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Cancer Research

Bruna Rodrigues Muys, Josane F Sousa, Jessica Rodrigues Plaça, Luíza F Araújo, Aishe A Sarshad, Dimitrios G Anastasakis, Xiantao Wang, Xiao L Li, Greice Andreotti de Molfetta, Anelisa Ramão, Ashish Lal, Daniel Onofre Vidal, Markus Hafner, Wilson A Silva
Dysregulation of miRNA expression is associated with multiple diseases, including cancers, in which small RNAs can have either oncogenic or tumor suppressive functions. Here we investigated the potential tumor suppressive function of miR-450a, one of the most significantly downregulated miRNAs in ovarian cancer. RNA-Seq analysis of the ovarian cancer cell line A2780 revealed that overexpression of miR-450a suppressed multiple genes involved in the epithelial-to-mesenchymal transition (EMT). Overexpression of miR-450a reduced tumor migration and invasion and increased anoikis in A2780 and SKOV-3 cell lines and reduced tumor growth in an ovarian tumor xenographic model...
May 17, 2019: Cancer Research
Lang Wu, Jifeng Wang, Qiuyin Cai, Taylor B Cavazos, Nima C Emami, Jirong Long, Xiao-Ou Shu, Yingchang Lu, Xingyi Guo, Joshua A Bauer, Bogdan Pasaniuc, Kathryn L Penney, Matthew L Freedman, Zsofia Kote-Jarai, John S Witte, Christopher A Haiman, Rosalind A Eeles, Wei Zheng
Genome-wide association studies have identified genetic variants associated with prostate cancer risk. However, these variants explain only a small fraction of the heritable component of prostate cancer risk, and the genes responsible for many of the identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets...
May 17, 2019: Cancer Research
Tian Lan, Kefei Yuan, Xiaokai Yan, Lin Xu, Haotian Liao, Xiangyong Hao, Jinju Wang, Hong Liu, Kunlin Xie, Jiaxin Li, Mingheng Liao, Jiwei Huang, Yong Zeng, Hong Wu
Understanding the roles of noncoding RNAs (ncRNA) in tumorigenesis and metastasis would establish novel avenues to identify diagnostic and therapeutic targets. Here we aimed to identify hepatocellular carcinoma (HCC)-specific ncRNA and investigate their roles in hepatocarcinogenesis and metastasis. RNA-seq of xenografts generated by lung metastasis identified lncRNA SNHG10 and its homolog SCARNA13 as novel drivers for the development and metastasis of HCC. SNHG10 expression positively correlated with SCARNA13 expression in 64 HCC cases, and high expression of SNHG10 or SCARNA13 was associated with poor overall survival...
May 17, 2019: Cancer Research
Minle Li, Ying Lu, Yakui Li, Lingfeng Tong, Xiao-Chuan Gu, Jian Meng, Yemin Zhu, Lifang Wu, Ming Feng, Na Tian, Ping Zhang, Tianle Xu, Shu-Hai Lin, Xuemei Tong
De novo nucleotide biosynthesis is essential for maintaining cellular nucleotide pools, the suppression of which leads to genome instability. The metabolic enzyme transketolase (TKT) in the non-oxidative branch of the pentose phosphate pathway (PPP) regulates ribose 5-phosphate (R5P) levels and de novo nucleotide biosynthesis. TKT is required for maintaining cell proliferation in human liver cancer cell lines, yet the role of TKT in liver injury and cancer initiation remains to be elucidated. In this study, we generated a liver-specific TKT knockout mouse strain by crossing TKTflox/flox mice with albumin-Cre mice...
May 17, 2019: Cancer Research
Emmanuelle Saint-Germain, Lian Mignacca, Geneviève Huot, Mariana Acevedo, Karine Moineau-Vallée, Viviane Calabrese, Véronique Bourdeau, Marie-Camille Rowell, Subburaj Ilangumaran, Frédéric Lessard, Gerardo Ferbeyre
Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53-SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence...
May 17, 2019: Cancer Research
Qiang Zhang, Michael D Green, Xueting Lang, Jenny Lazarus, Joshua Parsels, Shuang Wei, Leslie A Parsels, Jiaqi Shi, Nithya Ramnath, Daniel R Wahl, Marina Pasca di Magliano, Timothy L Frankel, Ilona Kryczek, Yu Lei, Theodore S Lawrence, Weiping Zou, Meredith A Morgan
Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Since ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I Interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition...
