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Molecular Cancer Research: MCR

Adhiraj Roy, Maria Victoria Veroli, Sahdeo Prasad, Qiming Jane Wang
Aurora A kinase (AURKA) is a master cell cycle regulator that is often dysregulated in human cancers. Its overexpression has been associated with genome instability and oncogenic transformation. The protein kinase D (PKD) family is an emerging therapeutic target of cancer. Aberrant PKD activation has been implicated in tumor growth and survival, yet the underlying mechanisms remain to be elucidated. This study identified, for the first time, a functional crosstalk between PKD2 and Aurora A kinase in cancer cells...
July 17, 2018: Molecular Cancer Research: MCR
Dong-Ming Su, Olga Sizova, Denis Kuriatnikov, Ying Liu
Tumor metastatic relapse is the primary cause for cancer-associated mortality. Metastatic relapse is believed to arise from quantities of tumor cells that are below detectable thresholds, which are able to resist radio/chemotherapy by obtaining a dormant state and hiding in certain organs, i.e. tumor reservoirs. The thymus, a central T cell immune organ, has been suggested to be a pre-metastatic tumor reservoir for B-lymphoma cells. However, it remains unknown whether the thymus is able to harbor non-lymphoid solid tumor cells, and whether chemotherapy can thoroughly eliminate cancer cells in the thymus...
July 13, 2018: Molecular Cancer Research: MCR
Anthony C Wang, David T W Jones, Isaac Joshua Abecassis, Bonnie L Cole, Sarah E S Leary, Christina M Lockwood, Lukas Chavez, David Capper, Andrey Korshunov, Aria Fallah, Shelly Wang, Chibawanye Ene, James M Olson, Russell Geyer, Eric C Holland, Amy Lee, Richard G Ellenogen, Jeffrey G Ojemann
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n=8) diagnosed histologically as DIG/DIGA...
July 13, 2018: Molecular Cancer Research: MCR
Xin Ming, Chenyi Bao, Tao Hong, Ying Yang, Xinbin Chen, Yong-Sam Jung, Yingjuan Qian
Differentiated embryonic chondrocyte expressed gene 1 (BHLHE40 also known as Sharp2/Stra13/DEC1), is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in circadian rhythms, cell proliferation, apoptosis, cellular senescence, hypoxia response, and epithelial-to-mesenchymal transition (EMT) of tumor cells. Secretory clusterin (sCLU) is a cytoprotective protein that guards against genotoxic stresses. Here, clusterin (CLU) was identified as a novel target gene of DEC1 and suppresses DNA damage-induced cell death in tumor cells...
July 12, 2018: Molecular Cancer Research: MCR
Deborah Ruth Caswell, Chen-Hua Chuang, Rosanna K Ma, Ian P Winters, Eric L Snyder, Monte M Winslow
The Nkx2-1 transcription factor in lung epithelial lineages promotes differentiation and suppresses malignant progression of lung adenocarcinoma. However, targets of Nkx2-1 that limit tumor growth and progression remain incompletely understood. Here, direct Nkx2-1 targets are identified whose expression correlates with Nkx2-1 activity in human lung adenocarcinoma. Selenium binding protein 1 (Selenbp1), an Nkx2-1 effector that limits phenotypes associated with lung cancer growth and metastasis, was investigated further...
July 12, 2018: Molecular Cancer Research: MCR
Sayyed K Zaidi, Jeffrey A Nickerson, Anthony N Imbalzano, Jane B Lian, Janet L Stein, Gary S Stein
Reconfiguration of nuclear structure and function during mitosis presents a significant challenge to resume the next cell cycle in the progeny cells without compromising structural and functional identity of the cells. Equally important is the requirement for cancer cells to retain the transformed phenotype i.e., unrestricted proliferative potential, suppression of cell phenotype and activation of oncogenic pathways. Mitotic gene bookmarking-retention of key regulatory proteins that include sequence specific transcription factors, chromatin modifying factors and components of RNA Pol (RNAP) I and II regulatory machineries at gene loci on mitotic chromosomes-plays key roles in coordinate control of cell phenotype, growth and proliferation post-mitotically...
