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  • American Association for Cancer Research (AACR)  (15)
  • 1
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 30, No. 10 ( 2021-10-01), p. 1875-1883
    Abstract: Bile acid (BA) and short chain fatty acid (SCFA) production is affected by diet and microbial metabolism. These metabolites may play important roles in human carcinogenesis. Methods: We used a fully quantitative targeted LC-MS/MS system to measure serum and fecal BA and SCFA concentrations in 136 Costa Rican adults at study baseline and 6-months. We randomly selected 50 participants and measured their baseline samples in duplicate. Our objective was to evaluate: Technical reproducibility; 6-month temporal variability; and concordance between sample type collected from the same individual at approximately the same time. Results: Technical reproducibility was excellent, with intraclass correlation coefficients (ICC) ≥0.83 for all BAs except serum tauroursodeoxycholic acid (ICC = 0.72) and fecal glycolithocholic acid (ICC = 0.66) and ICCs ≥0.81 for all SCFAs except serum 2-methylbutyric acid (ICC = 0.56) and serum isobutyric acid (ICC = 0.64). Temporal variability ICCs were generally low, but several BAs (i.e., deoxycholic, glycoursodeoxycholic, lithocholic, taurocholic, and tauroursodeoxycholic acid) and SCFAs (i.e., 2-methylbutyric, butyric, propionic, and valeric acid) had 6-month ICCs ≥0.44. The highest degree of concordance was observed for secondary and tertiary BAs. Conclusions: Serum and fecal BAs and SCFAs were reproducibly measured. However, 6-month ICCs were generally low, indicating that serial biospecimen collections would increase statistical power in etiologic studies. The low concordance for most serum and fecal metabolites suggests that consideration should be paid to treating these as proxies. Impact: Our findings will inform the design and interpretation of future human studies on associations of BAs, SCFAs, and potentially other microbial metabolites, with disease risk.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3172-3172
    Abstract: Embryonal Tumors with Multilayered Rosettes (ETMRs) are pediatric brain tumors mainly occurring in infants. Characteristic to ETMRs is the highly recurrent (~90%) amplification of the C19MC miRNA cluster fused to TTYH1 that drives the expression of this cluster. As the overall survival of these patients is very poor, there is an urgent need for a better understanding of these tumors that may lead to other treatment strategies. Whole genome and panel sequencing data have been generated for 60 ETMRs and matching germline when available. Data have been complemented with DNA methylation profiling and m(i)RNA sequencing data. Our results show that ETMR is a single disease entity without molecular subgroups. ETMRs lacking the C19MC amplification (~10%) are highly similar to tumors with C19MC amplification, based on methylation and m(i)RNA profiling, indicating that they do not represent a distinct subgroup. Germline sequencing revealed mutations in genes involved in DNA repair or miRNA processing, while tumor specific mutations included genes involved in the TP53-, SHH-, WNT-, or miRNA processing pathways. These pathways are also highly upregulated compared to other pediatric brain tumors. Mutations in DNA repair, miRNA processing, structural variations (SVs) and mutations in close proximity of SVs occur at high allele frequencies and are conserved in recurrent tumors while many other SNVs are lost. These data suggest that C19MC amplification/fusion, miRNA processing and DNA repair defects are the early (driving) events in tumor formation while aberrations involving for instance the SHH and WNT pathways are later (passenger) events. Aside from frequent and recurrent copy number changes, ETMRs show pluriploidy, complex rearrangements and strong presence of R-loops suggesting that ETMR genomes are highly unstable. We identified a high number of R-loops in the region forming the C19MC aberration and an enrichment of breakpoints in other R-loop forming regions. This may suggest a role for R-loops in both tumor progression and initiation. Finally, we tested whether further inducing the number of R-loops in these tumors may increase replication stress and cell death. Indeed, topoisomerase inhibition coupled to PARP inhibition increased the amount of R-loops and acted synergistically in killing ETMR cells. These data show that targeting the genomic instability in ETMRs could be a viable treatment option for treating ETMR patients. Citation Format: Sander Lambo, Andrey Korshunov, Christin Schmidt, Carolina Romero, Aparna Gorthi, Sonja Krausert, Tobias Rausch, Susanne Gröbner, Sebastian Brabetz, Sebastian Waszak, Alexander J. Bishop, Stefan Pfister, Marcel Kool. Targeting genomic instability in embryonal tumors with multilayered rosettes (ETMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3172.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 1_Supplement ( 2013-01-01), p. B48-B48
