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Molecular Oncology

Weihua Li, Tian Qiu, Yun Ling, Shugeng Gao, Jianming Ying
Next-generation sequencing (NGS) has recently been rapidly adopted in the molecular diagnosis of cancer, but it still faces some obstacles. In this study, 665 lung adenocarcinoma samples (558 TKI-naive and 107 TKI-relapsed samples) were interrogated using NGS, and the challenges and possible solutions of subjecting appropriate tissue samples to NGS testing were explored. The results showed that lower frequencies of HER2/BRAF/PIK3CA and acquired EGFR T790M mutations were observed in biopsy samples with <20% tumor cellularity than those with ≥20%, but there were no significant differences in the frequencies of EGFR or KRAS mutations...
March 8, 2018: Molecular Oncology
Laura Pietrovito, Angela Leo, Valentina Gori, Matteo Lulli, Matteo Parri, Valentina Becherucci, Luisa Piccini, Franco Bambi, Maria Letizia Taddei, Paola Chiarugi
There is growing evidence to suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) are key players in tumor stroma. Here, we investigated the cross-talk between BM-MSCs and osteosarcoma (OS) cells. We revealed a strong tropism of BM-MSCs towards these tumor cells, and identified MCP-1, GRO-α and TGF-β1 as pivotal factors for BM-MSC chemotaxis. Once in contact with OS cells, BM-MSCs transdifferentiate into cancer-associated fibroblasts, further increasing MCP-1, GRO-α, IL-6 and IL-8 levels in the tumor microenvironment...
March 8, 2018: Molecular Oncology
Yujiao Xie, Yi Zhang, Lutao Du, Xiumei Jiang, Suzhen Yan, Weili Duan, Juan Li, Yao Zhan, Lili Wang, Shujun Zhang, Shuhai Li, Lishui Wang, Shuo Xu, Chuanxin Wang
Lung cancer is the first leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Increasing evidence shows that long non-coding RNAs (lncRNAs) are capable of modulating tumor initiation, proliferation and metastasis. In the present study, we aimed to evaluate whether circulating lncRNAs could be used as biomarkers for diagnosis and prognosis of NSCLC. Expression profiles of 14 lncRNAs selected from other studies were validated in 20 pairs of tissues by quantitative real-time PCR (qRT-PCR), and the dysregulated lncRNAs thus identified were further validated in serum samples from two independent cohorts along with three tumor makers(CEA, CYFRA21-1 and SCCA)...
March 5, 2018: Molecular Oncology
Qiong Wu, Shihao Xiang, Jiali Ma, Pingping Hui, Ting Wang, Wenying Meng, Min Shi, Yugang Wang
Long non-coding RNAs (lncRNAs) are responsible for a diverse range of cellular functions, such as transcriptional and translational regulation and variance in gene expression. LncRNA CASC15 (cancer susceptibility candidate 15) is a lincRNA locus in chromosome 6p22.3. Previous researches show that lncRNA CASC15 is implicated in the biological behaviors of several cancers such as neuroblastoma and melanoma. Here, we aimed to explore in detail how CASC15 contributed to the growth of gastric cancer. As predicted, the expression of CASC15 was enriched in gastric cancer tissues and cell lines when compared to healthy tissues and cells using qRT-PCR...
February 28, 2018: Molecular Oncology
Anna Chorzalska, Nagib Ahsan, R Shyama Prasad Rao, Karim Roder, Xiaoqing Yu, John Morgan, Alexander Tepper, Steven Hines, Peng Zhang, Diana O Treaba, Ting C Zhao, Adam J Olszewski, John Reagan, Olin Liang, Philip A Gruppuso, Patrycja M Dubielecka
The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long-term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr-Abl1 protein and activity levels while maintaining proliferative potential...
February 27, 2018: Molecular Oncology
Josué Curto, Beatriz Del Valle-Pérez, Aida Villarroel, Guillem Fuertes, Meritxell Vinyoles, Raúl Peña, Antonio García de Herreros, Mireia Duñach
Canonical and non-canonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the non-canonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1ε is required for Dvl/Fz association in both canonical and non-canonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1ε does not require p120-catenin for the association with the Wnt5a co-receptor Ror2...
February 21, 2018: Molecular Oncology
Jiang-Jiang Li, Ruilei Li, Wenxiang Wang, Baihua Zhang, Xin Song, Chunfang Zhang, Yang Gao, Qianjin Liao, Ya He, Shuo You, Zheqiong Tan, Xiangjian Luo, Yueshuo Li, Min Tang, Xinxian Weng, Wei Yi, Shifang Peng, Shaohui Liu, Ying Tan, Ann M Bode, Ya Cao
Lung cancer is the most common leading cause of cancer-related death worldwide. Late diagnosis contributes to a high mortality rate and poor survival of this cancer. In our previous study, we found that IDH2 polymorphism rs11540478 is a risk factor for lung cancer. Here, we examined IDH2 protein expression in culture medium in which two non-small-cell lung cancer (NSCLC) cell lines, H460 and A549, were growing. We found that the IDH2 protein was elevated in the culture supernatant fraction in a time and cell number-dependent manner...
