bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1443: RhoE is underexpressed in hepatocellular carcinoma and suppresses cell motility and invasiveness
Authors: Ma Carmen Wei , Wong Chak-Lui , Wong Irene Chun-Ming , Ng Oi-Lin 
Published: June 2012

Abstract
Hepatocellular carcinoma (HCC) is a major malignancy worldwide and is the second commonest fatal cancer in Southeast Asia and Mainland China including Hong Kong, due to the high prevalence of hepatitis B viral infection. Despite definite improvements in the outcome of patients with HCC, the overall prognosis of this cancer is still unsatisfactory because of late presentation and frequent tumor recurrence after surgical resection. In this regard, knowledge of the molecular and cellular targets underlying the development and progression of liver cancer may provide novel opportunities for therapeutic interventions for this cancer. As part of our continual study on the Rho/ROCK pathway in HCC, in this current study, we aimed to find out the role of RhoE (also known as Rnd3), a member of the Rho family of small GTP-binding proteins, in HCC. We have found that RhoE was frequently underexpressed in 43/71 (60.6%) of our human HCCs at mRNA level using qPCR, as compared with their corresponding non-tumorous livers (p &lt;0.001). Moreover, RhoE knockdown in HCC cells by lentiviral infection of shRhoE enhanced cell migration and invasion in vitro. Using transwell migration assay, we showed that stable shRNA knockdown of RhoE in SMMC7721 and BEL7402 HCC cell lines resulted in faster migration of the cells than their corresponding non-target controls. Moreover, stable RhoE knockdown clones also invaded through the matrigel faster in matrigel invasion assay. Previous studies have indicated that phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr850 was essential for phosphorylation of myosin II and crucial for cell contractility. To further delineate the roles of RhoE on actomyosin contractility, the MYPT1 phosphorylation levels in the Rho stable knockdown transfectants in SMMC, BEL and Hep3B HCC cells were assessed by Western blotting and found to be increased as compared with their non-target control. This increased phosphorylation was reversed by ROCK inhibitor Y27632. Furthermore, the ROCK inhibitor Y27632 was able to suppress the accelerated cell migration brought by the knockdown of RhoE in SMMC, suggesting that RhoE may exert its effects by inhibiting the activity of ROCK1. Since MYPT1 is specifically phosphorylated by ROCK at Thr850, the finding suggests that RhoE interacts with and suppresses the activity of ROCK1 in HCC cells.
To conclude, our data suggest that RhoE in HCC suppresses both cell motility and invasiveness of HCC cells and that RhoE may exert its effects by inhibiting the activity of ROCK1.
(This study was funded by Hong Kong Research Grants Council CRF grants (RGC CRF HKU1/06C and HKU 7/CRG/09)
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 1443. doi:10.1158/1538-7445.AM2011-1443
Abstract 1446: Dissecting the role of PTEN/Akts in metastatic melanoma
Authors: Yu Yanlin , Liu Ziyang , Yu Yixin , Mendoza Arnulfo , Khanna Chand , Merlino Glenn 
Published: June 2012

