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Jente van Staalduinen, David Baker, Peter Ten Dijke, Hans van Dam
Chemoresistance remains a major complication of cancer treatments. Recent data provide strong evidence that chemoresistance is linked to epithelial-mesenchymal transition (EMT), a latent developmental process, which is re-activated during cancer progression. EMT involves transcriptional reprogramming and is driven by specific EMT transcription factors (EMT-TFs). In this review, we provide support for the idea that EMT-TFs contribute to the development of resistance against cancer therapy and discuss how EMT-TFs might be targeted to advance novel therapeutic approaches to the treatment of cancer...
July 12, 2018: Oncogene
Liyun Luo, Hailin Tang, Li Ling, Nan Li, Xiaoting Jia, Zhijie Zhang, Xiaorong Wang, Lejuan Shi, Jiang Yin, Ni Qiu, Hao Liu, Ying Song, Kai Luo, Hongsheng Li, Zhimin He, Guopei Zheng, Xiaoming Xie
Breast cancer is a heterogeneous disease, and triple-negative breast cancer (TNBC) continues to be a serious health problem. The potential involvement of lncRNAs in TNBC progression remains unexplored. Here, we demonstrated that LINC01638 is highly expressed in TNBC tissues and cells. LINC01638 maintains the mesenchymal traits of TNBC cells, including an enriched epithelial-mesenchymal transition (EMT) signature and cancer stem cell-like state. LINC01638 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo...
July 12, 2018: Oncogene
Manfred Kunz, Henry Löffler-Wirth, Michael Dannemann, Edith Willscher, Gero Doose, Janet Kelso, Tina Kottek, Birgit Nickel, Lydia Hopp, Jenny Landsberg, Steve Hoffmann, Thomas Tüting, Paola Zigrino, Cornelia Mauch, Jochen Utikal, Mirjana Ziemer, Hans-Joachim Schulze, Michael Hölzel, Alexander Roesch, Susanne Kneitz, Svenja Meierjohann, Anja Bosserhoff, Hans Binder, Manfred Schartl
Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-seq analysis of laser-microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2)...
July 11, 2018: Oncogene
Yuanshuai Zhou, Zhongjuan Xu, Daniel Quan, Fan Zhang, Hai Zhang, Tongqian Xiao, Shulan Hou, Hong Qiao, Olivier Harismendy, Jean Y J Wang, Guangli Suo
Epithelial cells aggregate into spheroids when deprived of matrix, and the proclivity for spheroid formation and survival is a hallmark of normal and tumorigenic mammary stem cells. We show here that Nuclear Respiratory Factor 1 (NRF1) is a spheroid promoter by in silico identification of this transcription factor as highly connected to top shRNA-hits deduced from re-iterative selections for shRNAs enriched in MCF10A spheroids. NRF1-promoted spheroid survival is linked to its stimulation of mitochondrial OXPHOS, cell migration, invasion, and mesenchymal transition...
July 11, 2018: Oncogene
Ying-Nan Wang, Zhao-Lei Zeng, Jiahuan Lu, Yun Wang, Ze-Xian Liu, Ming-Ming He, Qi Zhao, Zi-Xian Wang, Ting Li, Yun-Xin Lu, Qi-Nian Wu, Kai Yu, Feng Wang, Heng-Ying Pu, Bo Li, Wei-Hua Jia, Ming Shi, Dan Xie, Tie-Bang Kang, Peng Huang, Huai-Qiang Ju, Rui-Hua Xu
Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance...
July 11, 2018: Oncogene
Anders P Mutvei, Sebastian K-J Landor, Rhys Fox, Eike-Benjamin Braune, Yat Long Tsoi, Yee Peng Phoon, Cecilia Sahlgren, Johan Hartman, Jonas Bergh, Shaobo Jin, Urban Lendahl
Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2α, a key mediator of the cellular hypoxic response...
July 11, 2018: Oncogene
Syue-Ting Chen, Ting-Chun Kuo, Ying-Yu Liao, Mei-Chun Lin, Yu-Wen Tien, Min-Chuan Huang
Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells...
July 11, 2018: Oncogene
Yang Yang, Xiao-Qin Wu, Wan-Xia Li, Hui-Min Huang, Hai-di Li, Xue-Yin Pan, Xiao-Feng Li, Cheng Huang, Xiao-Ming Meng, Lei Zhang, Xiong-Wen Lv, Hua Wang, Jun Li
Macrophages play a crucial role in the progression of hepatic fibrosis (HF). In macrophages, epigenetic mechanisms are increasingly being recognized as crucial controllers of their phenotype. However, the functions of macrophage DNA methylation in experimental models of hepatic fibrosis have not been fully addressed. Here, we analyzed isolated hepatic macrophages DNA methylation from CCL4-induced (4 weeks) mice using reduced representation bisulfite sequencing (RRBS). We identified and validated the methylation status of 26 gene promoter regions associated with CpG islands...
July 11, 2018: Oncogene
Ajaz A Bhat, Heng Lu, Mohammed Soutto, Anthony Capobianco, Priyamvada Rai, Alexander Zaika, Wael El-Rifai
The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE...
July 10, 2018: Oncogene
Qihan Fu, Qi Zhang, Yu Lou, Jiaqi Yang, Gang Nie, Qi Chen, Yiwen Chen, Jingying Zhang, Jianxin Wang, Tao Wei, Hao Qin, Xiaowei Dang, Xueli Bai, Tingbo Liang
Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified that reactive oxygen species (ROS) regulated the adhesive molecules...
