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https://www.readbyqxmd.com/read/28102292/integrated-molecular-analysis-reveals-complex-interactions-between-genomic-and-epigenomic-alterations-in-esophageal-adenocarcinomas
#1
DunFa Peng, Yan Guo, Heidi Chen, Shilin Zhao, Kay Washington, TianLing Hu, Yu Shyr, Wael El-Rifai
The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the United States and Western countries. In this study, we carried out an integrative molecular analysis to identify interactions between genomic and epigenomic alterations in regulating gene expression networks in EAC. We detected significant alterations in DNA copy numbers (CN), gene expression levels, and DNA methylation profiles. The integrative analysis demonstrated that altered expression of 1,755 genes was associated with changes in CN or methylation...
January 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28093501/discrete-cytosolic-macromolecular-braf-complexes-exhibit-distinct-activities-and-composition
#2
Britta Diedrich, Kristoffer Tg Rigbolt, Michael Röring, Ricarda Herr, Stephanie Kaeser-Pebernard, Christine Gretzmeier, Robert F Murphy, Tilman Brummer, Jörn Dengjel
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC-PCP-SILAC, we analyzed protein-protein interactions of hyperactive BRAF(V)(600E) and wild-type BRAF (BRAF(WT))...
January 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28088467/stat3-signaling-mediates-tumour-resistance-to-egfr-targeted-therapeutics
#3
Ahmad A Zulkifli, Fiona H Tan, Tracy L Putoczki, Stanley S Stylli, Rodney B Luwor
Several EGFR inhibitors are currently undergoing clinical assessment or are approved for the clinical management of patients with varying tumour types. However, treatment often results in a lack of response in many patients. The majority of patients that initially respond eventually present with tumours that display acquired resistance to the original therapy. A large number of receptor tyrosine and intracellular kinases have been implicated in driving signaling that mediates this tumour resistance to anti-EGFR targeted therapy, and in a few cases these discoveries have led to overall changes in prospective tumour screening and clinical practice (K-RAS in mCRC and EGFR T790M in NSCLC)...
January 11, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28079954/conformational-sers-classification-of-k-ras-point-mutations-for-cancer-diagnostics
#4
Judit Morla-Folch, Patricia Gisbert-Quilis, Matteo Masetti, Eduardo Garcia-Rico, Ramon A Alvarez-Puebla, Luca Guerrini
Point mutations in Ras oncogenes are routinely screened for diagnostics and treatment of tumors (especially in colorectal cancer). Here, we develop an optical approach based on direct SERS coupled with chemometrics for the study of the specific conformations that single-point mutations impose on a relatively large fragment of the K-Ras gene (141 nucleobases). Results obtained offer the unambiguous classification of different mutations providing a potentially useful insight for diagnostics and treatment of cancer in a sensitive, fast, direct and inexpensive manner...
January 12, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28067274/computational-and-biochemical-characterization-of-two-partially-overlapping-interfaces-and-multiple-weak-affinity-k-ras-dimers
#5
Priyanka Prakash, Abdallah Sayyed-Ahmad, Kwang-Jin Cho, Drew M Dolino, Wei Chen, Hongyang Li, Barry J Grant, John F Hancock, Alemayehu A Gorfe
Recent studies found that membrane-bound K-Ras dimers are important for biological function. However, the structure and thermodynamic stability of these complexes remained unknown because they are hard to probe by conventional approaches. Combining data from a wide range of computational and experimental approaches, here we describe the structure, dynamics, energetics and mechanism of assembly of multiple K-Ras dimers. Utilizing a range of techniques for the detection of reactive surfaces, protein-protein docking and molecular simulations, we found that two largely polar and partially overlapping surfaces underlie the formation of multiple K-Ras dimers...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28065941/di2-ethylhexyl-phthalate-disrupts-thyroid-hormone-homeostasis-through-activating-the-ras-akt-trhr-pathway-and-inducing-hepatic-enzymes
#6
Hanfeng Ye, Mei Ha, Min Yang, Ping Yue, Zhengyuan Xie, Changjiang Liu
Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema...
January 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28061489/the-influence-of-biomarker-mutations-and-systemic-treatment-on-cerebral-metastases-from-nsclc-treated-with-radiosurgery
#7
Min Ho Lee, Doo-Sik Kong, Ho Jun Seol, Do-Hyun Nam, Jung-Il Lee
OBJECTIVE: The purpose of this study was to analyze outcomes and identify prognostic factors in patients with cerebral metastases from non-small cell lung cancer (NSCLC) treated with gamma knife radiosurgery (GKS) particularly, focusing on associations of biomarkers and systemic treatments. METHODS: We retrospectively reviewed the medical records of 134 patients who underwent GKS for brain metastases due to NSCLC between January 2002 and December 2012. Representative biomarkers including epidermal growth factor receptor (EGFR) mutation, K-ras mutation, and anaplastic lymphoma kinase (ALK) mutation status were investigated...
