bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B
Authors: Hopper-Borge Elizabeth , Xu Xiu , Shen Tong , Shi Zhi , Chen Zhe-Sheng , Kruh Gary D.
Published: March 2023

Abstract
Multidrug resistance protein 7 (MRP7; ABCC10) is an ATP-binding cassette transporter which is able to transport amphipathic anions and confer resistance to docetaxel and, to a lesser extent, vincristine and paclitaxel. Whereas some detail on the resistance profile of MRP7 is known, the activities of the pump have not been completely determined. Here, it is shown by the analysis of MRP7-transfected HEK293 cells that, in addition to natural product agents, MRP7 is also able to confer resistance to nucleoside-based agents, such as the anticancer agents cytarabine (Ara-C) and gemcitabine, and the antiviral agents 2′,3′-dideoxycytidine and PMEA. Consistent with the operation of an efflux pump, expression of MRP7 reduced the accumulation of Ara-C and PMEA. In addition, MRP7 is also able to confer resistance to the microtubule-stabilizing agent epothilone B. Ectopic expression of MRP7 in mouse embryo fibroblasts deficient in P-glycoprotein and Mrp1 revealed that MRP7 has a broad resistance profile for natural product agents. In this drug-sensitive cellular background, MRP7 conferred high levels of resistance to docetaxel (46-fold), paclitaxel (116-fold), SN-38 (65-fold), daunorubicin (7.5-fold), etoposide (11-fold), and vincristine (56-fold). Buthionine sulfoximine did not attenuate MRP7-conferred resistance to docetaxel or Ara-C. These experiments indicate that the resistance capabilities of MRP7 include nucleoside-based agents and a range of natural product anticancer agents that includes nontaxane antimicrotubule agents that are not susceptible to P-glycoprotein–mediated transport and that, unlike MRP1 and MRP2, MRP7-mediated drug transport does not involve glutathione. [Cancer Res 2009;69(1):178–84]
Data from A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis
Authors: Sætrom Pål , Biesinger Jacob , Li Sierra M. , Smith David , Thomas Laurent F. , Majzoub Karim , Rivas Guillermo E. , Alluin Jessica , Rossi John J. , Krontiris Theodore G. , Weitzel Jeffrey , Daly Mary B. , Benson Al B. , Kirkwood John M. , O'Dwyer Peter J. , Sutphen Rebecca , Stewart James A. , Johnson David , Larson Garrett P.
Published: March 2023

Abstract
MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor–stratified breast tumors and used local linkage disequilibirum patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong linkage disequilibrium with rs1434536, an SNP that resides within a miR-125b target site in the 3′ untranslated region of the bone morphogenic receptor type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture-corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b–mimics combined with quantitative reverse transcription-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease association for alleles that affect miRNA regulation. [Cancer Res 2009;69(18):7459–65]
Data from TGFBR1 Haplotypes and Risk of Non–Small-Cell Lung Cancer
Authors: Lei Zhe , Liu Reng-Yun , Zhao Jun , Liu Zeyi , Jiang Xiefang , You Weiming , Chen Xiao-Feng , Liu Xia , Zhang Kui , Pasche Boris , Zhang Hong-Tao
Published: March 2023

Abstract
Transforming growth factor β (TGF-β) receptors are centrally involved in TGF-β–mediated cell growth and differentiation and are frequently inactivated in non–small-cell lung cancer (NSCLC). Constitutively decreased type I TGF-β receptor (TGFBR1) expression is emerging as a novel tumor-predisposing phenotype. The association of TGFBR1 haplotypes with risk for NSCLC has not yet been studied. We tested the hypothesis that single-nucleotide polymorphisms (SNP) and/or TGFBR1 haplotypes are associated with risk of NSCLC. We genotyped six TGFBR1 haplotype-tagging SNPs (htSNP) by PCR-RFLP assays and one htSNP by PCR-single-strand conformation polymorphism assay in two case-control studies. Case-control study 1 included 102 NSCLC patients and 104 healthy controls from Suzhou. Case-control study 2 included 131 patients with NSCLC and 133 healthy controls from Wuxi. Individuals included in both case-control studies were Han Chinese. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of these seven htSNPs. None of the htSNP was associated with NSCLC risk in either study. However, a four-marker CTGC haplotype was significantly more common among controls than among cases in both studies (P = 0.014 and P = 0.010, respectively), indicating that this haplotype is associated with decreased NSCLC risk {adjusted odds ratio [OR], 0.09 [95% confidence interval (95% CI), 0.01–0.61] and 0.11 [95% CI, 0.02–0.59], respectively}. Combined analysis of both studies shows a strong association of this four-marker haplotype with decreased NSCLC risk (adjusted OR, 0.11; 95% CI, 0.03–0.39). This is the first evidence of an association between a TGFBR1 haplotype and risk for NSCLC. [Cancer Res 2009;69(17):7046–52]
Data from Functional Role of S100A14 Genetic Variants and Their Association with Esophageal Squamous Cell Carcinoma
Authors: Chen Hongyan , Yu Dianke , Luo Aiping , Tan Wen , Zhang Chunpeng , Zhao Dan , Yang Ming , Liu Junniao , Lin Dongxin , Liu Zhihua
Published: March 2023