Abstract
Melanoma is an aggressive human cancer whose incidence is increasing more rapidly than any other cancer in the United States. It is characterized by an extremely high potential to develop metastases and poor response to current therapy. Although the genetic studies indicated that melanoma genesis related with molecular lesions in c-MET, INK4a, Ras/Raf, p53 and PTEN pathways, the molecular mechanism inciting metastatic melanoma are poorly understood. PTEN is a major tumor suppressor in humans. To study the role of PTEN in progression of human melanoma, we first used tissue microarrays to examine PTEN expression in 30 lymph node melanoma metastases, 30 primary melanomas, and 9 normal skin tissues. Our results showed that PTEN loss was significantly correlated with progression to the metastatic state. Moreover, analysis of various human melanoma cell lines demonstrated that PTEN expression was related to metastatic behavior, supporting the notion that PTEN is involved in the metastatic regulation of melanoma. PTEN has phosphatase activity that can act upon both polypeptide and phosphoinositide substrates. The PTEN lipid phosphatase is a ubiquitous regulator of PI3K signaling pathway. The loss of expression or mutational inactivation of PTEN protein enhances the phosphorylation of PKB/AKT and thus influences cell survival signaling. Interestingly, a PTEN mutant, which loses lipid but not protein phosphatase activity, lacks the ability to induce either G1 arrest or apoptosis, but nonetheless retains the ability to inhibit cell spreading and motility, suggesting that PTEN protein phosphatase activity is important for these behaviors. To further dissect the role of this PTEN activity in metastasis, we have established a model system containing exploiting mutant PTEN proteins with various phosphatase activities. We found that wild type PTEN can inhibit cell motility and invasiveness, while PTEN mutants cannot. Notably, wild type PTEN was able to reduce the metastatic potential of melanoma cells, whereas phosphatase deficient PTEN could promote the melanoma cell metastatic behavior. We found that PTEN mediates metastatic activity through the AKT pathway. We further determined that Akt 3 was key mediators of metastatic potential in melanoma cells in vivo. Akt3 could also rescue PTEN-mediated inhibition of metastasis. PTEN loss and Akt3 overexpression functioned synergistically to promote metastasis. Our data demonstrate that metastatic behavior in melanoma cells is dependent on the status of PTEN protein phosphatase activity and downstream Akt3, and suggest that AKT/PTEN signaling should be considered as a therapeutic target in metastatic melanoma
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 1446. doi:10.1158/1538-7445.AM2011-1446
Abstract 1447: An unbiased screen for Nm23-H1 interacting proteins identifies the cytoskeletal crosslinking protein Ezrin
Authors: Marshall Jean-Claude A. , Collins Joshua , Zhou Ming , Veenstra Timothy , Khanna Chand , Steeg Patricia 
Published: June 2012

Abstract
We hypothesized that Nm23-H1 may suppress metastasis through binding and inactivation of proteins that promote aggressive behavior. An unbiased survey of Nm23-H1 binding proteins was conducted in a 4T1 murine mammary carcinoma model system. Flag tagged Nm23-H1 and its mouse variant, -M1, were transfected into 4T1 mouse mammary cancer cells. Clonal lines were inoculated into the number four mammary fat pad of mice and allowed to grow for 10 days prior to excision due to size of the primary tumor. Mice were then imaged weekly for the remainder of the experiment, 8 weeks to follow the metastatic spread of the 4T1 cells from each group. Primary tumor size was unaffected by over-expression of Nm23-H1 or -M1. Histological examination revealed a 75% decrease in liver metastasis by Nm23-H1 or -M1 over-expression (P &lt; 0.001). To characterize Nm23-H1/M1 binding proteins, Flag tagged Nm23 from both H1 and M1 clones were immunoprecipitated (IP) from in vitro cell lines as well as isolated primary tumors, lymph nodes, spleen and liver tissue after verification of metastasis by histological examination of the tissue. Mass spectrometry analysis of IP samples from cell lines and primary tumors showed 99 proteins of interest including Ezrin. Co-IP of Ezrin and Nm23-H1/M1 has been confirmed using both Nm23 and Ezrin as the IP antibodies, implicating Ezrin as a potential binding partner of NM23-H1 and M1. Ezrin belongs to a family of widely expressed proteins known as ERMs which have been described to link the actin cytoskeleton to membrane signaling pathways. To rule out potential interaction due to F-actin, cells were exposed to latrunculin B and co-IP of Nm23-H1 and Ezrin was again verified, indicating that the Ezrin and Nm23-H1/M1 interaction is not due to F-actin binding. To further elucidate this interaction plasmid constructs expressing either the N terminal FERM domain or C terminal F-actin binding domain of Ezrin coupled to GFP were constructed. Co-IP showed a binding of Nm23-H1 to the N terminal domain of Ezrin. In addition the expression of the N terminal overcame the motility and invasive inhibitory phenotype of Nm23-H1 expression in both 4T1 and MDA-MB-231 cells. The data identify a novel interaction of the metastasis suppressor Nm23-H1 and the cytoskeletal linker Ezrin. Suppression of metastasis by Nm23-H1 may be due, in part, to the abrogation of a pro-invasive function of the N-terminus of Ezrin.
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 1447. doi:10.1158/1538-7445.AM2011-1447
Abstract 1451: Inhibition of cell migration via reduced phosphorylation of focal adhesion kinase by TIS21/BTG2/PC3 in A549 cells
Authors: Lim Seo Kyung , Choi Yong Won , Lim In Kyoung , Park Tae Jun 
Published: June 2012