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 1_Supplement ( 2013-01-01), p. B48-B48
    Abstract: Ovarian cancer is the fifth cause of death in women, annually 13,850 deaths are reported in United States. Chemo is the conventional therapy after surgery but the initial response is between 60 to 80%, however, some patients that initially respond well to the therapy suffer recurrent disease or become resistant to the treatment. As a consequence, the overall 5 year survival is only 30%. There is a necessity to identify novel therapies for ovarian cancer or to discover drugs witch re sensitize tumor cells to existence therapy. It has been suggested that the resistance of the tumor cells is because of the increased expression of antiapoptotic proteins especially from the Bcl2 family (Bcl-2, Bcl-XL, Mcl-1). Obatoclax is a small molecule that mimics the BH3 domain of the BH3 only family members, inhibiting the effect of antiapoptotic Bcl-2 members. The objective of this study was to assess the susceptibility of ovarian cancer cell lines to chemo or immune therapy mediated apoptosis by obatoclax and also to elucidate the mechanism. Some ovarian cancer cell lines were treated with different concentrations of Obatoclax, CDDP or TRAIL alone or in combinational treatment to assess the reduction of viability measured by the XTT kit (Roche). Basal and cell treated total protein expressions were assessed by western. Induction of apoptosis was measured by TUNEL. As a single agent, Obatoclax or CDDP inhibited the growth of ovarian cancer cell lines in a dose response manner, TRAIL was no having an evident response showing a plateau with the concentration used. The combinational treatment after selecting the IC50 and IC20 response showed an increased inhibition of the viability. The induction of apoptosis was mediated by a caspase dependent manner. Our data suggest that obatoclax in combination with CDDP or TRAIL can re sensitize resistance cell lines to apoptosis and also it can be an optional treatment of patients with ovarian cancer. Citation Format: Melisa A. Martinez-Paniagua, Luis A. Romero-Gonzalez, Yu-Mei Anguiano-Hernandez, Carolina Gonzalez-Torres, Mario I. Vega. Resensitization to CDDP or trail-mediated apoptosis in ovarian cancer cells by Obatoclax. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B48.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1735-1735
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1735-1735
    Abstract: Epithelial ovarian cancer comprises the majority of malignant ovarian tumors in adult women. Ovarian cancer is the fifth cause of death in women and annually 13,850 deaths are reported in United States. Effective screening strategies are lacking and the majority of cases are diagnosed with advanced stage disease. Chemo is the conventional therapy after surgery but the initial response is between 60 to 80%, however, some patients that initially responded to the therapy suffer of recurrent disease or become resistant to the treatment. As a consequence, the overall 5 year survival is only about 30%. It is important to identify novel therapies for ovarian cancer to treat or sensitize tumor cells to the existence therapy. It has been suggested that the tumor cells become resistance due to an increased expression of antiapoptotic proteins especially from the Bcl2 family (Bcl-2, Bcl-XL, Mcl-1). Obatoclax is a small molecule that mimics the BH3 domain of the BH3 only family members and inhibits the effect of antiapoptotic Bcl-2 members. The objective of this study was to assess the susceptibility of ovarian cancer cell lines to chemo or immuno therapy mediated apoptosis by obatoclax and also to elucidate the mechanism. Four different epithelial ovarian adenocarcinomas cell lines (SKOV3, NIH-OVCAR-3, TOV112D and TOV21G) were treated with different concentrations of Obatoclax (nM-μM), CDDP (5-50μg/ml) or TRAIL (50-1200ng/ml) alone or with a combination of treatment to assess the viability, measured by the XTT kit (Roche). Basal and cell treated total protein expressions were assessed by western. Induction of apoptosis was measured by TUNEL. As a single agent, Obatoclax or CDDP inhibited the viability of the cells in a dose response form; TRAIL did not show an evident response. The combination of the treatment after selecting the IC50 and IC20 response showed an increased inhibition of the viability. TUNEL positive cells were measured and the induction of apoptosis was mediated by a caspase dependent manner and PARP cleavage. Our data suggest that obatoclax in combination with CDDP or TRAIL can enhance the induction of apoptosis in resistance cell lines, suggesting to be an optional treatment of patients with ovarian cancer. Citation Format: Melisa A. Martinez-Paniagua, Luis A. Romero-Gonzalez, Yu Mei Anguiano-Hernandez, Carolina Gonzalez-Torres, Mario I. Vega. Obatoclax enhances CDDP and trail-induced apoptosis in epithelial ovarian adenocarcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1735. doi:10.1158/1538-7445.AM2013-1735
