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Journal of Pathology

Jin-Fen Xiao, Qiao-Yang Sun, Ling-Wen Ding, Wenwen Chien, Xin-Yu Liu, Anand Mayakanda, Yan-Yi Jiang, Xin-Yi Loh, Xue-Bin Ran, Ngan B Doan, Brandon Castor, David Chia, Jonathan W Said, Kar Tong Tan, Henry Yang, Xin-Yuan Fu, De-Chen Lin, H Phillip Koeffler
Characterising the activated oncogenic signalling that leads to advanced breast cancer is of clinical importance. Here, we showed that SET domain, bifurcated 1 (SETDB1), a histone H3 lysine 9 methyltransferase is aberrantly expressed and behaves as an oncogenic driver in breast cancer. SETDB1 enhances c-MYC and Cyclin D1 protein expression via promoting the internal ribosome entry site (IRES) mediated translation of MYC/CCND1 mRNA, resulting in prominent signalling of c-MYC to promote cell cycle progression and confers a growth/self-renewal advantage to breast cancer cells...
June 21, 2018: Journal of Pathology
Marina Kazantseva, Ramona A Eiholzer, Sunali Mehta, Ahmad Taha, Sara Bowie, Imogen Roth, Jean Zhou, Sebastien M Joruiz, Janice A Royds, Noelyn A Hung, Tania L Slatter, Antony W Braithwaite
As tumour protein 53 (p53) isoforms have tumour promoting, migration and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full-length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT-qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumour-associated macrophage content and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163-positive macrophages and wild-type TP53...
June 10, 2018: Journal of Pathology
Christina Alidousty, Till Baar, Luciano G Martelotto, Carina Heydt, Svenja Wagener, Jana Fassunke, Nicolai Duerbaum, Andreas H Scheel, Sandra Frank, Barbara Holz, Elke Binot, Anna Kron, Sabine Merkelbach-Bruse, Michaela A Ihle, Jürgen Wolf, Reinhard Buettner, Anne Maria Schultheis
The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%) and YAP1 (5%)...
June 9, 2018: Journal of Pathology
Marieke van de Ven, Xiaoling Liu, Eline van der Burg, Sjoerd Klarenbeek, Xanthippi Alexi, Wilbert Zwart, Fred Dijcks, Peter Bouwman, Jos Jonkers
Hereditary breast cancers in BRCA1-mutation carriers are mostly estrogen receptor alpha (ERα) and progesterone receptor (PR) negative, however, hormone depletion via bilateral oophorectomy does result in a marked reduction of breast cancer risk, suggesting that BRCA1-associated breast tumorigenesis is dependent on hormone signaling. We used genetically engineered mouse models to dissect the individual influences of ERα and PR signaling in the development of BRCA1-deficient breast cancer. In line with the human data, BRCA1-deficient mouse mammary tumors are ERα-negative and bilateral ovariectomy leads to abrogation of mammary tumor development...
June 7, 2018: Journal of Pathology
Masafumi Horie, Naoya Miyashita, Johanna Sofia Margareta Mattsson, Yu Mikami, Martin Sandelin, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito
Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines...
June 7, 2018: Journal of Pathology
Zebing Liu, Ying Cai, Yu Yang, Anqi Li, Rui Bi, Lisha Wang, Xiaohan Shen, Weige Wang, Yijun Jia, Baohua Yu, Bing Cao, Wenli Cui, Ping Wei, Xiaoyan Zhou
Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers, however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo...
June 7, 2018: Journal of Pathology
Sandrine Tury, Franck Assayag, Florian Bonin, Sophie Chateau-Joubert, Jean-Luc Servely, Sophie Vacher, Véronique Becette, Martial Caly, Audrey Rapinat, David Gentien, Pierre de la Grange, Anne Schnitzler, François Lallemand, Elisabetta Marangoni, Ivan Bièche, Céline Callens
To ensure their high proliferation rate, tumor cells display an iron metabolic disorder with increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple negative tumors which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this work, we demonstrated that deferasirox (DFX) synergizes with standard chemotherapeutic agents such as with doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple-negative breast cancer (TNBC) cell lines...
June 7, 2018: Journal of Pathology
Lucas Treps
Glioblastoma multiforme (GBM) is a highly vascularized and aggressive brain tumor. Despite aggressive standard care, GBM remains predominantly fatal; hence new innovative therapies are required. Recent research published in The Journal of Pathology has identified the CGKRK peptide as a promising tool to specifically target tumor vasculature from high grade glioma. This tumor vessel homing peptide was fused to the TNF superfamily member LIGHT/TNFSF14 and injected intravenously to murine orthotopic GBM models...