January 1, 2017: Journal of Korean Neurosurgical Society
https://www.readbyqxmd.com/read/28044264/clinicopathological-associations-of-k-ras-and-n-ras-mutations-in-indonesian-colorectal-cancer-cohort
#8
Michael Levi, Gintang Prayogi, Farid Sastranagara, Edi Sudianto, Grace Widjajahakim, Winiarti Gani, Albert Mahanadi, Jocelyn Agnes, Bela Haifa Khairunisa, Ahmad R Utomo
BACKGROUND: K-RAS and recently N-RAS gene mutation testing are mandatory requirements prior to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment of metastatic CRC. Mutation prevalence and distribution in Indonesian colorectal cancer (CRC) are not known. METHODS: Combined methods of PCR high-resolution melt (HRM), restriction fragment length polymorphism (RFLP), and direct DNA sequencing were used to genotype exons 2, 3, and 4 of both K-RAS and N-RAS genes for routine clinical testing of CRC patients...
January 3, 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28044229/genetic-biomarker-prevalence-is-similar-in-fecal-immunochemical-test-positive-and-negative-colorectal-cancer-tissue
#9
Theodore R Levin, Douglas A Corley, Christopher D Jensen, Amy R Marks, Wei K Zhao, Alexis M Zebrowski, Virginia P Quinn, Lawrence W Browne, William R Taylor, David A Ahlquist, Graham P Lidgard, Barry M Berger
BACKGROUND: Fecal immunochemical test (FIT) screening detects most asymptomatic colorectal cancers. Combining FIT screening with stool-based genetic biomarkers increases sensitivity for cancer, but whether DNA biomarkers (biomarkers) differ for cancers detected versus missed by FIT screening has not been evaluated in a community-based population. AIMS: To evaluate tissue biomarkers among Kaiser Permanente Northern California patients diagnosed with colorectal cancer within 2 years after FIT screening...
January 2, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/28041850/lipid-sorting-specificity-encoded-in-k-ras-membrane-anchor-regulates-signal-output
#10
Yong Zhou, Priyanka Prakash, Hong Liang, Kwang-Jin Cho, Alemayehu A Gorfe, John F Hancock
K-Ras is targeted to the plasma membrane by a C-terminal membrane anchor that comprises a farnesyl-cysteine-methyl-ester and a polybasic domain. We used quantitative spatial imaging and atomistic molecular dynamics simulations to examine molecular details of K-Ras plasma membrane binding. We found that the K-Ras anchor binds selected plasma membrane anionic lipids with defined head groups and lipid side chains. The precise amino acid sequence and prenyl group define a combinatorial code for lipid binding that extends beyond simple electrostatics; within this code lysine and arginine residues are non-equivalent and prenyl chain length modifies nascent polybasic domain lipid preferences...
January 12, 2017: Cell
https://www.readbyqxmd.com/read/28032649/kras-mutation-coupled-with-p53-loss-is-sufficient-to-induce-ovarian-carcinosarcomas-in-mice
#11
Feng-Hsiang Tang, Tsung-Hua Hsieh, Chia-Yi Hsu, Hsiao-Yun Lin, Cheng-Yu Long, Kuang-Hung Cheng, Eing-Mei Tsai
Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-ras(G12D) p53(loxP/loxP) and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated...
December 29, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28013056/matrix-metalloproteinase-14-promotes-lung-cancer-by-cleavage-of-heparin-binding-egf-like-growth-factor
#12
Marcin Stawowczyk, Max D Wellenstein, Sharrell B Lee, Shira Yomtoubian, Anna Durrans, Hyejin Choi, Navneet Narula, Nasser K Altorki, Dingcheng Gao, Vivek Mittal
Molecularly targeted therapies benefit approximately 15-20% of non-small cell lung cancer (NSCLC) patients carrying specific drug-sensitive mutations. Thus, there is a clinically unmet need for the identification of novel targets for drug development. Here, we performed RNA-deep sequencing to identify altered gene expression between malignant and non-malignant lung tissue. Matrix Metalloproteinase 14 (MMP14), a membrane-bound proteinase, was significantly up-regulated in the tumor epithelial cells and intratumoral myeloid compartments in both mouse and human NSCLC...
December 22, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28008341/resection-margin-influences-the-outcome-of-patients-with-bilobar-colorectal-liver-metastases
#13
Sara Di Carlo, Derek Yeung, Jamie Mills, Abed Zaitoun, Iain Cameron, Dhanny Gomez
AIM: To evaluate the outcome of patients with bilobar colorectal liver metastases (CRLM) and identify clinico-pathological variables that influenced survival. METHODS: Patients with bilobar CRLM were identified from a prospectively maintained hepatobiliary database during the study period (January 2010-June 2014). Collated data included demographics, primary tumour treatment, surgical data, histopathology analysis and clinical outcome. Down-staging therapy included Oxaliplatin- or Irinotecan- based regimens, and Cetuximab was also used in patients that were K-RAS wild-type...
