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Tiara Bunga Mayang Permata, Yoshihiko Hagiwara, Hiro Sato, Takaaki Yasuhara, Takahiro Oike, Soehartati Gondhowiardjo, Kathryn D Held, Takashi Nakano, Atsushi Shibata
Programmed death-ligand 1 (PD-L1) is a key factor influencing cancer immunotherapy; however, the regulation of PD-L1 expression in cancer cells remains unclear, particularly regarding DNA damage, repair and its signalling. Herein, we demonstrate that oxidative DNA damage induced by exogenously applied hydrogen peroxide (H2 O2 ) upregulates PD-L1 expression in cancer cells. Further, depletion of the base excision repair (BER) enzyme DNA glycosylase augments PD-L1 upregulation in response to H2 O2 . PD-L1 upregulation in BER-depleted cells requires ATR/Chk1 kinase activities, demonstrating that PD-L1 upregulation is mediated by DNA damage signalling...
February 12, 2019: Oncogene
Francesco Alessandrini, Laura Menotti, Elisa Avitabile, Irene Appolloni, Davide Ceresa, Daniela Marubbi, Gabriella Campadelli-Fiume, Paolo Malatesta
Oncolytic herpes simplex viruses are proving to be effective in clinical trials against a number of cancers. Here, R-115, an oncolytic herpes simplex virus retargeted to human erbB-2, fully virulent in its target cells, and armed with murine interleukin-12 was evaluated in a murine model of glioblastoma. We show that a single R-115 injection in established tumors resulted, in about 30% of animals, in the complete eradication of the tumor, otherwise invariably lethal. The treatment also induced a significant improvement in the overall median survival time of mice and a resistance to recurrence from the same neoplasia...
February 12, 2019: Oncogene
Wenchu Wang, Xin Yang, Jinlu Dai, Yi Lu, Jian Zhang, Evan T Keller
Bone is the most frequent site of prostate cancer (PCa) metastasis; however, little is known about the role of the most common cell in bone, the osteocyte (OCy), in cancer biology. In this study we explored the crosstalk between PCa cells and OCys to determine if it contributes to PCa progression. PCa cells induced OCys to promote PCa proliferation, migration and invasion. A chemokine screen revealed that PCa cell induced OCys to produce growth-derived factor 15 (GDF15). Knockdown of GDF15 in OCys demonstrated that PCa cells conferred the ability on OCys to promote PCa proliferation, migration and invasion through GDF15...
February 12, 2019: Oncogene
Ines Block, Carolin Müller, Daniel Sdogati, Henriette Pedersen, Markus List, Aleksandra M Jaskot, Silje Damkjær Syse, Pernille Lund Hansen, Steffen Schmidt, Helle Christiansen, Cinzia Casella, Sidsel Bering Olsen, Monica M Blomstrøm, Angela Riedel, Mads Thomassen, Torben A Kruse, Søren W Karlskov Hansen, Petra Kioschis, Jan Mollenhauer
Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines...
February 12, 2019: Oncogene
Jun Zhang, Lin Jia, Tengfei Liu, Yim Ling Yip, Wing Chung Tang, Weitao Lin, Wen Deng, Kwok Wai Lo, Chanping You, Maria Li Lung, Hong Lok Lung, Annie Lai-Man Cheung, Sai Wah Tsao, Chi Man Tsang
EBV infection of preinvasive nasopharyngeal epithelium is believed to be an initiation step during pathogenesis of nasopharyngeal carcinoma (NPC), but the mechanisms remain poorly understood. Here we report a novel mechanism driving NPC metastasis through the EBV-encoded LMP1-mediated metabolic reprogramming, via activation of IGF1-mTORC2 signaling and nuclear acetylation of the Snail promoter by the PDHE1α, an enzyme involved in glucose metabolism. Mechanistically, EBV-LMP1 increases the cellular secretion of IGF1 which promotes phosphorylation of IGF1R to activate mTORC2/AKT signaling linking glucose metabolism to cell motility...
February 11, 2019: Oncogene
Li Zhang, Weilin Li, Lei Cao, Jiaying Xu, Yun Qian, Huarong Chen, Yanquan Zhang, Wei Kang, Hongyan Gou, Chi Chun Wong, Jun Yu
Promoter methylation plays a vital role in tumorigenesis through transcriptional silencing of tumor suppressive genes. Using genome-wide methylation array, we first identified PBX/Knotted Homeobox 2 (PKNOX2) as a candidate tumor suppressor in gastric cancer. PKNOX2 mRNA expression is largely silenced in gastric cancer cell lines and primary gastric cancer via promoter methylation. Promoter methylation of PKNOX2 was associated with poor survival in gastric cancer patients. A series of in vitro and in vivo functional studies revealed that PKNOX2 functions as a tumor suppressor...