Abstract
S100 proteins have been implicated in various human diseases, including certain types of cancer. Among them, S100A14 is down-regulated in esophageal squamous cell carcinoma (ESCC). In this study, we sought to identify functional genetic variants in the S100A14 locus and assessed their associations with susceptibility to ESCC. Thirty individual DNA samples were sequenced to search for genetic variations in S100A14, and the function of the variants was investigated by a set of biochemical assays. A case-control analysis was performed in 1,021 patients with ESCC and 1,253 control subjects. Odds ratios and 95% confidence intervals (95% CI) were computed by logistic regression model. Four single nucleotide polymorphisms, −43A>G, 461G>A, 1493A>G, and 1545A>T, were identified in the S100A14 locus and they are in absolute linkage disequilibrium. Among them, the 461G>A change was shown to diminish a P53-binding site and is therefore associated with decreased expression of S100A14 in vitro and in vivo in the target tissues. Case-control analysis showed that the 461A allele was associated with susceptibility to ESCC among smokers, with the ORs being 2.01 (95% CI, 1.50–2.69) or 2.10 (95% CI, 1.37–3.22) for the 461GA or 461AA genotype, respectively, compared with the 461GG genotype. These data constitute strong evidence in support of the notion that S100A14 might function as a cancer suppressor working in the P53 pathway and play a role in esophageal carcinogenesis. [Cancer Res 2009;69(8):3451–7]
Data from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma
Authors: Nishijo Koichi , Chen Qing-Rong , Zhang Lei , McCleish Amanda T. , Rodriguez Andrea , Cho Min Jung , Prajapati Suresh I. , Gelfond Jonathan A.L. , Chisholm Gary B. , Michalek Joel E. , Aronow Bruce J. , Barr Frederic G. , Randall R. Lor , Ladanyi Marc , Qualman Stephen J. , Rubin Brian P. , LeGallo Robin D. , Wang Chiayeng , Khan Javed , Keller Charles
Published: March 2023

Abstract
The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3:Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3:Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3:Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3:Fkhr signature, including the target gene, SKP2. We further identified 7 “druggable” kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model. [Cancer Res 2009;69(7):2902–11]
Data from Taspase1 Functions as a Non-Oncogene Addiction Protease that Coordinates Cancer Cell Proliferation and Apoptosis
Authors: Chen David Y. , Liu Han , Takeda Shugaku , Tu Ho-Chou , Sasagawa Satoru , Van Tine Brian A. , Lu Dongsi , Cheng Emily H-Y. , Hsieh James J-D.
Published: March 2023

Abstract
Taspase1, the mixed lineage leukemia and TFIIAα-β cleaving protease, enables cell proliferation and permits oncogenic initiation. Here, we show its critical role in cancer maintenance and thus offer a new anticancer target. Taspase1 is overexpressed in primary human cancers, and deficiency of Taspase1 in cancer cells not only disrupts proliferation but also enhances apoptosis. Mechanistically, loss of Taspase1 induces the levels of CDK inhibitors (CDKI: p16, p21, and p27) and reduces the level of antiapoptotic MCL-1. Therapeutically, deficiency of Taspase1 synergizes with chemotherapeutic agents and ABT-737, an inhibitor of BCL-2/BCL-XL, to kill cancer cells. Taspase1 alone or in conjunction with MYC, RAS, or E1A fails to transform NIH/3T3 cells or primary mouse embryonic fibroblasts, respectively, but plays critical roles in cancer initiation and maintenance. Therefore, Taspase1 is better classified as a “non-oncogene addiction” protease, the inhibition of which may offer a novel anticancer therapeutic strategy. The reliance of oncogenes on subordinate non-oncogenes during tumorigenesis underscores the non-oncogene addiction hypothesis in which a large class of non-oncogenes functions to maintain cancer phenotypes and presents attractive anticancer therapeutic targets. The emergence of successful cancer therapeutics targeting non-oncogenes to which cancers are addicted supports the future development and potential application of small-molecule Taspase1 inhibitors for cancer therapy. Cancer Res; 70(13); 5358–67. ©2010 AACR.
Data from Intratumoral Localization of Aromatase and Interaction between Stromal and Parenchymal Cells in the Non–Small Cell Lung Carcinoma Microenvironment
Authors: Miki Yasuhiro , Suzuki Takashi , Abe Keiko , Suzuki Satoshi , Niikawa Hiromichi , Iida Shinya , Hata Shuko , Akahira Jun-ichi , Mori Kazushige , Evans Dean B. , Kondo Takashi , Yamada-Okabe Hisafumi , Sasano Hironobu
Published: March 2023

