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  • American Association for Cancer Research (AACR)  (25)
  • 1
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 1 ( 2018-01-01), p. 37-48
    Abstract: Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy. Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR. See related commentary by Sundar and Tan, p. 14. See related article by Janjigian et al., p. 49. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4346-4346
    Abstract: Background: Bmi1 is a member of the polycomb-repressive complex 1 with an essential role in maintaining chromatin silencing. Bmi1 plays a function in the self-renewal of neuronal and hematopoietic stem cells through repression of the INK4A/ARF locus. Furthermore, Bmi1 is overexpressed in a variety of human cancers. The expression of Bmi1 is associated with poor prognosis of gastrointestinal cancer patients. On the other hand, solid tumors consist of cancer cells and various types of stromal cells, fibroblasts, endothelial cells and hematopoietic cells, mainly macrophages and lymphocytes. Tumor-associated macrophages (TAMs) contribute to tumor progression by producing various mediators. This study was performed to identify the tumor-associated macrophages (TAMs)-mediated regulation of Bmi1 expression in gastrointestinal cancers. Method: The relationship between the expression of Bmi1 and TAMs was assessed by immunohistochemistry and quantitative real-time PCR (qRT-PCR), and 3D sphere culture. Next, miRNAs microarray in gastric cancer cell co-cultured with macrophages was conducted. To examine the functional relevance of miR-30e* expression, we analyzed the relationship between miR-30e* and Bmi1 expression in high Bmi1 expressing cancer cell lines transfected with miR-30e* mimics, and low Bmi1 expressing cancer cell lines transfected with miR-30e* inhibitors. And we investigated if miR-30e* directly targets the 3′ UTR of Bmi1 using constructs containing the putative miR-30e* target site or a mutated sequence of the 3′ UTR of Bmi1 cloned immediately downstream of a luciferase gene. Furthermore Bmi1 and miR-30e* expression were assessed in cancer tissues. Results: We revealed the positive relationship between with tumor-infiltrating macrophages and Bmi1 expression in cancer cells. We showed co-culture with TAMs triggered Bmi1 expression in cancer cell lines and enhanced sphere formation ability. Based on microRNA screening analysis and in silico microRNA search, we focused on miR-30e* that could regulate Bmi1 expression. Western blot analysis revealed significantly reduced Bmi1 protein levels in high Bmi1 expressing cancer cell lines transfected with miR-30e* mimics compared with controls, and increased levels in low Bmi1 expressing cancer cell lines cells transfected with miR-30e* inhibitors compared with controls. And Bmi1 was a direct target for miR-30e* by interactions with the putative miR-30e* binding sites. MiR-30e* expression was down-regulated in tumor region compared with in non-tumor one. Furthermore Bmi1 expression was inverse correlation with miR-30e* expression. Conclusions: TAMs may cause increased Bmi1 expression through miR-30e* suppression, leading to tumor progression. Citation Format: Hidetaka Sugihara, Takatsugu Ishimoto, Daiauke Izumi, Hiroshi Sawayama, Yu Imamura, Satoshi Ida, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Novel discovery of miR-30e* regulating Bmi1 expression induced by tumor-associated macrophages in gastrointestinal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4346. doi:10.1158/1538-7445.AM2014-4346
    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: 2014
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3598-3598