July 12, 2018: Molecular Cancer Research: MCR
Merrida A Childress, Stephen M Himmelberg, Huiqin Chen, Wanleng Deng, Michael A Davies, Christine M Lovly
Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5' fusion partners have been reported, treatment of ALK-rearranged cancers is generally decided without regard to which 5' partner is present. There is little data addressing how the 5' partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKIs). Based on the hypothesis that the 5' partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs; clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated...
July 12, 2018: Molecular Cancer Research: MCR
Tarah M Regan Anderson, Shihong Ma, Carlos Perez Kerkvliet, Yan Peng, Taylor M Helle, Raisa I Krutilina, Ganesh V Raj, John A Cidlowski, Julie H Ostrander, Kathryn L Schwertfeger, Tiffany N Seagroves, Carol A Lange
The metastatic cascade is a complex process that requires cancer cells to survive despite conditions of high physiologic stress. Previously a cooperation between the glucocorticoid receptor (GR) and hypoxia inducible factors (HIFs) was reported as a point of convergence for host and cellular stress signaling. These studies indicated p38 MAPK-dependent phosphorylation of GR on Ser134 and subsequent p-GR/HIF-dependent induction of breast tumor kinase (PTK6/Brk), as a mediator of aggressive cancer phenotypes. Herein, p-Ser134 GR was quantified in human primary breast tumors (n=281) and the levels of p-GR were increased in triple negative breast cancer (TNBC) relative to luminal breast cancer...
July 10, 2018: Molecular Cancer Research: MCR
David Ya Dadey, Vaishali Kapoor, Arpine Khudanyan, Dinesh Thotala, Dennis E Hallahan
The aggressive nature and inherent therapeutic resistance of glioblastoma multiforme (GBM) has rendered the median survival of afflicted patients to 14 months. Therefore, it is imperative to understand the molecular biology of GBM to provide new treatment options to overcoming this disease. It has been demonstrated that the protein kinase R like endoplasmic reticulum kinase (PERK) pathway is an important regulator of the endoplasmic reticulum (ER) stress response. PERK signaling has been observed in other model systems after radiation; however, less is known in the context of GBM which is frequently treated with radiation-based therapies...
July 10, 2018: Molecular Cancer Research: MCR
Brian J Reon, Bruno Takao Real Karia, Manjari Kiran, Anindya Dutta
Long non-coding RNAs (lncRNAs) are increasingly implicated in oncogenesis. Here, it is determined that LINC00152/CYTOR is upregulated in glioblastoma multiforme (GBM) and aggressive wild-type IDH1/2 grade II/III gliomas and upregulation associates with poor patient outcomes. LINC00152 is similarly upregulated in over 10 other cancer types and associates with a poor prognosis in 7 other cancer types. Inhibition of the mostly cytoplasmic LINC00152 decreases, and overexpression increases cellular invasion. LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT)...
July 10, 2018: Molecular Cancer Research: MCR
Ningfang Ma, Xiaohui Zhao, Tian Xie, Ting Dai, Wenhui Zhao, Jing Li, Rui Xu, Chao Jiang, Peiqiong Li, Junyao Deng, Xiaobo Su
Calcineurin B homologous protein isoform 2 (CHP2), an essential cofactor for Na+/H+ exchanger isoform 1 (NHE1), is identified to be expressed in various malignant cell lines. However, the clinical significance and biological role of CHP2 in breast cancer remain to be established. Here, CHP2 was markedly overexpressed in breast cancer cells and clinical tumor specimens. Immunohistochemical (IHC) analysis revealed that the expression of CHP2 was significantly correlated with patients' clinicopathologic characteristics like clinical stage, and breast cancer patients with high CHP2 expression had shorter overall survival compared to patients with low CHP2 expression...
July 2, 2018: Molecular Cancer Research: MCR
Simone Lemeer, Celine Mulder, Nadine Prust, Sander van Doorn, Maria Reinecke, Bernhard Kuster, Paul van Bergen En Henegouwen
Targeted therapies against oncogenic receptor tyrosine kinases (RTKs) show promising results in the clinic. Unfortunately, despite the initial positive response, most patients develop therapeutic resistance. Most research has focused on acquired resistance occurring after an extensive time of treatment, however the question remains as to how cells can survive an initial treatment, as early resistance to apoptosis will enable cells to develop any growth stimulating mechanism. Here, the non-small cell lung cancer (NSCLC) PC9 cell line was used to systematically profile, by mass spectrometry, changes in the proteome, kinome and phosphoproteome during early treatment with the EGFR inhibitor afatinib...