Abstract
Estrogens produced as a result of intratumoral aromatization has been recently shown to play important roles in proliferation of human non–small cell lung carcinomas (NSCLC), but the details have remained largely unknown. Therefore, in this study, we evaluated the possible roles of intratumoral aromatase in NSCLCs as follows: (a) evaluation of intratumoral localization of aromatase mRNA/protein in six lung adenocarcinoma cases using laser capture microdissection combined with quantitative reverse transcriptase-PCR and immunohistochemistry; (b) examination of the possible effects of isolated stromal cells from lung carcinoma tissues on aromatase mRNA transcript expression in lung carcinoma cell lines (A549 and LK87) through a coculture system; and (c) screening of cytokines derived from stromal LK001S and LK002S cells using cytokine antibody arrays and subsequent evaluation of effects of these cytokines on aromatase expression in A549 and LK87. Both aromatase mRNA and protein were mainly detected in intratumoral carcinoma cells but not in stromal cells. Aromatase expression of A549 and LK87 was upregulated in the presence of LK001S or LK002S cells. Several cytokines such as interleukin-6 (IL-6), oncostatin M, and tumor necrosis factor-α, all known as inducible factors of aromatase gene, were detected in conditioned media of LK001S and LK002S cells. Treatment of both oncostatin M and IL-6 induced aromatase gene expression in A549 an LK87, respectively. These results all indicated that intratumoral microenvironments, especially carcinoma-stromal cell interactions, play a pivotal role in the regulation of intratumoral estrogen synthesis through aromatase expression in human lung adenocarcinomas. Cancer Res; 70(16); 6659–69. ©2010 AACR.
Data from The Human Ortholog of Granulocyte Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion Protein Induces Potent Ex vivo Natural Killer Cell Activation and Maturation
Authors: Penafuerte Claudia , Bautista-Lopez Norma , Mohamed-Rachid Boulassel , Routy Jean-Pierre , Galipeau Jacques
Published: March 2023

Abstract
Natural killer (NK) cells are appealing cellular pharmaceuticals for cancer therapy because of their innate ability to recognize and kill tumor cells. Therefore, the development of methods that can enhance the potency in their anticancer effect would be desirable. We have previously shown that a murine granulocyte macrophage colony-stimulating factor (GM-CSF)/interleukin 2 (IL-2) fusion protein displays novel antitumor properties in vivo compared with both cytokines in combination due to recruitment of NK cells. In the present work, we have found that human ortholog of the GM-CSF/IL-2 fusion protein (a.k.a. hGIFT2) induces robust NK cell activation ex vivo with significant secretion of RANTES and a 37-fold increase in IFNγ production when compared with either IL-2 or GM-CSF single cytokine treatment or their combination. Moreover, hGIFT2 upregulates the expression of NK cell activating receptors NKp44, NKp46, and DNAM-1 (CD226), as well as CD69, CD107a, and IL-2Rβ expression. In addition, hGIFT2 promotes NK cell maturation, based on the downregulation of CD117 expression and upregulation of CD11b. This phenotype correlates with significantly greater cytotoxicity against tumor cells. At the molecular level, hGIFT2 leads to a potent activation of Janus-activated kinases (JAK) downstream of both IL-2 and GM-CSF receptors (JAK1 and JAK2, respectively) and consequently leads to a hyperphosphorylation of signal transducers and activators of transcription (STAT)1, STAT3, and STAT5. In conclusion, hGIFT2 fusokine possesses unique biochemical properties distinct from IL-2 and GM-CSF, constitutes a novel and potent tool for ex vivo NK cell activation and maturation, and may be of use for cancer cell immunotherapy. [Cancer Res 2009;69(23):9020–8]
Data from Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma
Authors: Goto Yasuhiro , Shinjo Keiko , Kondo Yutaka , Shen Lanlan , Toyota Minoru , Suzuki Hiromu , Gao Wentao , An Byonggu , Fujii Makiko , Murakami Hideki , Osada Hirotaka , Taniguchi Tetsuo , Usami Noriyasu , Kondo Masashi , Hasegawa Yoshinori , Shimokata Kaoru , Matsuo Keitaro , Hida Toyoaki , Fujimoto Nobukazu , Kishimoto Takumi , Issa Jean-Pierre J. , Sekido Yoshitaka
Published: March 2023