June 7, 2018: Journal of Pathology
Tae Gyu Choi, Minh Nam Nguyen, Jieun Kim, Yong Hwa Jo, Miran Jang, Ngoc Ngo Yen Nguyen, Hyeong Rok Yun, Wonchae Choe, Insug Kang, Joohun Ha, Dean G Tang, Sung Soo Kim
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Chemoresistance is a major problem for effective therapy in CRC. Here, we investigated the mechanism by which peptidylprolyl isomerase B (PPIB; cyclophilin B, CypB) regulates chemoresistance in CRC. We found that CypB is a novel wild type p53 (p53WT)-inducible gene but a negative regulator of p53WT in response to oxaliplatin treatment. Overexpression of CypB shortens the half-life of p53WT and inhibits oxaliplatin-induced apoptosis in CRC cells, whereas knockdown of CypB lengthens the half-life of p53WT and stimulates p53WT dependent apoptosis...
June 6, 2018: Journal of Pathology
Hyun Young Koo, Lamis M F El-Baz, Stacey L House, Sarah N Cilvik, Samuel J Dorry, Nahla M Shoukry, Mohamed L Salem, Hani S Hafez, Nickolai O Dulin, David M Ornitz, Robert D Guzy
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA; TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or 7...
June 6, 2018: Journal of Pathology
Tian-Neng Li, Yi-Ju Wu, Hung-Wen Tsai, Cheng-Pu Sun, Yi-Hsuan Wu, Hui-Lin Wu, Yi-Ning Pei, Kuan-Ying Lu, Tim Ting-Chung Yen, Chien-Wen Chang, Hong-Lin Chan, Mi-Hua Tao, Jun-Yang Liou, Margaret Dah-Tsyr Chang, Ih-Jen Su, Lily Hui-Ching Wang
Hepatitis B virus (HBV) is an etiological factor of liver cirrhosis and hepatocellular carcinoma (HCC). Despite current antiviral therapies that successfully reduce viral load in patients with chronic hepatitis B, persistent viral surface antigen (HBsAg) remains a risk factor of HCC. To explore if intrahepatic viral antigens contribute directly to hepatocarcinogenesis, we monitored mitotic progression of HBV-positive cells. Cytokinesis failure was increased in HBV-positive HepG2.2.15 and 1.3ES2 cells, as well as HuH-7 cells transfected with wild type or X-deficient HBV construct, but not cells transfected with an HBsAg-deficient construct...
June 3, 2018: Journal of Pathology
Sara Namvar, Adrian S Woolf, Leo A H Zeef, Thomas Wilm, Bettina Wilm, Sarah E Herrick
Peritoneal fibrosis is a common complication of abdominal and pelvic surgery, and can also be triggered by peritoneal dialysis, resulting in treatment failure. In these settings, fibrosis is driven by activated myofibroblasts that are considered to be partly derived by mesothelial-to-mesenchymal transition (MMT). We hypothesised that if the molecular signature of MMT could be better defined, these insights could be exploited to block this pathological cellular transition. Rat peritoneal mesothelial cells were purified, using an antibody to HBME1, a protein present on mesothelial cell microvilli, and streptavidin nanobead technology...
May 17, 2018: Journal of Pathology
Dora Reglodi, Adel Jungling, Rémi Longuespée, Joerg Kriegsmann, Rita Casadonte, Mark Kriegsmann, Tamas Juhasz, Sebastian Bardosi, Andrea Tamas, Balazs Daniel Fulop, Krisztina Kovacs, Zsuzsanna Nagy, Jason Sparks, Attila Miseta, Gabriel Mazzucchelli, Hitoshi Hashimoto, Attila Bardosi
Dysregulation of neuropeptides may play an important role in aging-induced impairments. Among them, pituitary adenylate cyclase activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue-damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life, and the well-known general cytoprotective effects of PACAP lead to age-related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP...
May 17, 2018: Journal of Pathology
Jolien S de Groot, Max A K Rätze, Miranda van Amersfoort, Tanja Eisemann, Eva J Vlug, Mijanou T Niklaas, Suet-Feung Chin, Carlos Caldas, Paul J van Diest, Jos Jonkers, Johan de Rooij, Patrick W B Derksen
Mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), although approximately 10-15% of all ILCs retain membrane-localized E-cadherin, despite the presence of an apparent non-cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α-catenin (CTNNA1) loss in the regulation of anchorage independence of non-invasive breast carcinoma...