July 2, 2018: Molecular Cancer Research: MCR
Hans Petter Eikesdal, Lisa M Becker, Yingqi Teng, Akane Kizu, Julienne L Carstens, Keizo Kanasaki, Hikaru Sugimoto, Valerie S LeBleu, Raghu Kalluri
Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1) positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling crosstalk with the forestomach epithelium...
June 22, 2018: Molecular Cancer Research: MCR
Andrea C Chaikovsky, Julien Sage
Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) were originally designed to block proliferation and cell cycle progression of cancer cells in which the activity of these kinases is dysregulated. CDK4/6 inhibitors have already been FDA-approved for the treatment of estrogen receptor (ER)-positive breast cancer and are being tested in numerous other cancer types. However, several recent studies have identified novel effects of CDK4/6 inhibitors on tumor growth, most notably an indirect effect resulting from the activation of immune surveillance...
June 22, 2018: Molecular Cancer Research: MCR
Aparna Shinde, Sarah Libring, Aktan Alpsoy, Ammara Abdullah, James A Schaber, Luis Solorio, Michael K Wendt
Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces a EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin...
June 22, 2018: Molecular Cancer Research: MCR
Yuhong Lu, Yanfeng Liu, Sebastian Oeck, Peter M Glazer
The development of small-molecule tyrosine kinase inhibitors (TKIs) specific for epidermal growth factor receptors (EGFRs) with activating mutations has led to a new paradigm in the treatment of non-small cell lung cancer (NSCLC) patients. However, most patients eventually develop resistance. Hypoxia is a key micro-environmental stress in solid tumors that is associated with poor prognosis due, in part, to acquired resistance to conventional therapy. This study, documents that long-term, moderate hypoxia promotes resistance to the EGFR TKI, gefitinib, in the NSCLC cell line, HCC827, which harbors an activating EGFR mutation...
June 22, 2018: Molecular Cancer Research: MCR
Kevin Pruitt, Deborah Molehin, Isabel Castro-Piedras, Monica Sharma, Souad R Sennoune, Daphne Arena, Pulak R Manna
Aromatase, a cytochrome P450 member, is a key enzyme involved in estrogen biosynthesis and is dysregulated in the majority of breast cancers. Studies have shown that lysine deacetylase inhibitors (KDI) decrease aromatase expression in cancer cells, yet many unknowns remain regarding the mechanism by which this occurs. While advances have been made to clarify factors involved in the transcriptional regulation of the aromatase gene (CYP19A1). Yet, despite aromatase being a primary target for breast cancer therapy, its post-translational regulation has been virtually unexplored...
June 19, 2018: Molecular Cancer Research: MCR
Amanda R Wasylishen, Jeannelyn S Estrella, Vinod Pant, Gilda P Chau, Guillermina Lozano
Mutations in the death domain-associated protein (DAXX) have been recently identified in a substantial proportion of human pancreatic neuroendocrine tumors (PanNETs). Remarkably, however, little is known about the physiological role(s) of DAXX despite in vitro studies suggesting potential functions. Most prominently, and supported by tumor sequencing data, DAXX functions in concert with alpha thalassemia/mental retardation X-linked (ATRX) as a histone chaperone complex for the H3.3 variant. Studies have also identified potential roles in apoptosis, transcription, and negative regulation of the p53 tumor suppressor pathway...
June 14, 2018: Molecular Cancer Research: MCR
Jung-Chien Cheng, Evan Y Wang, Yuyin Yi, Avinash Thakur, Shu-Huei Tsai, Pamela A Hoodless
Dysregulation of the Hippo pathway in the liver results in overgrowth and eventually tumorigenesis. To date, several upstream mechanisms have been identified that affect the Hippo pathway; that ultimately regulate YAP, the major downstream effector of the pathway. However, upstream regulators of the Hippo pathway in the liver remain poorly defined. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that has been shown to stimulate hepatocellular carcinoma (HCC) cell proliferation, but whether the Hippo pathway is involved in S1P-stimulated HCC cell proliferation remains to be determined...
June 14, 2018: Molecular Cancer Research: MCR
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
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