Abstract
Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively. Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease. Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):9073–82]
Data from Folate Receptor β Is Expressed by Tumor-Associated Macrophages and Constitutes a Marker for M2 Anti-inflammatory/Regulatory Macrophages
Authors: Puig-Kröger Amaya , Sierra-Filardi Elena , Domínguez-Soto Angeles , Samaniego Rafael , Corcuera María Teresa , Gómez-Aguado Fernando , Ratnam Manohar , Sánchez-Mateos Paloma , Corbí Angel L.
Published: March 2023

Abstract
Macrophage activation comprises a continuum of functional states critically determined by cytokine microenvironment. Activated macrophages have been functionally grouped according to their response to pro-Th1/proinflammatory stimuli [lipopolysaccharide, IFNγ, granulocyte macrophage colony-stimulating factor (GM-CSF); M1] or pro-Th2/anti-inflammatory stimuli [interleukin (IL)-4, IL-10, M-CSF; M2]. We report that folate receptor β (FRβ), encoded by the FOLR2 gene, is a marker for macrophages generated in the presence of M-CSF (M2), but not GM-CSF (M1), and whose expression correlates with increased folate uptake ability. The acquisition of folate uptake ability by macrophages is promoted by M-CSF, maintained by IL-4, prevented by GM-CSF, and reduced by IFNγ, indicating a link between FRβ expression and M2 polarization. In agreement with in vitro data, FRβ expression is detected in tumor-associated macrophages (TAM), which exhibit an M2-like functional profile and exert potent immunosuppressive functions within the tumor environment. FRβ is expressed, and mediates folate uptake, by CD163+ CD68+ CD14+ IL-10–producing TAM, and its expression is induced by tumor-derived ascitic fluid and conditioned medium from fibroblasts and tumor cell lines in an M-CSF–dependent manner. These results establish FRβ as a marker for M2 regulatory macrophage polarization and indicate that folate conjugates of therapeutic drugs are a potential immunotherapy tool to target TAM. [Cancer Res 2009;69(24):9395–403]
Data from A Novel Senescence-Evasion Mechanism Involving Grap2 and Cyclin D Interacting Protein Inactivation by Ras Associated with Diabetes in Cancer Cells under Doxorubicin Treatment
Authors: Lee Inkyoung , Yeom Seon-Yong , Lee Sook-Ja , Kang Won Ki , Park Chaehwa
Published: March 2023

Abstract
Ras associated with diabetes (Rad) is a Ras-related GTPase that promotes cell growth by accelerating cell cycle transitions. Rad knockdown induced cell cycle arrest and premature senescence without additional cellular stress in multiple cancer cell lines, indicating that Rad expression might be critical for the cell cycle in these cells. To investigate the precise function of Rad in this process, we used human Rad as bait in a yeast two-hybrid screening system and sought Rad-interacting proteins. We identified the Grap2 and cyclin D interacting protein (GCIP)/DIP1/CCNDBP1/HHM, a cell cycle–inhibitory molecule, as a binding partner of Rad. Further analyses revealed that Rad binds directly to GCIP in vitro and coimmunoprecipitates with GCIP from cell lysates. Rad translocates GCIP from the nucleus to the cytoplasm, thereby inhibiting the tumor suppressor activity of GCIP, which occurs in the nucleus. Furthermore, in the presence of Rad, GCIP loses its ability to reduce retinoblastoma phosphorylation and inhibit cyclin D1 activity. The function of Rad in transformation is also evidenced by increased telomerase activity and colony formation according to Rad expression level. In vivo tumorigenesis analyses revealed that tumors derived from Rad knockdown cells were significantly smaller than those from control cells (P = 0.0131) and the preestablished tumors are reduced in size after the injection of siRad (P = 0.0064). Therefore, we propose for the first time that Rad may promote carcinogenesis at least in part by inhibiting GCIP-mediated tumor suppression. Cancer Res; 70(11); 4357–65. ©2010 AACR.
Data from Inhibition of Lipocalin 2 Impairs Breast Tumorigenesis and Metastasis
Authors: Leng Xiaohong , Ding Tian , Lin Hui , Wang Yan , Hu Limei , Hu Jianhua , Feig Barry , Zhang Wei , Pusztai Lajos , Symmans W. Fraser , Wu Yun , Arlinghaus Ralph B.
Published: March 2023