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2016-07-01), p. 1713-1725
    Abstract: Prostate cancer is the leading cause of cancer-related death among men in developed countries. Although castration therapy is initially effective, prostate cancers progress to hormone-refractory disease and in this case taxane-based chemotherapy is widely used. Castration-resistant prostate cancer cells often develop resistance to chemotherapy agents and the search for new therapeutic strategies is necessary. In this article, we demonstrate that PKCδ silencing favors mitotic arrest after paclitaxel treatment in PC3 and LNCaP cells; however, this is associated with resistance to paclitaxel-induced apoptosis. In prostate cancer cells, PKCδ seems to exert a proapoptotic role, acting as a negative regulator of the canonical Wnt/β-catenin pathway. PKCδ silencing induces activation of Wnt/β-catenin pathway and the expression of its target genes, including Aurora kinase A, which is involved in activation of Akt and both factors play a key role in GSK3β inactivation and consequently in the stabilization of β-catenin and antiapoptotic protein Mcl-1. We also show that combined treatments with paclitaxel and Wnt/β-catenin or Akt inhibitors improve the apoptotic response to paclitaxel, even in the absence of PKCδ. Finally, we observe that high Gleason score prostate tumors lose PKCδ expression and this correlates with higher activation of β-catenin, inactivation of GSK3β, and higher levels of Aurora kinase A and Mcl-1 proteins. These findings suggest that targeting Wnt/β-catenin or Akt pathways may increase the efficacy of taxane chemotherapy in advanced human prostate cancers that have lost PKCδ expression. Mol Cancer Ther; 15(7); 1713–25. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4267-4267
    Abstract: Gallbladder cancer is the most common biliary tract cancer. Globally, it is considered as a rare malignancy but shows a high incidence in certain geographic areas, such as Eastern and South Asia, Eastern Europe and Latin America. In Chile, this aggressive neoplasia is the second leading cause of cancer death among women, with a mortality rate of 15 deaths per 100.000 women, only slightly lower than breast cancer. Most patients with gallbladder cancer are diagnosed at advanced stages and the prognosis still remains low, even using the most current diagnostic techniques. Tumor biology of gallbladder cancer is still poorly understood and there are no therapeutic options to improve the prognosis of patients with advanced gallbladder cancer. The establishment of cell lines for their use as in vitro models is essential for the study of tumor biology and drug susceptibility. The aim of this study was to characterize and compare the malignant properties of three gallbladder cancer clones isolated from ascites-derived primary culture cells. Tumor cells were isolated from the ascites of an advanced gallbladder cancer patient using a previously established protocol. The primary culture cells were characterized to determine their epithelial origin by using immunohistochemical markers. Due to the heterogeneous nature of these cells, individual clones were isolated from them and maintained in culture until their establishment as immortal cell lines (less than 20 passages). Finally, three clones were obtained and evaluated in order to characterize and compare their malignant properties, determining their growth rate, chemosensitivity to gemcitabine, cisplatin and 5-fluoracil, migration capability and the in vivo tumorigenesis induction. The ascites-derived primary culture cells showed high expression of epithelial and tumor markers (Cytokeratin 7 and 19, CA 19-9, CA 125, CA 15-3) and negative expression of mesothelial markers (calretinin and mesothelin). Individual clones (clone 1, 2 and 3) derived from the primary culture showed differences from each other. The calculated doubling time was 60h for Clone 1, 35h for Clone 2, and 28h for Clone 3. All three clones were equally sensible to gemcitabine, cisplatin and 5-Fluoracil, compared to other established gallbladder cancer cell lines. Clone 5 exhibited the greater migration potential and Clone 6 resulted to have the most tumorigenic capability, although all were able to form xenograft