    Abstract: Background: CD44 has recently been identified as one of the cell surface markers associated with cancer stem cells (CSCs) in several types of tumor. We have reported the functional role of CD44 variant isoform in the maintenance of low reactive oxygen species (ROS) levels in gastrointestinal cancer cells. While, microRNA (miRNA) is involved in the pathogenesis of many cancers and the networks of miRNA regulate CSCs properties. However, the mechanism underlying the miRNA in the regulation of CSC marker is mostly unrevealed. Objectives: The aim of this study was to investigate the regulation of CD44 expression by miRNAs and to develop newmolecular targets in gastrointestinal cancer. Methods and Results: To investigate the mechanism in the regulation of CD44, We performed miRNA screening in six human gastrointestinal cancer cell lines and identified three candidate miRNAs that could regulate CD44 expression in gastrointestinal cancer. Among these, we focused on miR-328 and examined its functional relevance using growth assays and cytotoxicity assays. CD44 expression was reduced in gastrointestinal cancer cell lines forced to express miR-328, leading to inhibition of cancer cell growth in vitro and in vivo, and impaired resistance to chemotherapeutic drugs and reactive oxygen species (ROS). In contrast, induction of CD44 expression by miR-328 inhibitor led to promotion of cancer cell growth. Furthermore, we revealed that ROS produced by macrophages triggered CD44 expression through suppression of miR-328 in gastric cancer cells. Finally, tumor-infiltrating macrophages (CD68 and CD163) were closely related to both miR-328 down-regulation and CD44 up-regulation in 63 patients with surgically-resected gastric cancer. Conclusions: Macrophages in the tumor microenvironment may cause increased CD44 expression through miR-328 suppression, resulting in tumor progression by enhancing ROS defense. miR-328-CD44 signaling mediated by macrophages may thus represent a potential target for the treatment of gastrointestinal cancer. Citation Format: Takatsugu Ishimoto, Naoya Yoshida, Hidetaka Sugihara, Daisuke Izumi, Keisuke Miyake, Hiroshi Sawayama, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Hideo Baba. Macrophage-derived reactive oxygen species suppress miR-328 targeting CD44 in gastrointestinal cancer cells and promote redox adaptation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3598. doi:10.1158/1538-7445.AM2014-3598
    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: 2014
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 185-185
    Abstract: Objectives: Gastric cancer is one of the most threatening malignancies with a high incidence and metastasis rate. Many patients are diagnosed in an advanced stage sometimes with multi-organ metastasis, which leads a poor prognosis of gastric tumors. Chemokine and their receptors have been originally demonstrated as essential mediators of leukocyte directional migration, particularly during infection and inflammation, and have further emerged as crucial players in all stages of tumor development. It has been reported that an important CXCL12-CXCR4 signaling is involved in tumor development and metastasis in several types of cancer including gastric cancer. Cancer associated fibroblasts (CAF) are reported to communicate microenvironment-derived signals through chemokine/chemokine receptor interaction such as CXCL12-CXCR4 signaling. The aim of our study was to evaluate the role of CXCL12-CXCR4 signaling in crosstalk between gastric cancer and CAF. Methods and Results: We evaluated CXCL12 and CXCR4 expression status by immunohistochemistry using a nonbiased database of 89 curatively resected gastric cancers. As a result, CXCL12/ CXCR4 expression are significant correlation with metastasis. Furthermore, we performed Western blotting analysis for CXCL12 and CXCR4 in human gastric cancer cell lines. CXCR4 expression was detectable in all gastric cancer cell lines. We isolated CAF from human gastric cancer tissue resected in our institute. We performed Western blotting analysis for alpha-SMA and CXCL12 in CAF, and confirmed higher expression in CAF than normal fibroblast (NF) isolated from normal gastric mucosa of same patients. Then we established stable AGS gastric cancer cell line expressing GFP. Invasion assay revealed that AGS (gastric cancer cell line) cells with CAF showed more invasive phenotype than that without CAF. We also found the motility of GFP-expressing AGS was elevated during direct co-culture of GFP-expressing AGS cells and CAF compared with NF. Conclusions: These findings revealed that cancer associated fibroblasts were implicated in cancer cell invasion and metastasis through CXCL12-CXCR4 signaling in gastric cancer. The therapeutic blockade of this pathway with CXCR4 antagonist might abrogate gastric cancer cell invasion and metastasis. Citation Format: Daisuke Izumi, Takatsugu Ishimoto, Hietaka Sugihara, Hiroshi Sawayama, Ryuichi Karashima, Satoshi Ida, Yu Imamura, Shiro Iwagami, Yoshifumi Baba, Yasuo Sakamoto, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. Cancer associated fibroblasts stimulates cancer cell invasion through CXCL12-CXCR4 signaling in gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 185. doi:10.1158/1538-7445.AM2014-185