Abstract
Lipocalin 2 (LCN2; also known as NGAL) is a secreted glycoprotein and its elevated expression has been observed in breast cancers. However, the importance of LCN2 in breast tumorigenesis is unclear. Here, we employed a spontaneous mammary tumor mouse model showing that MMTV-ErbB2(V664E) mice lacking mouse LCN2 had significantly delayed mammary tumor formation and metastasis with reduced matrix metalloproteinase-9 activity in the blood. LCN2 expression is upregulated by HER2/phosphoinositide 3-kinase/AKT/NF-κB pathway. Decreasing LCN2 expression significantly reduced the invasion and migration ability of HER2+ breast cancer cells. Furthermore, injecting an anti-mouse LCN2 antibody into mice bearing established murine breast tumors resulted in significant blockage of lung metastasis. Our findings indicate that LCN2 is a critical factor in enhancing breast tumor formation and progression possibly in part by stabilizing matrix metalloproteinase-9. Our results suggest that inhibition of LCN2 function by an inhibitory monoclonal antibody has potential for breast cancer therapy, particularly by interfering with metastasis in aggressive types of breast cancer. [Cancer Res 2009;69(22):8579–84]
Data from Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity
Authors: Sottoriva Andrea , Verhoeff Joost J.C. , Borovski Tijana , McWeeney Shannon K. , Naumov Lev , Medema Jan Paul , Sloot Peter M.A. , Vermeulen Louis
Published: March 2023

Abstract
The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity. Cancer Res; 70(1); 46–56
Data from Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy
Authors: Sato Nagato , Yamabuki Takumi , Takano Atsushi , Koinuma Junkichi , Aragaki Masato , Masuda Ken , Ishikawa Nobuhisa , Kohno Nobuoki , Ito Hiroyuki , Miyamoto Masaki , Nakayama Haruhiko , Miyagi Yohei , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro
Published: March 2023

Abstract
Dickkopf-1 (DKK1) is an inhibitor of Wnt/β-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer. Cancer Res; 70(13); 5326–36. ©2010 AACR.
Data from microRNA-21 Negatively Regulates Cdc25A and Cell Cycle Progression in Colon Cancer Cells
Authors: Wang Peng , Zou Fangdong , Zhang Xiaodong , Li Hua , Dulak Austin , Tomko Robert J. , Lazo John S. , Wang Zhenghe , Zhang Lin , Yu Jian
Published: March 2023

Abstract
microRNAs (miRNA) are small noncoding RNAs that participate in diverse biological processes by suppressing target gene expression. Altered expression of miR-21 has been reported in cancer. To gain insights into its potential role in tumorigenesis, we generated miR-21 knockout colon cancer cells through gene targeting. Unbiased microarray analysis combined with bioinformatics identified cell cycle regulator Cdc25A as a miR-21 target. miR-21 suppressed Cdc25A expression through a defined sequence in its 3′-untranslated region. We found that miR-21 is induced by serum starvation and DNA damage, negatively regulates G1-S transition, and participates in DNA damage–induced G2-M checkpoint through down-regulation of Cdc25A. In contrast, miR-21 deficiency did not affect apoptosis induced by a variety of commonly used anticancer agents or cell proliferation under normal cell culture conditions. Furthermore, miR-21 was found to be underexpressed in a subset of Cdc25A-overexpressing colon cancers. Our data show a role of miR-21 in modulating cell cycle progression following stress, providing a novel mechanism of Cdc25A regulation and a potential explanation of miR-21 in tumorigenesis. [Cancer Res 2009;69(20):8157–65]
Data from Altered Runx1 Subnuclear Targeting Enhances Myeloid Cell Proliferation and Blocks Differentiation by Activating a miR-24/MKP-7/MAPK Network
Authors: Zaidi Sayyed K. , Dowdy Christopher R. , van Wijnen Andre J. , Lian Jane B. , Raza Azra , Stein Janet L. , Croce Carlo M. , Stein Gary S.
Published: March 2023