tumors before 2 weeks. Conclusions: To our knowledge, these are the first gallbladder cancer cell lines established from a Chilean patient and they may provide a useful tool for the study of gallbladder cancer biology and for in vitro and in vivo analysis aimed at identification of new potential therapeutic targets. Research supported by FONDECYT 11130515, 1151008, 1130204, 3140426 and 3140308. Citation Format: Javier Retamal, Carolina Bizama, Jaime Espinoza, Lorena Rosa, Francisca Alfaro, Diego Romero, María José Apud, Bruno Nervi, Pamela Leal, Helga Weber, Juan Carlos Roa, Patricia García. Establishment and biological characterization of a Chilean ascites-derived gallbladder cancer cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4267.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2130-2130
    Abstract: Introduction: Colorectal cancer (CRC) has the third-highest incidence and the fourth-highest mortality from cancer globally. In the genesis of CRC, mutations have been identified in the KRAS gene associated with prognosis and therapeutic management, however, the epigenetic mechanisms that modulate the expression of KRAS in CRC patients when there are no mutations in the gene are not well known. miR-18a-3p and miR-143 have been described to target KRAS and thus may regulate gene expression. Objective: To determine if there is a relationship between the expression of the wild-type KRAS gene (mRNA and protein) and the expression levels of miR-143 and miR-18a-3p in FFPE tissue samples from CRC patients. Methodology: RNA was extracted from FFPE tumor tissue samples from 51 cases of patients with CRC. Expression of wild-type KRAS mRNA, miR-143 and miR-18a-3p was evaluated by qRT-PCR and expression levels of KRAS protein by immunohistochemistry. Contingency tables, Pearson's Chi-square test and logistic regression analysis were used for data analysis. Results: Regarding the expression levels of wild-type KRAS protein, a higher number of cases with a cytoplasmic expression of the protein was identified (98%) compared to the expression in the cell membrane (31%). In 7,8% (4/51) of the cases, it was not possible to determine the mRNA expression of the KRAS gene, while in 21,3% (10/47) no expression was detected. In 78,7% of the cases in which KRAS mRNA expression was detected, low (40,4%; 19/47) and high (38,3%; 18/47) expression were categorized according to the results found. It was not evidenced by a correlation between protein expression levels and mRNA expression levels of the wild-type KRAS gene. When determining the expression levels of miR-18a-3p and miR-143, it was found that 64,7% (33/51) of cases had an absent expression of miR-18a-3p and 54,9% (28/51) of cases had an absent or very low expression for miR-143. By means of a logistic regression analysis adjusted by age, stage, sex and presence or absence of KRAS protein in the membrane, it was determined that the presence of miR-18a-3p is inversely related to KRAS mRNA levels significantly (p=0,048; OR=0,346) while miR-143 only shows a tendency to an inverse correlation with KRAS mRNA levels (p=0,119; OR=0,469). Conclusions: No correlation was found between mRNA and protein expression levels of the wild-type KRAS gene, suggesting that protein levels do not strictly depend on mRNA levels. A significant inverse association was found between miR-18a-3p and wild-type KRAS mRNA levels. Citation Format: Jehison-Alirio Herrera-Pulido, Orlando Ricaurte Guerrero, Jinneth Acosta Forero, Gustavo Hernández Suárez, Pablo Moreno-Acosta, María-Carolina Sanabria Salas, Humberto Arboleda Granados, Alfredo Romero Rojas, Martha Lucía Serrano López. Association between miR-18a-3p, miR-143 and expression of the wild-type KRAS gene in patients with sporadic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2130.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 18 ( 2018-09-15), p. 4579-4587
    Abstract: Purpose: The blockade of immune checkpoints such as PD-L1 and PD-1 is being exploited therapeutically in several types of malignancies. Here, we aimed to understand the contribution of the genetics of lung cancer to the ability of tumor cells to escape immunosurveillance checkpoints. Experimental Design: More than 150 primary non–small cell lung cancers, including pulmonary sarcomatoid carcinomas, were tested for levels of the HLA-I complex, PD-L1, tumor-infiltrating CD8+ lymphocytes, and alterations in main lung cancer genes. Correlations were validated in cancer cell lines using appropriate treatments to activate or inhibit selected pathways. We also performed RNA sequencing to assess changes in gene expression after these treatments. Results: MET-oncogenic activation tended to associate with positive PD-L1 immunostaining, whereas STK11 mutations were