December 8, 2016: World Journal of Hepatology
https://www.readbyqxmd.com/read/28008183/retraction-g9a-relb-regulates-self-renewal-and-function-of-colon-cancer-initiating-cells-by-silencing-let-7b-and-activating-the-k-ras-%C3%AE-catenin-pathway
#14
Shih-Ting Cha, Ching-Ting Tan, Cheng-Chi Chang, Chia-Yu Chu, Wei-Jiunn Lee, Been-Zen Lin, Ming-Tsan Lin, Min-Liang Kuo
No abstract text is available yet for this article.
December 23, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/28007785/p38mapk-builds-a-hyaluronan-cancer-niche-to-drive-lung-tumorigenesis
#15
Anna Brichkina, Thomas Bertero, Hui Mun Loh, Nguyet Thi Minh Nguyen, Alexander Emelyanov, Sidwell Rigade, Marius Ilie, Paul Hofman, Cedric Gaggioli, Dmitry V Bulavin
Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner...
December 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27998464/-mir-143-inhibits-cell-proliferation-through-targeted-regulating-the-expression-of-k-ras-gene-in-hela-cells
#16
H X Qin, H K Cui, Y Pan, R L Hu, L H Zhu, S J Wang
Objective: To explore the effect of microRNA miR-143 on the proliferation of cervical cancer HeLa cells through targeted regulating the expression of K-ras gene. Methods: The luciferase report carrier containing wild type 3'-UTR of K-ras gene (K-ras-wt) or mutated 3'-UTR of the K-ras (K-ras-mut) were co-transfected with iR-143 mimic into the HeLa cells respectively, and the targeting effect of miR-143 in the transfectants was verified by the dual luciferase report system. HeLa cells were also transfected with miR-143 mimic (miR-143 mimic group), mimic control (negative control group), and miR-143 mimic plus K-ras gene (miR-143 mimic+ K-ras group), respectively...
December 23, 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/27998437/-effects-of-tetrahydrobiopterin-on-the-angiogenesis-in-hepatocellular-carcinoma
#17
Y G Dai, P Gan, W M Li, Q Yao, Y Li, B Pei, J Cui
Objective: To investigate the effect and mechanism of tetrahydrobiopterin (BH4) on the angiogenesis in hepatocellular carcinoma (HCC). Methods: BALB/c-nu mice were subcutaneously injected with HepG-2 cells and randomly divided into control and BH4 groups. The BH4 group and control group received 20 mg/kg BH4 or saline by intraperitoneal injection daily for two weeks, respectively. The level of BH4 was measured by high performance liquid chromatography (HPLC), the level of nitric oxide (NO) was measured by Griess test array, the transcriptional level of K-ras was measured by quantitative RT-PCR, and the protein expressions of guanosine triphosphate cyclohydrolase Ⅰ(GTPCH), endothelial nitric oxide synthase (eNOS), phospho-Akt and Akt were determined by Western blot...
November 23, 2016: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
https://www.readbyqxmd.com/read/27991930/rho-gtpases-anti-or-pro-neoplastic-targets
#18
REVIEW
I Zandvakili, Y Lin, J C Morris, Y Zheng
Rho GTPases are critical signal transducers of multiple pathways. They have been proposed to be useful anti-neoplastic targets for over two decades, especially in Ras-driven cancers. Until recently, however, few in vivo studies had been carried out to test this premise. Several recent mouse model studies have verified that Rac1, RhoA, and some of their effector proteins such as PAK and ROCK, are likely anti-cancer targets for treating K-Ras-driven tumours. Other seemingly contradictory studies have suggested that at least in certain instances inhibition of individual Rho GTPases may paradoxically result in pro-neoplastic effects...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27991926/chronic-inflammation-initiates-multiple-forms-of-k-ras-independent-mouse-pancreatic-cancer-in-the-absence-of-tp53
#19
A K Swidnicka-Siergiejko, S B Gomez-Chou, Z Cruz-Monserrate, D Deng, Y Liu, H Huang, B Ji, N Azizian, J Daniluk, W Lu, H Wang, A Maitra, C D Logsdon
Chronic inflammation (CI) is a risk factor for pancreatic cancer (PC) including the most common type, ductal adenocarcinoma (PDAC), but its role and the mechanisms involved are unclear. To investigate the role of CI in PC, we generated genetic mouse models with pancreatic specific CI in the presence or absence of TP53. Mice were engineered to express either cyclooxygenase-2 (COX-2) or IκB kinase-2 (IKK2), and TP53(+/+) or TP53(f/f) specifically in adult pancreatic acinar cells by using a full-length pancreatic elastase promoter-driven Cre...
December 19, 2016: Oncogene
https://www.readbyqxmd.com/read/27981621/targeting-%C3%AE-catenin-in-hepatocellular-cancers-induced-by-co-expression-of-mutant-%C3%AE-catenin-and-k-ras-in-mice
#20
Junyan Tao, Rong Zhang, Sucha Singh, Minakshi Poddar, Emily Xu, Michael Oertel, Xin Chen, Shanthi Ganesh, Marc Abrams, Satdarshan P Monga
Recently we have shown that co-expression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to HCC in mice that represents around 10% of human HCC. In the current study, we investigate if Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice...
December 16, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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