July 10, 2018: Oncogene
Natalya V Kaverina, Zaira G Kadagidze, Anton V Borovjagin, Apollon I Karseladze, Chung Kwon Kim, Maciej S Lesniak, Jason Miska, Peng Zhang, Maria A Baryshnikova, Ting Xiao, David Ornelles, Charles Cobbs, Andrey Khramtsov, Ilya V Ulasov
Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads)...
July 10, 2018: Oncogene
Sarah A Best, Cassandra R Harapas, Ariena Kersbergen, Vivek Rathi, Marie-Liesse Asselin-Labat, Kate D Sutherland
Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3-TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3-TACC3 concomitant with loss of the p53 tumor suppressor gene...
July 10, 2018: Oncogene
Larissa Kotelevets, Francine Walker, Godefroy Mamadou, Thérèse Lehy, Peter Jordan, Eric Chastre
We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice...
July 9, 2018: Oncogene
Fanyang Kong, Xuan Deng, Xiangyu Kong, Yiqi Du, Lei Li, Huiyun Zhu, Yuxin Wang, Dacheng Xie, Shivani Guha, Zhaoshen Li, Ming Guan, Keping Xie
Long non-coding RNAs (lncRNAs) are implicated to be involved in the pathogenesis of many cancers. Herein we report on our discovery of a novel lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), and its critical role in gastric carcinogenesis. ZFPM2-AS1 expression in gastric cancer specimens was analyzed using Gene Expression Omnibus data set and validated in 73 paired gastric tumor and normal adjacent gastric tissue specimens using qRT-PCR. The effect of ZFPM2-AS1 expression on proliferation and apoptosis in gastric cancer cells was assessed by altering its expression in vitro and in vivo...
July 9, 2018: Oncogene
Tingting Yang, Chune Ren, Pengyun Qiao, Xue Han, Li Wang, Shijun Lv, Yonghong Sun, Zhijun Liu, Yu Du, Zhenhai Yu
Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer...
July 9, 2018: Oncogene
Xiao Guo, Yin Zhang, Anand Mayakonda, Vikas Madan, Ling-Wen Ding, Le-Hang Lin, Saadiya Zia, Sigal Gery, Jeffrey W Tyner, Wu Zhou, Dong Yin, De-Chen Lin, H Phillip Koeffler
As one of the primary members of SWI/SNF chromatin remodeling complexes, ARID1A contains frequent loss-of-function mutations in many types of cancers. However, the molecular mechanisms underlying ARID1A deficiency in cancer biology remain to be investigated. Using breast cancer as a model, we report that silencing ARID1A significantly increased cellular proliferation and migration. Mechanistically, primarily functioning as a transcriptional repressor, loss of ARID1A profoundly alters histone modifications and the transcriptome...
July 6, 2018: Oncogene
Charlotte E Johnson, Elaine A Dunlop, Sara Seifan, Henry D McCann, Trevor Hay, Geraint J Parfitt, Ashley T Jones, Peter J Giles, Ming H Shen, Julian R Sampson, Rachel J Errington, D Mark Davies, Andrew R Tee
Cancer cells lose homeostatic flexibility because of mutations and dysregulated signaling pathways involved in maintaining homeostasis. Tuberous Sclerosis Complex 1 (TSC1) and TSC2 play a fundamental role in cell homeostasis, where signal transduction through TSC1/TSC2 is often compromised in cancer, leading to aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 hyperactivation increases the basal level of endoplasmic reticulum (ER) stress via an accumulation of unfolded protein, due to heightened de novo protein translation and repression of autophagy...
July 6, 2018: Oncogene
Rossella Loria, Valentina Laquintana, Giulia Bon, Daniela Trisciuoglio, Roberta Frapolli, Renato Covello, Carla Azzurra Amoreo, Virginia Ferraresi, Carmine Zoccali, Mariangela Novello, Donatella Del Bufalo, Michele Milella, Roberto Biagini, Maurizio D'Incalci, Rita Falcioni
Although the medical treatments of sarcoma have evolved in the last years, a significant portion of patients develops recurrence after therapies suggesting the need to identify novel targets to improve the treatments. By the use of patient-derived and established cell lines from liposarcoma, as well as specimens from patient biopsies, we found that HMGA1 is involved in the progression of dedifferentiated and myxoid liposarcoma. The immunohistochemical and RT-PCR analyses of 68 liposarcoma specimens revealed a significant high expression of HMGA1, at the protein and RNA levels, both in myxoid and dedifferentiated liposarcoma subtypes compared with differentiated ones...
July 6, 2018: Oncogene
Ang Li, Ping Chen, Ye Leng, Jiuhong Kang
Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo...
July 6, 2018: Oncogene
Qingcai Meng, Si Shi, Chen Liang, Dingkong Liang, Jie Hua, Bo Zhang, Jin Xu, Xianjun Yu
The devastating prognosis of pancreatic ductal adenocarcinoma (PDAC) is partially attributed to chemotherapy resistance. Glutathione peroxidase-1 (GPx1) plays various roles in the development and progression of multiple tumors, with the exception of pancreatic cancer. Here, we tentatively explored the role of GPx1 in the malignant biological behavior and gemcitabine (GEM) resistance of PDAC. GPx1 levels were detected using tissue microarrays and were negatively correlated with the overall survival of patients with PDAC...
July 6, 2018: Oncogene
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