Abstract
It has been reported that TPA inducible sequence 21 (TIS21/BTG2/PC3) functions as a tumor suppressor in carcinogenesis of thymus, prostate, kidney, and liver. Although the expression of TIS21 is down-regulated in primary and metastatic cancers, the role of TIS21/BTG2/PC3 in cell migration and metastasis remains to be elucidated. In this study, we report a role of TIS21 in cancer cell migration. We observed that TIS21 inhibited cell migration and invasion in A549 lung cancer cells. Consistent with this observation, phosphorylation of focal adhesion kinase (FAK) on Y576 and Y925 residues, but not Y397, was markedly inhibited by over-expression of TIS21, which residues are known to be phosphorylated by activated Src. It has been known that activity of Src can be regulated either by phosphorylation at Y416 or oxidation of the molecule. Phosphorylation of Src on Y416 was not regulated by overexpression of TIS21 in A549 cells, whereas TIS21 significantly inhibited Src activity by reducing the generation of reactive oxygen species. In addition to that TIS21 down-regulated matrix metalloproteinase-2 (MMP-2) expression in A549 cells. In summary, therefore, we can suggest that TIS21 down-regulates FAK activity via inhibiting Src activation and reduces expression of MMP-2, resulting in antimetastatic phenomenon in cancer cells.
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 1451. doi:10.1158/1538-7445.AM2011-1451
Abstract 146: The role of Mir-150 as a tumor suppressor in malignant lymphoma
Authors: Tagawa Hiroyuki , Watanabe Atsushi , Sawada Kenichi 
Published: June 2012

Abstract
Disease specific genetic alteration or translocation have not been identified in NK/T cell lymphoma. We recently demonstrated that over expressions of miR-21 and/or miR-155 are frequently occurring in natural killer (NK) cell lymphoma/leukemia and deeply associated with their lymphomagenesis by deregulation of AKT signaling. In this study, we tried to identify tumor suppressor miRNA(s) in malignant lymphomas including B-cell, NK-cell and CD4+T-cell lymphoma, by using quantitative PCR and/or Northern blot analysis. We found that miR-150 in both cell lines and primary samples of NK and T-cell lymphoma showed significantly lower expression than those of normal natural killer cells and CD4+T cells. To examine the role for lymphomagenesis, we stably transduced miR-150 into lymphoma cell lines. Enforced expression of miR-150 in NK/T cell lymphoma cell lines showed increased levels of susceptibility of apoptosis, and showed senescence with reduced levels of telomerase activity and telomere DNA shortening. We further demonstrated that miR-150 directly down regulate AKT2, leading to reduced expression of phosphorylated AKTser473/474 with upregulation of tumor suppressors, Bim, p27 and p53. Since it has been proven that AKT kinase phosphorylate hTERT (human telomerase reverse transcript), downregulation of miR-150 in lymphomas lead to activate telomerase activity, resulting immortalization of the cancer cells. These results suggest that miR-150 play as a role of tumor suppressor in NK/T-cell lymphoma. Our recent and previous report demonstrate that downregulation of miR-150 and upregulation of miR-21/miR-155 collaborately contribute to NK/T-cell lymphomagenesis by deregulating AKT signaling. These findings will give a new insight into the pathogenesis of NK/T cell lymphoma and the miR-150 itself and/or AKT targeting therapy can be a useful against aggressive lymphoma.
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 146. doi:10.1158/1538-7445.AM2011-146
Abstract 1464: Significance and therapeutic potential of PELP1 axis in ER-negative breast cancer
Authors: Vadlamudi Ratna K. , Roy Sudipa Saha 
Published: June 2012