    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: 2014
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3955-3955
    Abstract: Background: The number of patients with pancreatic cancer is rapidly growing, and the disease is the fifth leading cause of cancer-related death in Japan. At end stage of the disease, the patients are prone to suffer peritonitis carcinomatosa with chemorefractory ascites. It is known that cancer cells surviving in ascites show cancer stem cell (CSC)-like features (PLoS One 2012). The CSC-like cells robustly secrete extracellular vesicle called exosome, which plays important roles in tumorigenesis, tumor growth, metastasis, angiogenesis, pre-metastatic niche formation, immunosuppression, drug resistance, and epithelial-mesenchymal transition. The AIM of this prospective study was to assess whether exosomes taken from malignant ascites of patients with advanced pancreatic cancer included the CSC-associated proteins, that might be predictive markers for chemoresistance and prognosis. Methods: The malignant ascites was collected from the cancer patients who underwent abdominocentesis and/or cell-free and concentrated ascites reinfusion therapy (CART) in Kurume University Hospital. Ascites derived from patients with benign diseases, including decompensated liver cirrhosis (d-LC), was used as control. Informed consent was obtained from all of the patients. Exosomes in ascites were purified by using ExoQuick Exosome Precipitation Solution (System Biosciences) according to the manufacturer's protocol. Western blot analysis was performed to detect CSC-associated proteins, including CD133, CD44, CD44v9, xCT, CD24, and Dclk1. Results: Successful purification of exosomes from both the malignant ascites and the benign one was confirmed by monitoring exosome-specific proteins such as CD68, CD9, CD81, and HSP70. Among the CSC-associated proteins examined, CD133 was predominantly expressed in exosomes obtained from ascites of the pancreatic cancer patients compared with those obtained from ascites of the d-LC patients. Other molecules were faintly expressed or absent even in the malignant ascites. Conclusions: We first demonstrated abundant expression of CD133, a human pancreatic CSC marker, in exosomes derived from ascites of patients with the disease. The finding suggests that exosomal CD133 might be a potential biomarker for chemoresistance and prognosis of the patients. Citation Format: Takahiko Sakaue, Hironori Koga, Masaru Fukahori, Yasuko Imamura, Toru Nakamura, Yoshinobu Okabe, Yu Ikezono, Fumitaka Wada, Hideki Iwamoto, Atsutaka Masuda, Tomoyuki Ushijima, Keisuke Miwa, Tatsuyuki Kakuma, Osamu Tsuruta, Takuji Torimura. Expression of cancer stem cell-associated proteins in exosomes derived from ascites of patients with advanced pancreatic 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 3955.
    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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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 5 ( 2013-03-01), p. 1600-1610
    Abstract: Dysregulation of the WNT/β-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses' Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18–1.53 for 5.0 kg/m2 increment; Ptrend = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92–1.25 for 5.0 kg/m2 increment; Ptrend = 0.36; Pheterogeneity = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87–1.00 for 10 MET-h/wk increment; Ptrend = 0.044) but not with CTNNB1-positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91–1.05 for 10 MET-h/wk increment; Ptrend = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. Cancer Res; 73(5); 1600–10. ©2012 AACR.