May 17, 2018: Journal of Pathology
Vassilis G Gorgoulis, Dafni-Eleftheria Pefani, Ioannis S Pateras, Ioannis P Trougakos
Cells have developed during evolution a wide spectrum of stress response modules to assure homeostasis. The genome and proteome damage response pathways constitute the pillars of this interwoven "defensive" network. Consequently, the deregulation of these pathways correlates with aging and various pathophysiological states, including cancer. In the present review we highlight: i) the structure of the genome and proteome damage response pathways, ii) their functional crosstalk and, iii) the conditions under which they predispose to cancer...
May 13, 2018: Journal of Pathology
Elena Martínez-Terroba, Carmen Behrens, Fernando J de Miguel, Jackeline Agorreta, Eduard Monsó, Laura Millares, Cristina Sainz, Miguel Mesa-Guzman, Jose Luis Pérez-Gracia, María Dolores Lozano, Javier J Zulueta, Ruben Pio, Ignacio I Wistuba, Luis M Montuenga, María J Pajares
Each of the pathological stages (I-IIIa) in which surgically resected non-small cell lung cancer patients are classified conceals hidden biological heterogeneity, manifested in heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers to assess individual patient risk is an unmet medical need. Here we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI and SLC2A1) to stratify early lung adenocarcinoma patients according to their risk of recurrence or death...
May 13, 2018: Journal of Pathology
Tsugio Eto, Keisuke Miyake, Katsuhiko Nosho, Masaki Ohmuraya, Yu Imamura, Kota Arima, Shinichi Kanno, Lingfeng Fu, Yuki Kiyozumi, Daisuke Izumi, Hidetaka Sugihara, Yukiharu Hiyoshi, Yuji Miyamoto, Hiroshi Sawayama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Toru Furukawa, Kimi Araki, Hideo Baba, Takatsugu Ishimoto
RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus using pyrosequencing technology detected RNF43 hotspot mutations in 1 (0.88%) of 113 colorectal polyp cases and 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harboring mutated RNF43 experienced a higher recurrence rate than those harboring non-mutated RNF43...
May 13, 2018: Journal of Pathology
Elizabeth Ann L Enninga, Kyriakos Chatzopoulos, John T Butterfield, Shari L Sutor, Alexey A Leontovich, Wendy K Nevala, Thomas J Flotte, Svetomir N Markovic
In patients with metastatic melanoma, high blood levels of galectin-9 are correlated with worse overall survival and a bias towards a Th2 inflammatory state supportive of tumor growth. Although galectin-9 signaling through TIM3 on T cells has been described, less is known about the interaction of galectin-9 with macrophages. We aimed to determine whether galectin-9 is a binding partner of CD206 on macrophages and whether the result of this interaction is tumor-supportive. It was determined that incubation of CD68+ macrophages with galectin-9 or anti-CD206 blocked target binding and that both CD206 and galectin-9 were detected by immunoprecipitation of cell lysates...
May 7, 2018: Journal of Pathology
Pauline Bardin, Emmeline Marchal-Duval, Florence Sonneville, Sabine Blouquit-Laye, Nathalie Rousselet, Philippe Le Rouzic, Harriet Corvol, Olivier Tabary
Cystic fibrosis (CF) is the most common lethal genetic disease, caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. CF is characterized by an ionic imbalance and thickened mucus, which impair mucociliary clearance, promote bacterial colonization, and the establishment of infection/inflammation cycles. However, the origin of this inflammation remains unclear, although microRNA (miRNA) are suspected to be involved. MiRNA are small non-coding RNA that bind to the 3'-untranslated regions (UTR) of target gene mRNA, thereby repressing their translation and/or inducing their degradation...
May 7, 2018: Journal of Pathology
Jinfeng Cao, Kelly C S Pontes, Renier C Heijkants, Niels J Brouwer, Arwin Groenewoud, Ekaterina S Jordanova, Marina Marinkovic, Sjoerd van Duinen, Amina F A S Teunisse, Robert M Verdijk, Ewa Snaar-Jagalska, Aart G Jochemsen, Martine J Jager
Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier Enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy. Immunohistochemical analysis showed that EZH2 protein expression was absent in normal conjunctival melanocytes and primary acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and seven (88%) of eight lymph node metastases...
May 7, 2018: Journal of Pathology
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