cells is usually resulted from dysregulations in cell cycle progression or apoptosis induction. Current evidence indicates that the cytoplasmic serine/threonine kinase Mammalian Sterile-20 like kinase 1 (Mst1) suppresses HCC development by inactivating the oncoprotein YAP65 in normal livers. Furthermore, upon DNA damage, the caspase cleavage of the full-length cytoplasmic Mst1 proteins is activated, which then leads to Mst1 nuclear translocation and apoptosis induction via transcriptional activation of the Forkhead tumor suppressor Foxo3a. Using an HCC cell line model, the Hep3B cells, we found that transient transfection of Mst1 did not induce apoptosis, but rather enhanced the cellular proliferation by 74% within 2 days after transfection. The growth-promoting activity of Mst1 in the HCC cells was confirmed as Hep3B cell growth was significantly reduced by transient expression of the Mst1 kinase dead mutant (26% reduction) or Mst1 specific shRNAs (62% reduction). The Mst1-induced cell proliferation was further evidenced by the presence of Ki67 nuclear staining in the transfected Hep3B cells while the cells expressing the kinase dead mutant of Mst1 did not have Ki67 nuclear staining. Moreover, Western blot analyses showed that phosphorylation of YAP65 was not dependent upon Mst1 overexpression, suggesting that the hippo pathway was not involved in the Mst1 induced cell proliferation. Interestingly, Western blotting showed that such a growth-promoting activity of Mst1 in Hep3B cells was associated with a sustained upregulation of Cyclin D1 expression, an important marker for proliferation, after Mst1 overexpression. Our findings suggest that an alteration of Mst1 function exists in HCC cells, which drives aberrant HCC proliferation via Cycin D1 upregulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3088.
Abstract 309: RSK2 mediates NF-κB activity through the phosphorylation of IκBα in the TNF-R1 pathway
Authors: Cho Yong Yeon , Peng Cong , Ma WeiYa , Bode Ann , Dong Zigang 
Published: February 2011

Abstract
The ribosomal S6 kinase 2 (RSK2) mediates proliferation, survival, and malignant transformation. Activation of nuclear factor kappa B (NF-κB) results in the transcription of anti-apoptotic genes and is mediated by I-kappaB kinases (IKKs). IKK(α/β) phosphorylates IκBα at Ser32/Ser36 in the presence of TNF-α to induce IκBα degradation and NF-κB activation. The purpose of this study was to determine the potential role of RSK2 in mediating TNF-α-induced signaling. Notably, we found that RSK2 is activated by TNF-α and directly phosphorylates IκBα at Ser32 leading to IκBα degradation to promote the activation and translocation of the NF-κB subunits, p65 and p50, to the nucleus. This resulted in increased NF-κB activity, which served as a mechanism for RSK2 blockage of TNF-α induction of apoptosis and enhanced cell survival. Thus a new kinase that directly phosphorylates IκBα to promote its degradation is identified in TNF-R1 pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 309.
Abstract 3091: Oncogenic roles of nuclear VCP in oral cancer development
Authors: Chiu I-Wen , Li Chien-Feng , Lai Chien-Chen , Lai Ming-Tsung , Chen Chih-Mei , Lin Ying-Ju , Wan Lei , Tseng Hsien-Chang , Hua Chun-Hung , Tsai Ming-Hsui , Hsu Wei-Yi , Tsai Fuu-Jen , Sheu jim Jinn-Chyuan 
Published: February 2011

Abstract
VCP is a member of AAA-ATPase family that includes putative ATP-binding proteins involved in nuclear envelope reconstruction, cell cycle regulation, Golgi reassembly, suppression of apoptosis, and DNA-damage response. Due to the novel functions, VCP overexpression was linked to cancer development and suggested as a prognostic tumor marker for poor clinical outcome. Our preliminary data of SNP array analysis on 33 fresh clinical OSCC samples identified an amplified region at chromosome 9p13.3 containing the VCP gene. This finding was further validated by FISH analysis on a larger scale using paraffin-embedded oral cancer tissues. Consistent with genomic copy alterations, the mRNA and protein expression levels of VCP were also found higher in OSCC tissues. Interestingly, the nuclear VCP staining correlates with VCP gene amplification and shorter overall survival, suggesting the novel functions of VCP in nucleus during OSCC development. In this study, we identified several nuclear binding partners for VCP in OSCC cells, and signaling networks controlled by VCP during OSCC development were discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3091.
Abstract 3092: The roles of SRC-3 and its isoform SRC-3Δ4 during the progression of DCIS to invasive breast cancer
Authors: Long Weiwen , Medina Daniel , Tsai Sophia , Tsai Ming-Jer , O'Malley Bert 
Published: February 2011

Abstract
Accumulating evidence has shown that SRC-3 plays important roles in tumor metastasis. SRC-3 gene deletion suppresses both v-Ha-ras- and polyomavirus middle T (PyMT) transgene-induced breast tumor metastasis to the lung. SRC-3 overexpression is highly correlated with metastatic phenotype in human breast cancer. SRC-3 promotes cancer cell invasion by co-activating AP-1 and PEA-3-mediated matrix metalloproteinase (MMP) expression. We recently found that a SRC-3 isoform with the deletion of exon 4 (SRC-3Δ4) promotes breast cancer cell migration and mammary tumor metastasis by directly mediating EGF signal transduction from EGFR to c-Src and FAK. One of the key tasks in the field of breast cancer research is to identify what factors regulate the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer. Given the importance of SRC-3 and SRC-3Δ4 in breast tumor metastasis, we hypothesize that SRC-3 and/or SRC-3Δ4 promote the progression of DCIS to invasive breast cancer. To test this hypothesis, we either stably overexpressed or stably knocked down SRC-3 or SRC-3Δ4 in two DCIS cell lines (DCIS.COM and SUM225) by lentiviral transduction. Stable knockdown of SRC-3 significantly decreased cell proliferation and cell invasion, whereas knockdown of SRC-3Δ4 only decreased cell invasion. Conversely, Overexpression of either SRC-3 or SRC-3Δ4 promote cell invasion, which is partly due to the increased Akt phosphorylation. We then injected the DCIS cells into the mammary ducts of athymic nude mice. The effect of SRC-3 and SRC-3Δ4 on the formation of DCIS and invasive lesions is under investigation. Furthermore, the underlying molecular mechanisms will be analyzed as well.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3092.