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https://www.readbyqxmd.com/read/28637023/cationic-liquid-crystalline-nanoparticles-for-the-delivery-of-synthetic-rnai-based-therapeutics
#1
Emanuela Gentile, Taro Oba, Jing Lin, Ruping Shao, Feng Meng, Xiaobo Cao, Heather Y Lin, Majidi Mourad, Apar Pataer, Veerabhadran Baladandayuthapani, Dong Cai, Jack A Roth, Lin Ji
RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half-life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems to facilitate the use of RNAi. We developed a novel cationic liquid crystalline nanoparticle (CLCN) to efficiently deliver synthetic siRNAs and miRNAs. CLCNs were prepared by using high-speed homogenization and assembled with synthetic siRNA or miRNA molecules in nuclease-free water to create CLCN/siRNA or miRNA complexes...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28637004/autophagy-is-required-for-crizotinib-induced-apoptosis-in-met-amplified-gastric-cancer-cells
#2
Rebecca D Schroeder, Woonyoung Choi, David S Hong, David J McConkey
MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug-sensitive cells in a concentration-dependent manner...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636389/tumor-microenvironment-responsive-multistaged-nanoplatform-for-systemic-rnai-and-cancer-therapy
#3
Xiaoding Xu, Phei Er Saw, Wei Tao, Yujing Li, Xiaoyuan Ji, Mikyung Yu, Morteza Mahmoudi, Jonathan Rasmussen, Dana Ayyash, Yuxiao Zhou, Omid C Farokhzad, Jinjun Shi
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core...
June 21, 2017: Nano Letters
https://www.readbyqxmd.com/read/28633016/mll-wdr5-complex-regulates-kif2a-localization-to-ensure-chromosome-congression-and-proper-spindle-assembly-during-mitosis
#4
Aamir Ali, Sailaja Naga Veeranki, Akash Chinchole, Shweta Tyagi
Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28631377/state-of-the-art-technologies-to-explore-long-non-coding-rnas-in-cancer
#5
REVIEW
Saeede Salehi, Mohammad Naser Taheri, Negar Azarpira, Abdolhossein Zare, Abbas Behzad-Behbahani
Long non-coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell-specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single-molecule RNA in situ hybridization (sm-RNA FISH), cross-linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions...
June 19, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28619457/in-vitro-studies-of-phospholipid-modified-pamam-simdr1-complexes-for-the-reversal-of-multidrug-resistance-in-human-breast-cancer-cells
#6
Jing Liu, Jun Li, Nan Liu, Nana Guo, Chen Gao, Yanli Hao, Lei Chen, Xiaoning Zhang
The application of RNAi therapeutics is promising in combating several major human diseases including malignant tumors. However, this approach is limited due to its delivery barriers. In this study, we designed a new carrier system loaded with a functional siRNA targeting MDR1 gene to reverse multi-drug resistance (MDR) in human breast cancer MCF-7/ADR cells. Phospholipid-modified PAMAM-siMDR1 complexes were designed on the external decoration of polyamidoamine (PAMAM) with phospholipid (PL) and the electrostatical interaction between PAMAM and siMDR1 to form hybrid nanocomplexes (PL-dendriplexes)...
June 12, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28606919/expression-and-therapeutic-potential-of-sox9-in-chordoma
#7
Hua Chen, Cassandra Garbutt, Dimitrios Spentzos, Edwin Choy, Francis J Hornicek, Zhenfeng Duan
Conventional chemotherapeutic agents are ineffective in the treatment of chordoma. We investigated the functional roles and therapeutic relevance of the sex-determining region Y (SRY)-box 9 (SOX9) in chordoma. <br /><br />Experimental Design: <p>SOX9 expression was examined by immunohistochemistry (IHC) using 50 chordoma tissue samples. SOX9 expression in chordoma cell lines was examined by Western blot and immunofluorescence assays. We used synthetic human SOX9 siRNA to inhibit the expression of SOX9...
June 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28594407/egr-1-aspp1-inter-regulatory-loop-promotes-apoptosis-by-inhibiting-cyto-protective-autophagy
#8
Kunming Zhao, Miao Yu, Yifu Zhu, Dong Liu, Qiong Wu, Ying Hu
The decrease of ASPP1 (Apoptosis-Stimulating Protein of p53 1), a known p53 activator, has been linked to carcinogenesis and the cytotoxic resistance in various cancers, yet the underlying mechanisms of ASPP1 expression and its complex functions are not yet clear. Here, we report that ASPP1 forms an inter-regulatory loop with Early Growth Response 1 (EGR-1), and promotes apoptosis via inhibiting cyto-protective autophagy, independent of the well-documented p53-dependent mechanisms. We show that ASPP1 mRNA and protein were remarkably elevated by ectopic EGR-1 expression or endogenous EGR-1 activation, in cells with different tissue origins and p53 status...