Abstract
The molecular basis of breast cancer progression to metastasis remains poorly understood. Even though ER and PR explain the biology of ER-positive tumors; it remains unknown as to what drives ER-negative metastatic tumors. PELP1 is an ER coregulator that functions as a proto-oncogene, its expression is deregulated in metastatic breast tumors and its expression is retained in ER-negative tumors. In this study, we examined the mechanism and significance of PELP1 mediated signaling in ER-negative breast cancer progression. We have established ER-negative model cells (MDA-MB231 and 4T1 cells) that stably express PELP1-shRNA. These model cells showed decreased PELP1 expression (75% of endogenous levels) and exhibited decreased propensity to proliferate in in vitro growth assays. Boyden chamber and wound healing assays showed PELP1 down regulation substantially affect migration of ER-negative cells and showed alterations in the expression of the EMT markers. Focused microarray studies identified PELP1 modulate expression of eight genes involved in the EMT (including MMPs, E-cadherin, MTA1). Overexpression of PELP1 in nonmetastatic cells increases their propensity for metastasis in vivo xenograft assays, while, PELP1 knockdown in metastatic model cells decreased in vivo metastatic potential of ER negative breast cancer cells. Whole genome microRNA array analysis revealed that miR 200a and miR141 were upregulated in MDA-MB231 and 4T1 cells expressing PELP1-shRNA compared to control shRNA expressing cells. Over expression of PELP1 in low metastatic model cells decreased expression of miR 200a and miR141. Mechanistic studies showed PELP1 down regulate expression of metastasis suppressive microRNAs (miR 200a and miR141) by promoting chromatin modifications. Ectopic expression of miR 200a and miR141 mimetics decreased PELP1 oncogenic function in ER-negative cells. These results suggest that PELP1 play a role in ER-negative breast cancer metastasis by promoting cell motility / EMT by modulating microRNA expression and blockage of PELP1 axis has potential to reduce metastasis potential of ER-negative breast cancer cells. Understanding how NR coregulator PELP1 plays a role in metastasis will be useful in maximizing treatment opportunities for metastatic breast cancer.
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 1464. doi:10.1158/1538-7445.AM2011-1464
Abstract 147: Identification of miRNA associated with chemoresponse using combined clinical, population, and cellular data in lung cancer
Authors: Putila Joseph J. , Guo Lan 
Published: June 2012

Abstract
Introduction: MiRNA are potentially important moderators of chemoresponse in human cancer due to their widespread regulatory function. Identification of a set of clinically validated and biologically relevant miRNA could serve as potential markers for prognostication, chemoresponse prediction, and novel therapeutic targets. The objective of this study was to utilize population, clinical, and cell-line data as an integrative approach to identifying miRNA showing a consistent association with chemoresponse.
Materials and Methods: Patients diagnosed with squamous cell carcinomas of the lung between 2004 and 2007 were retrieved from the linked SEER-Medicare database with data on tumor TNM markers, grade, survival, and treatment information (N=6,215). Medicare HCPCS and Revenue codes were used to identify patients receiving cisplatin (N=142), carboplatin (N=1,125), etoposide, (N=37), and paclitaxel (N=779). The AJCC TNM markers and grade were used to partition patients into disjoint groups indicative of tumor progression, with the average survival being calculated for each group. A second set of clinical data containing miRNA expression (N=57, GSE 16025) was partitioned in the same manner, with the average miRNA expression on 328 probes being calculated for each group. Linear regression was used to estimate the association between miRNA expression in the clinical cohort and survival in the population sample given similar tumor characteristics. This analysis was also performed on two subsets of patients receiving surgery and chemotherapy both with and without preoperative radiation. A second analysis utilizing the NCI-60 anti-cancer screen estimated the association between miRNA expression and the amount of each chemotherapeutic agent needed for 50% growth-inhibition in an experimental setting. MiRNA which showed a significant association in at least one of the analyses and concordance in all others were considered for further analysis using IPA software.
Results: Multiple miRNA showed consistent associations with chemoresponse across analytic approaches as well as having documented interactions with molecular species known to play a role in human cancers. Notably, over-expression of miR-25, 27a, 141, and 181a showed a strong association with chemosensitivity in three of the four agents considered and formed an interaction network including transcriptional regulation, HDAC, and EGF activity. Over-expression of miR-133b was associated with chemoresistance in three of four agents. Numerous other miRNA formed networks specific to a single agent.
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 147. doi:10.1158/1538-7445.AM2011-147
Abstract 1470: Depletion of glycosphingolipids with MBO-asGCS eliminates cancer cell metastasis
Authors: Bhinge Kaustubh N. , Gupta Vineet , Liu Yong Y. 
Published: June 2012