    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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  • 7
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 4 ( 2014-04-01), p. 452-465
    Abstract: Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)–related kinases Tank-binding kinase-1 (TBK1) and IKKϵ promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKϵ inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKϵ promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKϵ, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS. Significance: In addition to activating MAPK and PI3K, oncogenic KRAS engages cytokine signaling to promote tumorigenesis. CYT387, originally described as a selective JAK inhibitor, is also a potent TBK/IKKϵ inhibitor that uniquely disrupts a cytokine circuit involving CCL5, IL-6, and STAT3. The efficacy of CYT387-based treatment in murine Kras-driven lung cancer models uncovers a novel therapeutic approach for these refractory tumors with immediate translational implications. Cancer Discov; 4(4); 452–65. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 377
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2607892-2
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 23 ( 2018-12-01), p. 5963-5976
    Abstract: MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non–small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14-mutant NSCLC and propose a combination therapy to target it. Experimental Design: The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14-mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays. Results: KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition. Conclusions: Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
    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
    detail.hit.zdb_id: 1225457-5
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2872-2872
    Abstract: Background The development of rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib. A significant relationship exists between the severity of a rash and survival in various cancers. However, whether erlotinib becomes distributed to the skin and whether its concentration is higher in a rash than in normal skin of treated cancer patients remains unknown. Here, using quantitative mass spectrometry imaging (qMSI), we successfully visualized the distribution of erlotinib in rashes and normal skin of patients with advanced pancreatic cancer receiving this drug. Methods We studied five patients with advanced pancreatic cancer who developed rashes after treatment with gemcitabine (1000 mg/m² by intravenous infusion for 30 minutes on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We biopsied both rashes and normal skin, and compared the distribution of erlotinib using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The plasma concentration of erlotinib was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Erlotinib concentrations in five patients were 2.55 ± 1.46 ng/mm3 in normal skin and 3.18 ± 1.53 ng/mm3 (mean ± SD) in rashes (p=0.123). In four out of five patients, the erlotinib concentration in rashes was higher than that in normal skin. The epidermis showed the strongest expression of EGFR in skin as judged by immunohistological staining. Erlotinib showed a greater tendency for distribution to the epidermis than subcutaneous tissue. There was no correlation between erlotinib plasma concentrations vs. concentrations in rashes or normal skin. Conclusions Using qMSI, we, for the first time, visualized the distribution of erlotinib in skin tissue of pancreatic cancer patients receiving erlotinib. We found a tendency for a higher concentration of erlotinib in rashes than in normal skin. A greater distribution of erlotinib to the epidermis than subcutaneous tissue suggests erlotinib may directly bind EGFR expressed in the epidermis. Citation Format: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami. Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2017-2872
    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: 2017
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  • 10
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 6 ( 2009-03-15), p. 1915-1922
    Abstract: Purpose: MicroRNAs are ∼22 nucleotide noncoding RNA molecules that posttranscriptionally regulate gene expression. The aim of this study was (a) to determine a role of microRNA-21 in esophageal squamous cell carcinoma and (b) to elucidate the regulation of the programmed cell death 4 (PDCD4) gene by microRNA-21. Experimental Design: MicroRNA-21 expression was investigated in 20 matched normal esophageal epitheliums and esophageal squamous cell carcinomas and seven esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30) by TaqMan quantitative real-time PCR and in situ hybridization. To evaluate the role of microRNA-21, cell proliferation and invasion were analyzed with anti–microRNA-21–transfected cells. In addition, the regulation of PDCD4 by microRNA-21 was elucidated to identify the mechanisms of this regulation. Results: Of 20 paired samples, 18 cancer tissues overexpressed microRNA-21 in comparison with matched normal epitheliums. Specifically, patients with lymph node metastasis or venous invasion showed significantly high expression of microRNA-21. In situ hybridization for microRNA-21 showed strong positive staining in paraffin-embedded esophageal squamous cell carcinoma tissues. All seven esophageal squamous cell carcinoma cell lines also overexpressed microRNA-21, and anti–microRNA-21–transfected cells showed significant reduction in cellular proliferation and invasion. The PDCD4 protein levels in esophageal squamous cell carcinoma cells have an inverse correlation with microRNA-21 expression. Anti–microRNA-21–transfected cells increased PDCD4 protein expression without changing the PDCD4 mRNA level and increased a luciferase-reporter activity containing the PDCD4-3′ untranslated region construct. Conclusions: MicroRNA-21 targets PDCD4 at the posttranscriptional level and regulates cell proliferation and invasion in esophageal squamous cell carcinoma. It may serve as a novel therapeutic target in esophageal squamous cell carcinoma.
    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: 2009
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