Abstract
Disruption of Runx1/AML1 subnuclear localization, either by a single amino acid substitution or by a chromosomal translocation [e.g., t(8;21)], is linked to the etiology of acute myeloid leukemia (AML). Here, we show that this defect induces a select set of micro-RNAs (miR) in myeloid progenitor cells and AML patients with t(8;21). Both Runx1 and the t(8;21)-encoded AML1-ETO occupy the miR-24-23-27 locus and reciprocally control miR-24 transcription. miR-24 directly downregulates mitogen-activated protein kinase (MAPK) phosphatase-7 and enhances phosphorylation of both c-jun-NH2-kinase and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of interleukin-3, and blocks granulocytic differentiation. Thus, compromised Runx1 function induces a miR-dependent mechanism that, through MAPK signaling, enhances myeloid proliferation but blocks differentiation—key steps that contribute to leukemia. [Cancer Res 2009;69(21):8249–55]
Data from Monitoring of Natural Killer Cell Immunotherapy Using Noninvasive Imaging Modalities
Authors: Jha Priyanka , Golovko Daniel , Bains Sukhmine , Hostetter Daniel , Meier Reinhard , Wendland Michael F. , Daldrup-Link Heike E.
Published: March 2023

Abstract
Cancer immunotherapies can be guided by cellular imaging techniques, which can identify the presence or absence of immune cell accumulation in the tumor tissue in vivo and in real time. This review summarizes various new and evolving imaging techniques employed for tracking and monitoring of adoptive natural killer cell immunotherapies. Cancer Res; 70(15); 6109–13. ©2010 AACR.
Data from Preclinical Profile of a Potent γ-Secretase Inhibitor Targeting Notch Signaling with In vivo Efficacy and Pharmacodynamic Properties
Authors: Luistro Leopoldo , He Wei , Smith Melissa , Packman Kathryn , Vilenchik Maria , Carvajal Daisy , Roberts John , Cai James , Berkofsky-Fessler Windy , Hilton Holly , Linn Michael , Flohr Alexander , Jakob-Røtne Roland , Jacobsen Helmut , Glenn Kelli , Heimbrook David , Boylan John F.
Published: March 2023

Abstract
Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of γ-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. [Cancer Res 2009;69(19):7672–80]
Data from Autotaxin Promotes Cancer Invasion via the Lysophosphatidic Acid Receptor 4: Participation of the Cyclic AMP/EPAC/Rac1 Signaling Pathway in Invadopodia Formation
Authors: Harper Kelly , Arsenault Dominique , Boulay-Jean Stephanie , Lauzier Annie , Lucien Fabrice , Dubois Claire M.
Published: March 2023

Abstract
The ability of cancer cells to invade and metastasize is the major cause of death in cancer patients. Autotaxin (ATX) is a secreted lysophospholipase whose level of expression within tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major enzyme involved in the production of lysophosphatidic acid (LPA), a phospholipid that is known to act mostly through its three first characterized receptors (LPA1, LPA2, and LPA3). Tumor cell invasion across tissue boundaries and metastasis are dependent on the capacity of invasive cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA4 signaling in fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of EPAC by cyclic AMP and subsequent Rac1 activation. Results using LPA4 shRNA support the requirement of the LPA4 receptor for cell invasion and in vivo metastasis formation. This work presents evidence that blocking the LPA receptor, LPA4, in fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of metastasis in patients. Because LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA4, together with other LPA receptors, in various cancer patients. Cancer Res; 70(11); 4634–43. ©2010 AACR.
Data from A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/β-catenin Pathway
Authors: Chow Kim Hei-Man , Sun Raymond Wai-Yin , Lam Janice B.B. , Li Carrie Ka-Lei , Xu Aimin , Ma Dik-Lung , Abagyan Ruben , Wang Yu , Che Chi-Ming
Published: March 2023

Abstract
Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling. Cancer Res; 70(1); 329–37
Data from The Polycomb Group Protein Bmi-1 Is Essential for the Growth of Multiple Myeloma Cells
Authors: Jagani Zainab , Wiederschain Dmitri , Loo Alice , He Dan , Mosher Rebecca , Fordjour Paul , Monahan John , Morrissey Michael , Yao Yung-Mae , Lengauer Christoph , Warmuth Markus , Sellers William R. , Dorsch Marion
Published: March 2023