Abstract
Tumor metastasis, particularly multi-organ metastasis often causes failure of cancer treatment. It is well-known that the interaction of tumor cells with extracellular matrix (ECM) determines the metastatic ability of cancer cells; however, it is not clear whether depletion of glycosphingolipids (GSLs), a major component of GSL-enriched microdomain on plasma membrane is an approach to eliminate tumor metastasis. Glucosylceramide synthase (GCS) that converts ceramide to glucosylceramide is a limiting enzyme controlling GSL synthesis. We found that overexpression of GCS enhanced metastatic ability of human breast cancer cells. In MCF-7/Dox cells, GCS protein levels were increased 39 folds and GCS activity were increased 2 folds, as compared to MCF-7 cells. The wound healing, Matrigel attachment and MMP-9 activity in MCF-7/Dox cells increased 1.5 folds, 3 folds, and 2 folds respectively compared to MCF-7 cells. Introduction of GCS gene overexpressed GCS protein and significantly increased wound healing and Matrigel attachment by 2 folds and cell invasion 1.5 folds in MCF-7 cells. MBO-asGCS is a mixed backbone oligonucleotide that substantially suppresses GCS expression. Silencing of GCS with MBO-asGCS (100 nM) decreased the wound healing by 2 folds, Matrigel attachment by 1.5 folds and cell invasion by 3 folds in MCF/Dox cells. These results were also observed in MCF-7/DOX cells treated with d-PDMP, a GCS inhibitor. Mechanistic study indicated that overexpression of GCS increased GSLs, particular globo-series GSLs and enhanced VEGF and uPA to promote the mobility, cellular attachment and invasion of cancer cells. As GCS overexpression is tightly associated with drug-resistant cancer cells, this study may suggest that depletion of GSLs with MBO-asGCS is an effective approach to eliminate the metastasis of cancers that even fail in conventional chemotherapy.
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 1470. doi:10.1158/1538-7445.AM2011-1470
Abstract 1474: Semaphorin 3A potentiates metastatic disease by binding to endothelial Neuropilin-1 and disrupting vascular barrier function
Authors: Acevedo Lisette M. , Desgrosellier Jay , Cheresh David A. 
Published: June 2012

Abstract
We previously showed that Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, inhibits VEGF-induced angiogenesis yet induces vascular permeability. In patient samples, immunohistochemical analysis of Sema3A showed that its expression increased with disease progression and metastasis. Similarly, Sema3A expression was higher in cell lines with enhanced metastatic potential. We considered whether Sema3A expression in a variety of highly malignant tumor cells might contribute to their metastatic properties based on Sema3A's capacity to disrupt vascular barrier function. To evaluate this, we stably knocked down Sema3A expression in CT26 (colon) and B16-BL6 (skin) cells and examined their growth and invasive properties both in vitro and in vivo. Loss of Sema3A significantly decreased the incidence of pulmonary lung metastasis. Importantly, Sema3A knockdown did not impair tumor cell adhesion, migration, proliferation, or anchorage-independent growth in vitro; and it had no effect on primary tumor growth and angiogenesis in vivo, suggesting a role for Sema3A in tumor cell extravasation. Furthermore, tamoxifen-inducible conditional knockout of the Sema3A receptor Neuropilin-1 (Nrp1) within the adult endothelium inhibited lung colonization and metastasis but had no effect on primary tumor growth. Similarly, a function blocking antibody against Nrp1 known to inhibit Sema3A-mediated permeability prevented lung colonization. Because Nrp1 is also a co-receptor for VEGF, we reintroduced a mutant of Nrp1 that lacks Sema3A but not VEGF binding capability into our tamoxifen-inducible endothelial-specific Nrp1 knockout mouse. Expression of mutant Nrp1 inhibited experimental metastasis, but not primary tumor growth confirming a specific role for Sema3A-Nrp1 interaction in extravasation. Together these findings define a pathological role for tumor cell secreted Sema3A as a potentiator of tumor cell metastasis and vascular barrier disruption.
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 1474. doi:10.1158/1538-7445.AM2011-1474