May 17, 2019: Cancer Research
Avihai Ron, Xosé Luís Deán-Ben, Sven Gottschalk, Daniel Razansky
Mapping tumor heterogeneity and hypoxia within a living intact organism is essential for understanding the processes involved in cancer progression and assessing long-term responses to therapies. Efficient investigations into tumor hypoxia mechanisms have been hindered by the lack of intravital imaging tools capable of multi-parametric probing of entire solid tumors with high spatial and temporal resolution. Here we exploit volumetric multi-spectral optoacoustic tomography (vMSOT) for accurate, label-free delineation of tumor heterogeneity and dynamic oxygenation behavior...
May 16, 2019: Cancer Research
Hongjie Ji, Yongjie Zhou, Xiang Zhuang, Yongjie Zhu, Zhenru Wu, Yannrong Lu, Shengfu Li, Yong Zeng, Qing R Lu, Yanying Huo, Yujun Shi, Hong Bu
DNA damage triggers diverse cancers, particularly hepatocellular carcinoma (HCC), but the intrinsic link between DNA damage and tumorigenesis remains unclear. Due to its role as an epigenetic and transcriptional regulator, histone deacetylase 3 (HDAC3) is essential for DNA damage control and is often aberrantly expressed in human HCC. In this study, we used individual class I HDAC member-deficient mice to demonstrate that K9 in histone H3 (H3K9), which is the critical site for the assembly of DNA damage response complexes, is exclusively targeted by HDAC3...
May 16, 2019: Cancer Research
Kalpana Deepa Priya Dorayappan, Miranda L Gardner, Colin L Hisey, Roman A Zingarelli, Brentley Q Smith, Michelle D S Lightfoot, Rajan Gogna, Meghan M Flannery, John Hays, Derek J Hansford, Michael A Freitas, Lianbo Yu, David E Cohn, Karuppaiyah Selvendiran
Due to limits on specificity and purity to allow for in-depth protein profiling, a standardized method for exosome isolation has yet to be established. In this study, we describe a novel, in-house microfluidic-based device to isolate exosomes from culture media and patient samples. This technology overcomes contamination issues because sample separation is based on the expression of highly specific surface markers CD63 and EpCAM. Top exosome proteins were identified based on their fold change and statistical significance between groups...
May 16, 2019: Cancer Research
Pei-Ju Sung, Nicolas Rama, Jeromine Imbach, Stephany Fiore, Benjamin Ducarouge, David Neves, Huei-Wen Chen, David Bernard, Pan-Chyr Yang, Agnès Bernet, Stephane Depil, Patrick Mehlen
Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when co-cultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness...
May 14, 2019: Cancer Research
Richard L Hesketh, Jiazheng Wang, Alan J Wright, David Y Lewis, Alice E Denton, Richard Grenfell, Jodi L Miller, Robert Bielik, Marcel Gehrung, Maria Fala, Susana Ros, Bangwen Xie, De-En Hu, Kevin M Brindle
Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here we assess the abilities of positron emission tomography (PET) measurement of [18F]FDG uptake and magnetic resonance imaging (MRI) measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death...
May 14, 2019: Cancer Research
Meghan Travers, Stephen M Brown, Matthew Dunworth, Cassandra E Holbert, Karla R Wiehagen, Kurtis E Bachman, Jackson R Foley, Meredith L Stone, Stephen B Baylin, Robert A Casero, Cynthia A Zahnow
Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (AZA) activates type I interferon signaling to increase IFNγ+ T cells and NK cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome...
May 14, 2019: Cancer Research
Pavlina K Todorova, Eliot Fletcher-Sananikone, Bipasha Mukherjee, Rahul Kollipara, Vamsidhara Vemireddy, Xian-Jin Xie, Peter M Guida, Michael D Story, Kimmo Hatanpaa, Amyn A Habib, Ralf Kittler, Robert Bachoo, Robert Hromas, John R Floyd, Sandeep Burma
Glioblastomas (GBM) are lethal brain tumors which are treated with conventional radiation (X-rays and gamma rays) or particle radiation (protons and carbon ions). Paradoxically, radiation is also a risk factor for GBM development, raising the possibility that radiotherapy of brain tumors could promote tumor recurrence or trigger secondary gliomas. In this study, we determined whether tumor suppressor losses commonly displayed by GBM patients confer susceptibility to radiation-induced glioma. Mice with Nestin-Cre-driven deletions of Trp53 and Pten alleles were intracranially irradiated with X-rays or charged particles of increasing atomic number and linear energy transfer (LET)...
