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Cancer AND CRISPR-Cas9

Christopher R Clark, Makayla Maile, Patrick Blaney, Stefano R Hellweg, Anna Strauss, Wilaiwan Durose, Sambhawa Priya, Juri Habicht, Michael B Burns, Ran Blekhman, Juan E Abrahante, Timothy K Starr
New therapeutic targets for advanced colorectal cancer (CRC) are critically needed. Our laboratory recently performed an insertional mutagenesis screen in mice to identify novel CRC driver genes and, thus, potential drug targets. Here, we define Transmembrane 9 Superfamily 2 (TM9SF2) as a novel CRC oncogene. TM9SF2 is an understudied protein, belonging to a well conserved protein family characterized by their nine putative transmembrane domains. Based on our transposon screen we found that TM9SF2 is a candidate progression driver in digestive tract tumors...
October 17, 2018: Scientific Reports
Scott A Hinger, Diana J Cha, Jeffrey L Franklin, James N Higginbotham, Yongchao Dou, Jie Ping, Lihua Shu, Nripesh Prasad, Shawn Levy, Bing Zhang, Qi Liu, Alissa M Weaver, Robert J Coffey, James G Patton
The regulation and functional roles of secreted coding and long noncoding RNAs (lncRNAs; >200 nt) are largely unknown. We previously showed that mutant KRAS colorectal cancer (CRC) cells release extracellular vesicles (EVs) containing distinct proteomes, microRNAs (miRNAs), and circular RNAs. Here, we comprehensively identify diverse classes of CRC extracellular long RNAs secreted in EVs and demonstrate differential export of specific RNAs. Distinct noncoding RNAs, including antisense transcripts and transcripts derived from pseudogenes, are enriched in EVs compared to cellular profiles...
October 16, 2018: Cell Reports
Xingliang Guo, Hua Jiang, Bizhi Shi, Min Zhou, Honghong Zhang, Zhimin Shi, Guoxiu Du, Hong Luo, Xiuqi Wu, Yi Wang, Ruixin Sun, Zonghai Li
Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system...
2018: Frontiers in Pharmacology
Xiaoyun Sun, Ji Chen, Yanyong Zhang, Mumingjiang Munisha, Scott Dougan, Yuhua Sun
MAX giant associated protein (MGA) is a dual transcriptional factor containing both T-box and bHLHzip DNA binding domains. In vitro studies have shown that MGA functions as a transcriptional repressor or activator to regulate transcription of promotors containing either E-box or T-box binding sites. BS69 (ZMYND11), a multidomain-containing (i.e., PHD, BROMO, PWWP, and MYND) protein, has been shown to selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3), modulates RNA Polymerase II elongation, and functions as RNA splicing regulator...
2018: Frontiers in Cell and Developmental Biology
Yi Ding, Chang Gong, De Huang, Rui Chen, Pinpin Sui, Kevin H Lin, Gehao Liang, Lifeng Yuan, Handan Xiang, Junying Chen, Tao Yin, Peter B Alexander, Qian-Fei Wang, Er-Wei Song, Qi-Jing Li, Kris C Wood, Xiao-Fan Wang
Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification...
October 15, 2018: Nature Communications
Shuai Zhen, Jiaojiao Lu, Ling Hua, Yun-Hui Liu, Wei Chen, Xu Li
Targeted therapy results in objective responses in cervical cancer. However, the responses are short. In contrast, treatment with immune checkpoint inhibitors results in a lower responses rate, but the responses tend to be more durable. Based on these findings, we hypothesized that HPV16 E6/E7-targeted therapy may synergize with the PD-1 pathway blockade to enhance antitumor activity. To test the hypothesis, we described the effects of CRISPR/Cas9 which targeted to the HPV and PD1 in vitro and in vivo. Our data showed that gRNA/cas9 targeted HPV16 E6/E7 induced cervical cancer cell SiHa apoptosis, and suggested that overexpression of PD-L1, induced by HPV16 E6/E7, may be responsible for lymphocyte dysfunction...
October 10, 2018: Archives of Biochemistry and Biophysics
King Pan Ng, Aditi Manjeri, Lin Ming Lee, Zhu En Chan, Chin Yee Tan, Qiancheng Darren Tan, A'Qilah Majeed, Kian Leong Lee, Charles Chuah, Toshio Suda, S Tiong Ong
Cancer cells, including in chronic myeloid leukemia (CML), depend on the hypoxic response to persist in hosts and evade therapy. Accordingly, there is significant interest in drugging cancer-specific hypoxic responses. However, a major challenge in leukemia is identifying differential and druggable hypoxic responses between leukemic and normal cells. Previously, we found that arginase 2 (ARG2), an enzyme of the urea cycle, is overexpressed in CML but not normal progenitors. ARG2 is a target of the hypoxia inducible factors (HIF1-α and HIF2-α), and is required for the generation of polyamines which are required for cell growth...