Abstract
Bmi-1 is a member of the Polycomb group family of proteins that function in the epigenetic silencing of genes governing self-renewal, differentiation, and proliferation. Bmi-1 was first identified through its ability to accelerate c-Myc–induced lymphomagenesis. Subsequent studies have further supported an oncogenic role for Bmi-1 in several cancers including those of the breast, lung, prostate, and brain. Using a stable and inducible shRNA system to silence Bmi-1 gene expression, we show a novel role for Bmi-1 in regulating the growth and clonogenic capacity of multiple myeloma cells both in vitro and in vivo. Moreover, to elucidate novel gene targets controlled by Bmi-1, global transcriptional profiling studies were performed in the setting of induced loss of Bmi-1 function. We found that the expression of the proapoptotic gene Bim is negatively regulated by Bmi-1 and that Bim knockdown functionally rescues the apoptotic phenotype induced upon loss of Bmi-1. Therefore, these studies not only highlight Bmi-1 as a cancer-dependent factor in multiple myeloma, but also elucidate a novel antiapoptotic mechanism for Bmi-1 function involving the suppression of Bim. Cancer Res; 70(13); 5528–38. ©2010 AACR.
Data from Recurrent Focal Copy-Number Changes and Loss of Heterozygosity Implicate Two Noncoding RNAs and One Tumor Suppressor Gene at Chromosome 3q13.31 in Osteosarcoma
Authors: Pasic Ivan , Shlien Adam , Durbin Adam D. , Stavropoulos Dimitrios J. , Baskin Berivan , Ray Peter N. , Novokmet Ana , Malkin David
Published: March 2023

Abstract
Osteosarcomas are copy number alteration (CNA)–rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes. Cancer Res; 70(1); 160–71
Data from MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor–Dependent Fashion to Suppress Carcinoma Growth
Authors: Zhang Yu-Wen , Staal Ben , Essenburg Curt , Su Yanli , Kang Liang , West Rich , Kaufman Dafna , DeKoning Tom , Eagleson Bryn , Buchanan Sean G. , Vande Woude George F.
Published: March 2023

Abstract
The hepatocyte growth factor (HGF)-MET pathway supports several hallmark cancer traits, and it is frequently activated in a broad spectrum of human cancers (http://www.vai.org/met/). With the development of many cancer drugs targeting this pathway, there is a need for relevant in vivo model systems for preclinical evaluation of drug efficacy. Here, we show that production of the human HGF ligand in transgenic severe combined immunodeficient mice (hHGFtg-SCID mice) enhances the growth of many MET-expressing human carcinoma xenografts, including those derived from lung, breast, kidney, colon, stomach, and pancreas. In this model, the MET-specific small-molecule kinase inhibitor SGX523 partially inhibits the HGF-dependent growth of lung, breast, and pancreatic tumors. However, much greater growth suppression is achieved by combinatorial inhibition with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. Together, these results validate the hHGFtg-SCID mouse model for in vivo determination of MET sensitivity to drug inhibition. Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated. Cancer Res; 70(17); 6880–90. ©2010 AACR.
Data from Involvement of the Tubulin Tyrosine Ligase-Like Family Member 4 Polyglutamylase in PELP1 Polyglutamylation and Chromatin Remodeling in Pancreatic Cancer Cells
Authors: Kashiwaya Kotoe , Nakagawa Hidewaki , Hosokawa Masayo , Mochizuki Yasuo , Ueda Koji , Piao Lianhua , Chung Suyoun , Hamamoto Ryuji , Eguchi Hidetoshi , Ohigashi Hiroaki , Ishikawa Osamu , Janke Carsten , Shinomura Yasuhisa , Nakamura Yusuke
Published: March 2023

Abstract
Polyglutamylation is a new class of posttranslational modification in which glutamate side chains are formed in proteins, although its biological significance is not well known. Through our genome-wide gene expression profile analyses of pancreatic ductal adenocarcinoma (PDAC) cells, we identified the overexpression of tubulin tyrosine ligase-like family member 4 (TTLL4) in PDAC cells. Subsequent reverse transcription-PCR and Northern blot analyses confirmed its upregulation in several PDACs. TTLL4 belongs to the TTLL family which was reported to have polyglutamylase activity. Knockdown of TTLL4 by short hairpin RNA in PDAC cells attenuated the growth of PDAC cells and exogenous introduction of TTLL4 enhanced cell growth. We also found that TTLL4 expression was correlated with polyglutamylation levels of a glutamate stretch region of the proline, glutamate, and leucine–rich protein 1 (PELP1) that was shown to interact with various proteins such as histone H3, and was involved in several signaling pathways through its function as a scaffold protein. PELP1 polyglutamylation could influence its interaction with histone H3 and affect histone H3 acetylation. We also identified the interaction of PELP1 with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involving chromatin remodeling. Our findings imply that TTLL4 could play important roles in pancreatic carcinogenesis through its polyglutamylase activity and subsequent coordination of chromatin remodeling, and might be a good molecular candidate for the development of new therapeutic strategies for pancreatic cancer. Cancer Res; 70(10); 4024–33. ©2010 AACR.
Data from Poly(ADP-Ribose) Polymerase Inhibitor Induces Accelerated Senescence in Irradiated Breast Cancer Cells and Tumors
Authors: Efimova Elena V. , Mauceri Helena J. , Golden Daniel W. , Labay Edwardine , Bindokas Vytautas P. , Darga Thomas E. , Chakraborty Chaitali , Barreto-Andrade Juan Camilo , Crawley Clayton , Sutton Harold G. , Kron Stephen J. , Weichselbaum Ralph R.
Published: March 2023