May 14, 2019: Cancer Research
Paola D Vermeer
The naïve view of tumors as isolated islands of rogue cells has given way to a deeper understanding of cancer as being closer to a foreign organ. This "organ" contains immunologic, vascular, and neural connections to its host that provide not only mechanisms for disease progression but also opportunities for therapeutic intervention. The presence of nerves within tumor tissues has long been appreciated. However, a mechanistic understanding of how tumors recruit nerves has been slower to emerge. Tumor release of neurotrophic factors and axonal guidance molecules likely directs axons toward the tumor bed...
May 14, 2019: Cancer Research
Barry E Kennedy, John Patrick Murphy, Derek R Clements, Prathyusha Konda, Namit Holay, Youra Kim, Gopal P Pathak, Michael A Giacomantonio, Yassine El Hiani, Shashi Gujar
Oncolytic viruses (OV) such as reovirus preferentially infect and kill cancer cells. Thus, the mechanisms that dictate the susceptibility of cancer cells to OV-induced cytotoxicity hold the key to their success in clinics. Here we investigated whether cancer cell metabolism defines its susceptibility to OV, and if OV-induced metabolic perturbations can be therapeutically targeted. Using mass spectrometry-based metabolomics and extracellular flux analysis on a panel of cancer cell lines with varying degrees of susceptibility to reovirus, we found that OV-induced changes in central energy metabolism, pyruvate metabolism, and oxidative stress correlate with their susceptibility to reovirus...
May 14, 2019: Cancer Research
Yingfeng Xia, Bingwei Ye, Jane Ding, Yajie Yu, Ahmet Alptekin, Muthusamy Thangaraju, Puttur D Prasad, Zhi-Chun Ding, Eun Jeong Park, Jeong-Hyeon Choi, Bei Gao, Oliver Fiehn, Chunhong Yan, Zheng Dong, Yunhong Zha, Han-Fei Ding
MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy...
May 14, 2019: Cancer Research
Yoonha Hwang, Laura C Kim, Wenqiang Song, Deanna N Edwards, Rebecca S Cook, Jin Chen
Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that acts in two distinct complexes, mTORC1 and mTORC2, and is dysregulated in many diseases including cancer. mLST8 is a shared component of both mTORC1 and mTORC2, yet little is known regarding how mLST8 contributes to assembly and activity of the mTOR complexes. Here we assessed mLST8 loss in a panel of normal and cancer cells and observed little to no impact on assembly or activity of mTORC1. However, mLST8 loss blocked mTOR association with mTORC2 cofactors Rictor and Sin1 and impaired mTORC2 kinase activity, including phosphorylation of AKT at S473...
May 13, 2019: Cancer Research
Mengjia Song, Yu Ping, Kai Zhang, Li Yang, Feng Li, Chaoqi Zhang, Shaoyan Cheng, Dongli Yue, Nomathamsanqa Resegofetse Maimela, Jiao Qu, Shasha Liu, Ting Sun, Zihai Li, Jianchuan Xia, Bin Zhang, Liping Wang, Yi Zhang
Interferon-γ (IFN-γ) is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFN-γ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFN-γ can induce cancer progression, yet the mechanisms underlying the controversial role of IFN-γ in tumor development remain unclear. Here we reveal a dose-dependent effect of IFN-γ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types...
May 13, 2019: Cancer Research
Ramona Palombo, Paola Frisone, Marco Fidaleo, Neri Mercatelli, Claudio Sette, Maria Paola Paronetto
Most Ewing sarcomas are characterized by the in frame chromosomal translocation t(11;22), generating the EWS-FLI1 oncogene. EWS-FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including CCND1 (the cyclin D1 gene), which contributes to cell cycle dysregulation in cancer. In this study, we found that CCND1 expression is significantly higher in Ewing sarcoma patients compared to other sarcomas and that the pncCCND1_B RNA, a previously uncharacterized CCND1 promoter-associated non-coding (pnc) transcript, is expressed in Ewing sarcoma cells...
May 9, 2019: Cancer Research
Xiaojie Zhang, Kathleen A Ashcraft, Allison Betof Warner, Smita K Nair, Mark W Dewhirst
The immune system plays an important role in controlling cancer growth. However, cancers evolve to evade immune detection. Immune tolerance and active immune suppression results in unchecked cancer growth and progression. A major contributor to immune tolerance is the tumor physiologic microenvironment, which includes hypoxia, hypoglucosis, lactosis, and reduced pH. Preclinical and human studies suggest that exercise elicits mobilization of leukocytes into circulation (also known as "exercise-induced leukocytosis"), especially cytotoxic T cells and natural killer cells...
May 8, 2019: Cancer Research
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