2018: PloS One
Colm J Ryan, Ilirjana Bajrami, Christopher J Lord
Synthetic lethality has long been proposed as an approach for targeting genetic defects in tumours. Despite a decade of screening efforts, relatively few robust synthetic lethal targets have been identified. Improved genetic perturbation techniques, including CRISPR/Cas9 gene editing, have resulted in renewed enthusiasm for searching for synthetic lethal effects in cancer. An implicit assumption behind this enthusiasm is that the lack of reproducibly identified targets can be attributed to limitations of RNAi technologies...
October 2018: Trends in Cancer
Franklin L Zhong, Kim Robinson, Daniel Eng Thiam Teo, Kiat-Yi Tan, Chrissie Lim, Cassandra R Harapas, Chien-Hsiung Yu, William H Xie, Radoslaw M Sobota, Veonice Bijin Au, Richard Hopkins, Andrea D'Osualdo, John C Reed, John E Connolly, Seth L Masters, Bruno Reversade
The inflammasome is a critical molecular complex that activates IL-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor, NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase, DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice...
October 5, 2018: Journal of Biological Chemistry
Susana Lechuga, Parth H Amin, Aaron R Wolen, Andrei I Ivanov
Cell migration is a critical mechanism controlling tissue morphogenesis, epithelial wound healing and tumor metastasis. Migrating cells depend on orchestrated remodeling of the plasma membrane and the underlying actin cytoskeleton, which is regulated by the spectrin-adducin-based membrane skeleton. Expression of adducins is altered during tumorigenesis, however, their involvement in metastatic dissemination of tumor cells remains poorly characterized. This study investigated the roles of α-adducin (ADD1) and γ-adducin (ADD3) in regulating migration and invasion of non-small cell lung cancer (NSCLC) cells...
October 2, 2018: Biochimica et biophysica acta. Molecular cell research
Malgorzata Bajor, Agata O Zych, Agnieszka Graczyk-Jarzynka, Angelika Muchowicz, Malgorzata Firczuk, Lech Trzeciak, Pawel Gaj, Antoni Domagala, Marta Siernicka, Agnieszka Zagozdzon, Pawel Siedlecki, Monika Kniotek, Patrick C O'Leary, Jakub Golab, Radoslaw Zagozdzon
BACKGROUND: Our previous work has shown peroxiredoxin-1 (PRDX1), one of major antioxidant enzymes, to be a biomarker in human breast cancer. Hereby, we further investigate the role of PRDX1, compared to its close homolog PRDX2, in mammary malignant cells. METHODS: CRISPR/Cas9- or RNAi-based methods were used for genetic targeting PRDX1/2. Cell growth was assessed by crystal violet, EdU incorporation or colony formation assays. In vivo growth was assessed by a xenotransplantation model...
October 2018: British Journal of Cancer
Aarti Sethuraman, Martin Brown, Raya Krutilina, Zhao-Hui Wu, Tiffany N Seagroves, Lawrence M Pfeffer, Meiyun Fan
BACKGROUND: Metastasis is responsible for a significant number of breast cancer-related deaths. Hypoxia, a primary driving force of cancer metastasis, induces the expression of BHLHE40, a transcription regulator. This study aimed to elucidate the function of BHLHE40 in the metastatic process of breast cancer cells. METHODS: To define the role of BHLHE40 in breast cancer, BHLHE40 expression was knocked down by a lentiviral construct expressing a short hairpin RNA against BHLHE40 or knocked out by the CRISPR/Cas9 editing system...
October 1, 2018: Breast Cancer Research: BCR
Wenwen Wu, Nana Rokutanda, Jun Takeuchi, Yongqiang Lai, Reo Maruyama, Yukiko Togashi, Hiroyuki Nishikawa, Naoko Arai, Yasuo Miyoshi, Nao Suzuki, Yasushi Saeki, Keiji Tanaka, Tomohiko Ohta
BLM and WRN are RecQ DNA helicases essential for genomic stability. Here we demonstrate that HERC2, a HECT E3 ligase, is critical for their functions to suppress G-quadruplex (G4) DNA. HERC2 interacted with BLM, WRN, and replication protein A (RPA) complexes during the S-phase of the cell cycle. Depletion of HERC2 dissociated RPA from BLM and WRN complexes and significantly increased G4 formation. Triple depletion revealed that HERC2 has an epistatic relationship with BLM and WRN in their G4-suppressing function...