June 8, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28592880/expression-and-transcriptional-regulation-of-human-atp6v1a-gene-in-gastric-cancers
#9
Pin Wang, Lei Wang, Jie Sha, Guochun Lou, Nannan Lu, Bo Hang, Jian-Hua Mao, Xiaoping Zou
Recent studies demonstrate that the invasion and metastasis of gastric cancer (GC) is closely associated with a multi-subunit vacuolar H+-ATPase (V-ATPase). Here we investigated the expression and role of the human ATP6V1A gene that encodes the catalytic subunit A of V-ATPase in GC. We found that ATP6V1A expression level is significantly elevated in GCs compared to normals, but GC patients with higher expression levels of ATP6V1A have a better prognosis. Genomic analysis revealed that APT6V1A copy number is gained in a small fraction of GC patients and lost in a minimum number...
June 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28589243/rnai-targeting-stmn-alleviates-the-resistance-to-taxol-and-collectively-contributes-to-down-regulate-the-malignancy-of-nsclc-cells-in-vitro-and-in-vivo
#10
Dan Long, Ting Yu, Xian Chen, Ying Liao, Xuechi Lin
Stathmin (STMN) plays a vital role in maintaining the malignant behavior of cancer through directly regulating microtubule dynamics equilibrium. Taxol, an effective chemotherapeutics mainly acting to promote microtubule polymerization, has been commercially applied in treating solid tumors, which results in serious drug resistance. Our study demonstrated that STMN RNA interference (RNAi) enlarged taxol-induced inhibitions in cellular proliferation, colony formation, and multidimensional spaces of cell immigration and decreased half maximal inhibitory concentration (IC50) of taxol in nonsmall cell lung cancer (NSCLC) NCI-H1299 cells; STMN RNAi and taxol jointly attenuated the expressions of extracellular regulated kinase (ERK), nuclear factor kappa B (NF-κB) and B cell lymphoma-2 (Bcl-2), but up regulated Bax expression and initiated intrinsic cell death pathway by activating caspase-3 and caspase-9, while inhibited interleukin 10 (IL-10) autocrine from cell culture supernatant and xenografted mouse serum, as well as intracellular expressions of IL-10 protein and mRNA in vitro; additionally, neutralizing IL-10 alone would incur cell apoptosis to some degree; the further study confirmed that RNAi targeting STMN promoted the sensitivity of taxol in different NSCLC cells...
June 7, 2017: Cell Biology and Toxicology
https://www.readbyqxmd.com/read/28587379/long-non-coding-rna-malat1-is-upregulated-and-involved-in-cell-proliferation-migration-and-apoptosis-in-ovarian-cancer
#11
Liqin Wu, Xiaoyu Wang, Yuna Guo
Ovarian cancer (OC) is the leading cause of mortality among gynecological malignancies. Although microRNAs are known to have a key regulatory role in OC, the involvement of long non-coding RNAs in the disease is less established. Previous studies have demonstrated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a tumor oncogene in many cancers, though its role in OC remains unclear. The present study reported that MALAT1 expression was markedly upregulated in OC, by knockdown of MALAT1 expression in vivo, using RNA interference (RNAi) with small-interfering RNA (siRNA)...
June 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28576884/mdm2-is-required-for-survival-and-growth-of-p53-deficient-cancer-cells
#12
Kyle Feeley, Clare M Adams, Ramkrishna Mitra, Christine M Eischen
p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T cell lymphomas or sarcomas lacking p53 induced apoptosis and G2 cell cycle arrest, prolonging survival of mice with these tumors. p53(-/-) fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to pre-malignant cells...
June 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/28574511/signalome-wide-rnai-screen-identifies-gba1-as-a-positive-mediator-of-autophagic-cell-death
#13
Santosh K Dasari, Shani Bialik, Smadar Levin-Zaidman, Vered Levin-Salomon, Alfred H Merrill, Anthony H Futerman, Adi Kimchi
Activating alternative cell death pathways, including autophagic cell death, is a promising direction to overcome the apoptosis resistance observed in various cancers. Yet, whether autophagy acts as a death mechanism by over consumption of intracellular components is still controversial and remains undefined at the ultrastructural and the mechanistic levels. Here we identified conditions under which resveratrol-treated A549 lung cancer cells die by a mechanism that fulfills the previous definition of autophagic cell death...