February 21, 2018: Molecular Oncology
Gertrud E Feiersinger, Kristina Trattnig, Peter D Leitner, Fabian Guggenberger, Alexander Oberhuber, Sarah Peer, Martin Hermann, Ira Skvortsova, Jana Vrbkova, Jan Bouchal, Zoran Culig, Frédéric R Santer
A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor Olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa we evaluated a potential use for Olaparib in combination with first-line endocrine treatments, androgen deprivation and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy...
February 21, 2018: Molecular Oncology
Christa Haldrup, Anne Lykke Pedersen, Nadia Øgaard, Siri H Strand, Søren Høyer, Michael Borre, Torben Falck Ørntoft, Karina Dalsgaard Sørensen
Current diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, leading to overdiagnosis and overtreatment. Aberrant promoter hypermethylation of specific genes has been suggested as novel candidate biomarkers for PC that may improve diagnosis and prognosis. We here analyzed ST6GALNAC3 and ZNF660 promoter methylation in prostate tissues, and ST6GALNAC3, ZNF660, CCDC181, and HAPLN3 promoter methylation in liquid biopsies. First, using four independent patient sample sets, including a total of 110 non-malignant (NM) and 705 PC tissue samples, analyzed by methylation specific qPCR or methylation array, we found that hypermethylation of ST6GALNAC3 and ZNF660 was highly cancer-specific with areas under the curve (AUC) of receiver operated characteristic (ROC) curve analysis of 0...
February 21, 2018: Molecular Oncology
Yan Zhang, Xin Li, Dianshuang Zhou, Hui Zhi, Peng Wang, Yue Gao, Maoni Guo, Ming Yue, Yanxia Wang, Weitao Shen, Shangwei Ning, Yixue Li, Xia Li
Differences in individual drug responses is an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response-related ceRNAs (DRCEs) by combining the sequence and expression data of long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) and the survival data of cancer patients treated with drugs...
February 21, 2018: Molecular Oncology
Maud Kamal, Gabi Tarcic, Sylvain Dureau, Oded Edelheit, Zohar Barbash, Charlotte Lecerf, Claire Morel, Benjamin Miron, Celine Callens, Nicolas Servant, Ivan Bieche, Michael Vidne, Christophe Le Tourneau
It still remains to be demonstrated that using molecular profiling to guide therapy improves patient outcome in oncology. Classification of somatic variants is not straightforward, rendering treatment decisions based on variants with unknown significance (VUS) hard to implement. The oncogenic activity of VUS and mutations identified in 12 patients treated with molecularly targeted agents (MTA) in the frame of SHIVA01 trial was assessed using Functional Annotation for Cancer Treatment (FACT). MTA response prediction was measured in vitro, blinded to the actual clinical trial results and survival predictions according to FACT were correlated with the actual PFS of SHIVA01 patients...
February 21, 2018: Molecular Oncology
Zhiping Fu, Cheng Xi, Jie Kuang, Haoran Feng, Lingxie Chen, Juyong Liang, Xiaonan Shen, Stanley Yuen, Peng Chenghong, Shen Baiyong, Jin Zhijian, Weihua Qiu
As an established anti-cancer drug, gemcitabine (GEM) is an effective systemic treatment for advanced pancreatic cancer (PC). However, little is known about the potential effectors that may modify tumour cell sensitivity towards GEM. Autophagy, as a physiological cellular mechanism, is involved in both cell survival and cell death. In this study, we found that exposure to GEM induced a significant increase in autophagy in a dose-dependent manner in PANC-1 and BxPC-3 cells. Inhibition of autophagy by chloroquine (CQ) and ATG7 siRNA increased GEM-induced cytotoxicity, and CQ was more effective than ATG7 siRNA...
February 17, 2018: Molecular Oncology
Ilija Crnčec, Madhura Modak, Claire Gordziel, Jasmin Svinka, Irene Scharf, Stefan Moritsch, Paulina Pathria, Michaela Schlederer, Lukas Kenner, Gerald Timelthaler, Mathias Müller, Birgit Strobl, Emilio Casanova, Editha Bayer, Thomas Mohr, Johannes Stöckl, Karlheinz Friedrich, Robert Eferl
The interferon-inducible transcription factor STAT1 is a tumor suppressor in various malignancies. We investigated sex-specific STAT1 functions in colitis and colitis-associated colorectal cancer (CRC) using mice with specific STAT1 deletion in intestinal epithelial cells (STAT1 ∆ IEC ). Male but not female STAT1 ∆ IEC mice were more resistant to DSS-induced colitis than sex-matched STAT1 flox/flox controls and displayed reduced intraepithelial infiltration of CD8 + TCRαβ + Granzyme B + T cells. Moreover, DSS treatment failed to induce expression of T cell-attracting chemokines in intestinal epithelial cells of male but not of female STAT1 ∆ IEC mice...