February 11, 2019: Oncogene
Mizuho Ishikawa, Mitsuhiko Osaki, Makoto Yamagishi, Kunishige Onuma, Hisao Ito, Futoshi Okada, Hideya Endo
Extensive studies on metastasis-associated proteins, S100A4 and MTA1, have been carried out for over two decades, but correlation of both proteins remains obscure. Here we show evidence for the correlation in angiogenesis. First, silencing of each protein by siRNA-mediated knockdown in mouse endothelial MSS31 cells resulted in the inhibition of tube formation. Unexpectedly, the knockdown of MTA1 affected not only its own expression but also the expression of S100A4, whereas silencing of S100A4 did not affect the MTA1 expression...
February 11, 2019: Oncogene
Alejandro Torres-Hernandez, Wei Wang, Yuri Nikiforov, Karla Tejada, Luisana Torres, Aleksandr Kalabin, Yue Wu, Muhammad Israr Ul Haq, Mohammed Y Khan, Zhen Zhao, Wenyu Su, Jimmy Camargo, Mautin Hundeyin, Brian Diskin, Salma Adam, Juan A Kochen Rossi, Emma Kurz, Berk Aykut, Sorin A A Shadaloey, Joshua Leinwand, George Miller
Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis...
February 11, 2019: Oncogene
Irene Vázquez-Domínguez, Laura González-Sánchez, Pilar López-Nieva, Pablo Fernández-Navarro, María Villa-Morales, María Á Cobos-Fernández, Isabel Sastre, Mario F Fraga, Agustín F Fernández, Marcos Malumbres, María Salazar-Roa, Osvaldo Graña-Castro, Javier Santos, Pilar Llamas, José L López-Lorenzo, José Fernández-Piqueras
FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the absence of mutations in its sequence. We observed that decreased expression mainly affected the FBXW7β isoform and to a lesser extent FBXW7α and may be attributed to the combined effect of epigenetic changes, alteration of upstream factors and upregulation of miRNAs...
February 11, 2019: Oncogene
A C Hepburn, R E Steele, R Veeratterapillay, L Wilson, E E Kounatidou, A Barnard, P Berry, J R Cassidy, M Moad, A El-Sherif, L Gaughan, I G Mills, C N Robson, R Heer
Stem cell characteristics have been associated with treatment resistance and poor prognosis across many cancer types. The ability to induce and regulate the pathways that sustain these characteristic hallmarks of lethal cancers in a novel in vitro model would greatly enhance our understanding of cancer progression and treatment resistance. In this work, we present such a model, based simply on applying standard pluripotency/embryonic stem cell media alone. Core pluripotency stem cell master regulators (OCT4, SOX2 and NANOG) along with epithelial-mesenchymal transition (EMT) markers (Snail, Slug, vimentin and N-cadherin) were induced in human prostate, breast, lung, bladder, colorectal, and renal cancer cells...
February 11, 2019: Oncogene
Jian Yang, Yuqi Guo, Cuijie Lu, Ruohan Zhang, Yaoyu Wang, Liang Luo, Yanli Zhang, Catherine H Chu, Katherine J Wang, Sabrine Obbad, Wenbo Yan, Xin Li
Prostate cancer (PCa) initiation and progression requires activation of numerous oncogenic signaling pathways. Nuclear-cytoplasmic transport of oncogenic factors is mediated by Karyopherin proteins during cell transformation. However, the role of nuclear transporter proteins in PCa progression has not been well defined. Here, we report that the KPNB1, a key member of Karyopherin beta subunits, is highly expressed in advanced prostate cancers. Further study showed that targeting KPNB1 suppressed the proliferation of prostate cancer cells...
February 11, 2019: Oncogene
Wanming He, Bishan Liang, Chunlin Wang, Shaowei Li, Yang Zhao, Qiong Huang, Zexian Liu, Zhiqi Yao, Qijing Wu, Wangjun Liao, Shuyi Zhang, Yajing Liu, Yi Xiang, Jia Liu, Min Shi
Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients and chemotherapy resistance is the major obstacle to effective cancer therapy. Increasing evidence suggests that mesenchymal stem cells (MSCs) make important contributions to development of drug resistance. However, the underlying mechanism remains elusive. In this study, we discovered that abundant MSCs in tumor tissues predicted a poor prognosis in GC patients. MSCs promoted stemness and chemoresistance in GC cells through fatty acid oxidation (FAO) in vitro and in vivo...