Abstract
Persistent DNA double-strand breaks (DSB) may determine the antitumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe, or permanent growth arrest. IR induces rapid modification of megabase chromatin domains surrounding DSBs via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these IR-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked the relocalization of green fluorescent protein fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase (PARP) with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy. Cancer Res; 70(15); 6277–82. ©2010 AACR.
Data from Identification of ASF/SF2 as a Critical, Allele-Specific Effector of the Cyclin D1b Oncogene
Authors: Olshavsky Nicholas A. , Comstock Clay E.S. , Schiewer Matthew J. , Augello Michael A. , Hyslop Terry , Sette Claudio , Zhang Jinsong , Parysek Linda M. , Knudsen Karen E.
Published: March 2023

Abstract
The cyclin D1b oncogene arises from alternative splicing of the CCND1 transcript, and harbors markedly enhanced oncogenic functions not shared by full-length cyclin D1 (cyclin D1a). Recent studies showed that cyclin D1b is selectively induced in a subset of tissues as a function of tumorigenesis; however, the underlying mechanism(s) that control tumor-specific cyclin D1b induction remain unsolved. Here, we identify the RNA-binding protein ASF/SF2 as a critical, allele-specific, disease-relevant effector of cyclin D1b production. Initially, it was observed that SF2 associates with cyclin D1b mRNA (transcript-b) in minigene analyses and with endogenous transcript in prostate cancer (PCa) cells. SF2 association was altered by the CCND1 G/A870 polymorphism, which resides in the splice donor site controlling transcript-b production. This finding was significant, as the A870 allele promotes cyclin D1b in benign prostate tissue, but in primary PCa, cyclin D1b production is independent of A870 status. Data herein provide a basis for this disparity, as tumor-associated induction of SF2 predominantly results in binding to and accumulation of G870-derived transcript-b. Finally, the relevance of SF2 function was established, as SF2 strongly correlated with cyclin D1b (but not cyclin D1a) in human PCa. Together, these studies identify a novel mechanism by which cyclin D1b is induced in cancer, and reveal significant evidence of a factor that cooperates with a risk-associated polymorphism to alter cyclin D1 isoform production. Identification of SF2 as a disease-relevant effector of cyclin D1b provides a basis for future studies designed to suppress the oncogenic alternative splicing event. Cancer Res; 70(10); 3975–84. ©2010 AACR.
Data from Myc-Induced MicroRNAs Integrate Myc-Mediated Cell Proliferation and Cell Fate
Authors: Kim Jong Wook , Mori Seiichi , Nevins Joseph R.
Published: March 2023

Abstract
The Myc pathway, often deregulated in cancer, is critical in determining cell fate by coordinating a gene expression program that links the control of cell proliferation with cell fate decisions. As such, precise control of the Myc pathway activity must be achieved to ensure faithful execution of appropriate cellular response and to prevent progressing toward a malignant state. With recent highlighted roles of microRNAs (miRNA) as critical components of gene control, we sought to evaluate the extent to which miRNAs may contribute in the execution of Myc function. Combined analysis of mRNA and miRNA expression profiles reveals an integration whereby the Myc-mediated induction of miRNAs leads to the repression of various mRNAs encoding tumor suppressors that block cell proliferation including p21, p27, and Rb. In addition, the proapoptotic PTEN tumor suppressor gene is also repressed by Myc-induced miRNAs, suggesting that Myc-induced miRNAs contribute to the precise control of a transcriptional program that coordinates the balance of cell proliferation and cell death. Cancer Res; 70(12); 4820–8. ©2010 AACR.