February 8, 2018: Molecular Oncology
Caiguo Zhang, Bin Chen, Kaibiao Jiang, Lifeng Lao, Hongxing Shen, Zhi Chen
Cullin 4B, a member of the Cullins, which serve as scaffolds to facilitate the assembly of E3 ligase complexes, is aberrantly expressed in many cancers, including osteosarcoma. Recently, we observed that CUL4B forms the CRL4BDCAF11 E3 ligase, which specifically ubiquitinates and degrades the cyclin-dependent kinase (CDK) inhibitor p21Cip1 in human osteosarcoma cells. However, the underlying mechanisms regarding the aberrant expression of CUL4B and the upstream members of this signaling pathway are mostly unknown...
January 27, 2018: Molecular Oncology
Weixing Dai, Yaqi Li, Shaobo Mo, Yang Feng, Long Zhang, Ye Xu, Qingguo Li, Guoxiang Cai
Colon cancer patients experiencing early relapse consistently exhibited poor survival. The aim of our study was to develop an mRNA signature that can help to detect early relapse cases in stage I-III colon cancer. Public microarray datasets of stage I-III colon cancer samples were extracted from the Gene Expression Omnibus database. Propensity score matching analysis was performed between patients in the early relapse group and the long-term survival group from GSE39582 discovery series (N = 386), and patients were 1 : 1 matched...
January 27, 2018: Molecular Oncology
Margaret Stromecki, Nazanin Tatari, Ludivine Coudière Morrison, Ravinder Kaur, Jamie Zagozewski, Gareth Palidwor, Vijay Ramaswamy, Patryk Skowron, Matthias Wölfl, Till Milde, Marc R Del Bigio, Michael D Taylor, Tamra Werbowetski-Ogilvie
Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo...
January 27, 2018: Molecular Oncology
Yixin Li, Liren Li, Miao Chen, Xinfa Yu, Zhuoyu Gu, Huijuan Qiu, Ge Qin, Qian Long, Xiaoyan Fu, Tianze Liu, Wenbin Li, Meihua Luo, Dingbo Shi, Tiebang Kang, Wenlin Huang, Xiaojun Wu, Wuguo Deng
Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP-MS) analysis was used to detect, identify and verify the proteins that interacted with NCOA3 in CRC cells...
January 23, 2018: Molecular Oncology
Mikkel Staberg, Rikke Darling Rasmussen, Signe Regner Michaelsen, Henriette Pedersen, Kamilla Ellermann Jensen, Mette Villingshøj, Jane Skjoth-Rasmussen, Jannick Brennum, Kristoffer Vitting-Seerup, Hans Skovgaard Poulsen, Petra Hamerlik
Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter- and intra-patient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem-like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain...
January 23, 2018: Molecular Oncology
Kanika Sharma, Thien-Trang Vu, Wade Cook, Mitra Naseri, Kevin Zhan, Wataru Nakajima, Hisashi Harada
The platinum-based DNA damaging agent cisplatin is used as a standard therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underpinning the cytotoxic effects of this compound are not entirely elucidated. Cisplatin produces anticancer effects primarily via activation of the DNA damage response, followed by inducing BCL-2 family-dependent mitochondrial apoptosis. We have previously demonstrated that cisplatin induces the expression of pro-apoptotic BCL-2 family protein, Noxa, that can bind to the pro-survival BCL-2 family protein, MCL-1, to inactivate its function and induce cell death...
January 19, 2018: Molecular Oncology
Yue Meng, Lu Wang, Jianjun Xu, Qingyun Zhang
Polymorphisms of the Lysosomal-Associated Protein Transmembrane-4 beta (LAPTM4B) gene are related to various forms of tumour susceptibility, which led us to hypothesize that some unique transcription factors targeting this polymorphism region may affect the biological function of LAPTM4B in tumour progression. In this study, we found that the transcription factor AP4 directly binds to the polymorphism region of the LAPTM4B gene promoter and induces its transcription. In addition, we demonstrated that AP4 promotes hepatocellular carcinoma cell proliferation and metastasis, and depresses chemotherapy sensitivity via LAPTM4B by activating the PI3K/AKT signalling pathway and caspase-dependent pathway...
January 16, 2018: Molecular Oncology
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