February 11, 2019: Oncogene
Guang-Xi Zhao, Ying-Ying Xu, Shu-Qiang Weng, Si Zhang, Ying Chen, Xi-Zhong Shen, Ling Dong, She Chen
Colorectal cancer (CRC) is a common gastrointestinal cancer with high mortality rate mostly due to metastasis. Ca2+ -dependent activator protein for secretion 1 (CAPS1) was originally identified as a soluble factor that reconstitutes Ca2+ -dependent secretion. In this study, we discovered a novel role of CAPS1 in CRC metastasis. CAPS1 is frequently up-regulated in CRC tissues. Increased CAPS1 expression is associated with frequent metastasis and poor prognosis of CRC patients. Overexpression of CAPS1 promotes CRC cell migration and invasion in vitro, as well as liver metastasis in vivo, without affecting cell proliferation...
February 11, 2019: Oncogene
Chong Chen, Lipeng Bai, Fengqi Cao, Shengnan Wang, Huiwen He, Mingcheng Song, Huilin Chen, Yan Liu, Jian Guo, Qin Si, Yundi Pan, Ruizhe Zhu, Tsung-Hsien Chuang, Rong Xiang, Yunping Luo
The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo...
February 11, 2019: Oncogene
Varadha Balaji Venkadakrishnan, Adam D DePriest, Sangeeta Kumari, Dhirodatta Senapati, Salma Ben-Salem, Yixue Su, Giridhar Mudduluru, Qiang Hu, Eduardo Cortes, Elena Pop, James L Mohler, Gissou Azabdaftari, Kristopher Attwood, Rajal B Shah, Christina Jamieson, Scott M Dehm, Cristina Magi-Galluzzi, Eric Klein, Nima Sharifi, Song Liu, Hannelore V Heemers
Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP...
February 11, 2019: Oncogene
Feng Zhou, Shuai Gao, Dong Han, Wanting Han, Sujun Chen, Susan Patalano, Jill A Macoska, Housheng Hansen He, Changmeng Cai
The aberrant activation of the ERG oncogenic pathway due to the TMPRSS2-ERG gene fusion is the major event that contributes to prostate cancer (PCa) development. However, the critical downstream effectors that can be therapeutically targeted remain to be identified. In this study, we have found that the expression of the α1 and β1 subunits of soluble guanylyl cyclase (sGC) was directly and specifically regulated by ERG in vitro and in vivo and was significantly associated with TMPRSS2-ERG fusion in clinical PCa cohorts...
February 4, 2019: Oncogene
Zhiping Li, Xuanmao Jiao, Gabriele Di Sante, Adam Ertel, Mathew C Casimiro, Min Wang, Sanjay Katiyar, Xiaoming Ju, D V Klopfenstein, Aydin Tozeren, William Dampier, Iouri Chepelev, Albert Jeltsch, Richard G Pestell
Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known...
February 4, 2019: Oncogene
Mengxiong Wang, Renan B Ferreira, Mary E Law, Bradley J Davis, Elham Yaaghubi, Amanda F Ghilardi, Abhisheak Sharma, Bonnie A Avery, Edgardo Rodriguez, Chi-Wu Chiang, Satya Narayan, Coy D Heldermon, Ronald K Castellano, Brian K Law
While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms...
February 4, 2019: Oncogene
M H Kang, K J Jeong, W Y Kim, H J Lee, G Gong, N Suh, B Győrffy, S Kim, S Y Jeong, G B Mills, Y-Y Park
The original version of this article contained an error in Fig. 2e. In Fig. 2e, the sixth colony image of T47D cells treated with shMSI2 was inadvertently replaced with a duplicate of the seventh colony image. However, the conclusions reported in the paper are not affected by figure replacement. The authors regret that these errors were made and apologize for the confusion and inconvenience. The correct version of this figure panel appears in the Author Correction associated with this Article.
February 4, 2019: Oncogene
Valentina Perotti, Paola Baldassari, Alessandra Molla, Gabriella Nicolini, Ilaria Bersani, Giulia Grazia, Fabio Benigni, Andrea Maurichi, Mario Santinami, Andrea Anichini, Roberta Mortarini
Discovery of new actionable targets and functional networks in melanoma is an urgent need as only a fraction of metastatic patients achieves durable clinical benefit by targeted therapy or immunotherapy approaches. Here we show that NFATc2 expression is associated with an EMT-like transcriptional program and with an invasive melanoma phenotype, as shown by analysis of melanoma cell lines at the mRNA and protein levels, interrogation of the TCGA melanoma dataset and characterization of melanoma lesions by immunohistochemistry...
February 1, 2019: Oncogene
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