correlated with negative immunostaining. In MET-altered cancer cells, MET triggered a transcriptional increase of PD-L1 that was independent of the IFNγ-mediated JAK/STAT pathway. The activation of MET also upregulated other immunosuppressive genes (PDCD1LG2 and SOCS1) and transcripts involved in angiogenesis (VEGFA and NRP1) and in cell proliferation. We also report recurrent inactivating mutations in JAK2 that co-occur with alterations in MET and STK11, which prevented the induction of immunoresponse-related genes following treatment with IFNγ. Conclusions: We show that MET activation promotes the expression of several negative checkpoint regulators of the immunoresponse, including PD-L1. In addition, we report inactivation of JAK2 in lung cancer cells that prevented the response to IFNγ. These alterations are likely to facilitate tumor growth by enabling immune tolerance and may affect the response to immune checkpoint inhibitors. Clin Cancer Res; 24(18); 4579–87. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2274-2274
    Abstract: Gallbladder cancer (GBC) is lethal and aggressive disease characterized by late diagnosis, poor prognosis and lack of effective therapeutic options. An excellent candidate for targeting therapy in cancer is the Hippo signaling pathway that has been reported to be deregulated in different types of cancer and recently has emerged as a master regulator that plays a critical role in multiple processes such as tumorigenesis, apoptosis, tumor stem cell phenotype, drug cell resistance and metastatic potential. However, little is known about the status of the Hippo kinase pathway in human GBC. The aim of this study is determinate the Hippo pathway activity in GBC and evaluate the potential therapeutic role of YAP1 siRNA and the pharmacological inhibitor Verteporfin, a small molecule that inhibit TEAD-YAP interaction. Immunohistochemistry was used to analyze the expression of YAP1 and Survivin, a major downstream effector and transcriptional target gene of Hippo signaling pathway, in tissue microarray containing 198 advanced GBC samples. Then, we performed an exploratory analysis of Hippo pathway activity by qRT- PCR in advanced GBC and cholecystitis samples. The levels of expression of the Hippo core kinase proteins in GBC cell lines was studied by western blot and the inhibition of YAP1 was performed thought specific siRNA and Verteporfin. Immunohistochemistry showed high nuclear expression of YAP1 in vast majority of advanced GBC, which is correlated significantly with nuclear Survivin expression. The 5-year survival rates of patients with survivin-positive cancer were significantly lower compared with survivin-negative cancer patients (p & lt;0.05, Log-rank test). The gene expression analysis showed a significant down-regulation of the Hippo kinase core suppressor genes STK3 (MST2), STK4 (MST1), SAV1, LATS2 and up-regulation of GPCR5A and BIRC5 in GBC tissues compared with cholecystitis. In addition, western blot analysis show high levels of nuclear YAP1 in 4 GBC cells and its expression were associated with a reduction in the phosphorylation status of LATS1 and MOB. Our findings indicate that targeting YAP1 with siRNA reduced mRNA and protein levels of this oncogene in almost 80% and inhibited the clonogenic capacity of GBC cell lines. Otherwise, the in vitro pharmacological inhibition of YAP1 with Verterporfin reduces YAP1 protein in a dose-dependent manner and was associated with down-regulation of survivin. Our results showed that the Hippo- pathway is deregulated in advanced GBC and mediates its oncogenic effects through of attenuation of their suppressor core components, nuclear translocation of YAP1 and up-regulation of survivin expression. Targeting YAP1 by siRNA and Verteporfin leads to inactivation of YAP1 and survivin affecting cancer cell survival capacity. Targeting the Hippo/YAP has the potential to provide a novel strategy for GBC therapy. Research supported by FONDECYT 3140426, 1130204, 11130515, 3140308. Citation Format: Carolina Bizama, Patricia García, Jaime A Espinoza, Nicole Elgueta, Ismael Riquelme, Francisca Alfaro, Diego Romero, Helga Weber, Pamela Leal, Javier Retamal, Lorena Rosa, Juan Carlos Roa. Deregulated Hippo pathway is a potential therapeutic target for advanced gallbladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2274.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Therapeutics Vol. 13, No. 10 ( 2014-10-01), p. 2372-2383
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 13, No. 10 ( 2014-10-01), p. 2372-2383
    Abstract: PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting. Mol Cancer Ther; 13(10); 2372–83. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    SSG: 12
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