October 2, 2018: Cancer Research
Christian Borgo, Jordi Vilardell, Valentina Bosello-Travain, Lorenzo A Pinna, Andrea Venerando, Mauro Salvi
BACKGROUND: HSP27 plays a role in various diseases, including neurodegenerative diseases, ischemia, and atherosclerosis. It is particularly important in the regulation of the development, progression and metastasis of cancer as well as cell apoptosis and drug resistance. However, the absence of an ATP binding domain, that is, instead, present in other HSPs such as HSP90 and HSP70, hampers the development of small molecules as inhibitors of HSP27. METHODS: Knockout cell lines generated by Crispr/Cas9 gene editing tool, specific kinase inhibitors and siRNA transfections were exploited to demonstrate that the expression of HSP27 is dependent on the integrity/activity of protein kinase CK2 holoenzyme...
September 20, 2018: Biochimica et biophysica acta. General subjects
Susan C Kandarian, Rachel L Nosacka, Andrea E Delitto, Andrew R Judge, Sarah M Judge, John D Ganey, Jesse D Moreira, Robert W Jackman
BACKGROUND: Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour-derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. METHODS: A C26 Lif null tumour cell line was made using CRISPR-Cas9...
September 30, 2018: Journal of Cachexia, Sarcopenia and Muscle
Ian P Winters, Christopher W Murray, Monte M Winslow
Large-scale sequencing of human tumours has uncovered a vast array of genomic alterations. Genetically engineered mouse models recapitulate many features of human cancer and have been instrumental in assigning biological meaning to specific cancer-associated alterations. However, their time, cost and labour-intensive nature limits their broad utility; thus, the functional importance of the majority of genomic aberrations in cancer remains unknown. Recent advances have accelerated the functional interrogation of cancer-associated alterations within in vivo models...
September 28, 2018: Nature Reviews. Genetics
Ziqi Zhu, Yoon-Mi Chung, Olga Sergeeva, Vladimir Kepe, Michael P Berk, Jianneng Li, Hyun-Kyung Ko, Zhenfei Li, Marianne Petro, Frank DiFilippo, Zhenghong Lee, Nima Sharifi
Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending androgen resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment-sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation...
September 27, 2018: Journal of Biological Chemistry
Xiaohong Zhang, Yanqing Qian, Fan Li, Songhua Bei, Meiyi Li, Li Feng
LIM homeobox transcription factor 1, alpha (LMX1A) is downregulated in human gastric cancer (GC), functioning as a tumor suppressor. The current study aims to identify specific microRNA that can regulate LMX1A expression. By sequence analysis of LMX1A mRNA 3'-untranslated region (3'-UTR), we show that microRNA-9 (miR-9) putatively targets human LMX1A. In established (AGS cells) and primary human GC cells, ectopic overexpression of miR-9 by a lentiviral construct decreased LMX1A 3'-UTR activity, causing LMX1A mRNA and protein downregulation...
September 24, 2018: Biochemical and Biophysical Research Communications
Hasan Mollanoori, Hojat Shahraki, Yazdan Rahmati, Shahram Teimourian
Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) technology, an acquired immune system in bacteria and archaea, has provided a new tool for accurately genome editing. Using only a single nuclease protein in complex with 2 short RNA as a site-specific endonuclease made it a simple and flexible genome editing tool to target nearly any genomic locus. Due to recent developments in therapeutic engineered T cell and effective responses of CD19-directed chimeric antigen receptor T cells (CART19) in patients with B-cell leukemia and lymphoma, adoptive T cell immunotherapy, particularly CAR-T cell therapy became a rapidly growing field in cancer therapy and recently Kymriah and Yescarta (CD19-directed CAR-T cells) were approved by FDA...
September 24, 2018: Human Immunology
Pouria Samadi, Sahar Saki, Fatemeh Karimi Dermani, Mona Pourjafar, Massoud Saidijam
BACKGROUND: Breast cancer (BC) is the most common cancer among women and it is responsible for more than 40,000 deaths in the United States and more than 500,000 deaths worldwide each year. In previous decades, the development of improved screening, diagnosis and treatment methods has led to decreases in BC mortality rates. More recently, novel targeted therapeutic options, such as the use of monoclonal antibodies and small molecule inhibitors that target specific cancer cell-related components, have been developed...
September 27, 2018: Cellular Oncology (Dordrecht)
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