June 2, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28569207/seed-effect-modeling-improves-the-consistency-of-genome-wide-loss-of-function-screens-and-identifies-synthetic-lethal-vulnerabilities-in-cancer-cells
#14
Alok Jaiswal, Gopal Peddinti, Yevhen Akimov, Krister Wennerberg, Sergey Kuznetsov, Jing Tang, Tero Aittokallio
BACKGROUND: Genome-wide loss-of-function profiling is widely used for systematic identification of genetic dependencies in cancer cells; however, the poor reproducibility of RNA interference (RNAi) screens has been a major concern due to frequent off-target effects. Currently, a detailed understanding of the key factors contributing to the sub-optimal consistency is still a lacking, especially on how to improve the reliability of future RNAi screens by controlling for factors that determine their off-target propensity...
June 1, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28562667/therapeutic-silence-of-pleiotrophin-by-targeted-delivery-of-sirna-and-its-effect-on-the-inhibition-of-tumor-growth-and-metastasis
#15
Lisha Zha, Lichun He, Weidong Xie, Jin Cheng, Tong Li, Mona O Mohsen, Fan Lei, Federico Storni, Martin Bachmann, Hongquan Chen, Yaou Zhang
Pleiotrophin (PTN) is a secreted cytokine that is expressed in various cancer cell lines and human tumor such as colon cancer, lung cancer, gastric cancer and melanoma. It plays significant roles in angiogenesis, metastasis, differentiation and cell growth. The expression of PTN in the adult is limited to the hippocampus in an activity-dependent manner, making it a very attractive target for cancer therapy. RNA interference (RNAi) offers great potential as a new powerful therapeutic strategy based on its highly specific and efficient silencing of a target gene...
2017: PloS One
https://www.readbyqxmd.com/read/28558758/fgf2-fgfr1-regulates-autophagy-in-fgfr1-amplified-non-small-cell-lung-cancer-cells
#16
Hong Yuan, Zi-Ming Li, Jiaxiang Shao, Wen-Xiang Ji, Weiliang Xia, Shun Lu
BACKGROUND: Autophagy is a conserved catabolic process to degrade cellular organelles. The role of autophagy in cancer development is complex. Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC). Whether fibroblast growth factor 2 (FGF2)/FGFR1 contributes to the regulation of autophagy remains elusive. METHODS: Autophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3), formation of GFP-LC3 puncta, and monodansylcadaverine (MDC) staining...
May 30, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28558729/high-throughput-validation-of-cerna-regulatory-networks
#17
Hua-Sheng Chiu, María Rodríguez Martínez, Mukesh Bansal, Aravind Subramanian, Todd R Golub, Xuerui Yang, Pavel Sumazin, Andrea Califano
BACKGROUND: MicroRNAs (miRNAs) play multiple roles in tumor biology. Interestingly, reports from multiple groups suggest that miRNA targets may be coupled through competitive stoichiometric sequestration. Specifically, computational models predicted and experimental assays confirmed that miRNA activity is dependent on miRNA target abundance, and consequently, changes in the abundance of some miRNA targets lead to changes to the regulation and abundance of their other targets. The resulting indirect regulatory influence between miRNA targets resembles competition and has been dubbed competitive endogenous RNA (ceRNA)...
May 30, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28557434/dual-targeting-of-wee1-and-plk1-by-azd1775-elicits-single-agent-cellular-anticancer-activity
#18
Gabriela Wright, Volha Golubeva, Lily L Remsing Rix, Norbert Berndt, Yunting Luo, Grace A Ward, Jhanelle E Gray, Ernst Schonbrunn, Harshani R Lawrence, Alvaro N A Monteiro, Uwe Rix
Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. However, AZD1775 also exhibits anticancer activity as a single agent although the underlying mechanism is not fully understood. Using a chemical proteomics approach, we here describe a proteome-wide survey of AZD1775 targets in lung cancer cells and identify several previously unknown targets in addition to WEE1...
June 7, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28548675/inducible-bcl-2-gene-rna-interference-mediated-by-aptamer-integrated-hdv-ribozyme-switch
#19
Yuanyuan Zhang, Jine Wang, Hui Cheng, Na Sun, Min Liu, Zhengyan Wu, Renjun Pei
The regulation of RNA interference (RNAi) could be a powerful method for the study of temporal and dose dependent effects of gene expression. In this study, we designed the hepatitis delta virus (HDV) ribozyme with an embedded theophylline aptamer as the sensor domain and the pri-miRNA of endogenous gene Bcl-2 as the effector domain to engineer an RNAi-regulatory device in MCF-7 cells. The system allowed us to control gene expression by adding theophylline into the culture media in a dose dependent fashion...
May 26, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/28545088/transcriptional-activation-of-hif-1-by-a-ros-erk-axis-underlies-the-resistance-to-photodynamic-therapy
#20
María Julia Lamberti, María Florencia Pansa, Renzo Emanuel Vera, Martín Ernesto Fernández-Zapico, Natalia Belén Rumie Vittar, Viviana Alicia Rivarola
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT...
2017: PloS One
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