bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Long Noncoding RNA AB074169 Inhibits Cell Proliferation via Modulation of KHSRP-Mediated CDKN1a Expression in Papillary Thyroid Carcinoma
Authors: Gou Qiheng , Gao Linbo , Nie Xinwen , Pu Wenchen , Zhu Jingqiang , Wang Yichao , Liu Xuesha , Tan Shuangyan , Zhou Jian-Kang , Gong Yanqiu , He Juan , Wu Ke , Xie Yuxin , Zhao Wanjun , Dai Lunzhi , Liu Lunxu , Xiang Rong , Wei Yu-Quan , Zhang Lin , Peng Yong
Published: March 2023

Abstract
Long noncoding RNAs (lncRNA) are emerging as a novel class of regulators in gene expression associated with tumorigenesis. However, the role of lncRNAs in papillary thyroid carcinoma (PTC) is poorly understood. Here, we conducted global lncRNA profiling and identified lncRNA AB074169 (lncAB) as significantly downregulated in PTC. Decreased expression of lncAB in PTC was caused by CpG hypermethylation within its gene promoter. Functional studies showed that lncAB overexpression led to cell-cycle arrest and tumor growth inhibition in vitro and in vivo, whereas lncAB knockdown promoted cell proliferation. Mechanistic analyses revealed that lncAB bound KH-type splicing regulatory protein (KHSRP) and also decreased expression of KHSRP, thus increasing CDKN1a (p21) expression and decreasing CDK2 expression to repress cell proliferation. Taken together, these findings demonstrate that lncAB functions as a tumor suppressor during PTC tumorigenesis.

Significance: These findings identify a tumor-suppressive long noncoding RNA in papillary thyroid carcinoma.

Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/78/15/4163/F1.large.jpg. Cancer Res; 78(15); 4163–74. ©2018 AACR.
Data from Twist1 Regulates Vimentin through Cul2 Circular RNA to Promote EMT in Hepatocellular Carcinoma
Authors: Meng Jing , Chen Shuang , Han Jing-Xia , Qian Baoxin , Wang Xiao-Rui , Zhong Wei-Long , Qin Yuan , Zhang Heng , Gao Wan-Feng , Lei Yue-Yang , Yang Wei , Yang Lan , Zhang Chao , Liu Hui-Juan , Liu Yan-Rong , Zhou Hong-Gang , Sun Tao , Yang Cheng
Published: March 2023

Abstract
Twist is a critical epithelial–mesenchymal transition (EMT)–inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.

Significance: A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg. Cancer Res; 78(15); 4150–62. ©2018 AACR.
Data from Inflammatory Breast Cancer Promotes Development of M2 Tumor-Associated Macrophages and Cancer Mesenchymal Cells through a Complex Chemokine Network
Authors: Valeta-Magara Amanda , Gadi Abhilash , Volta Viviana , Walters Beth , Arju Rezina , Giashuddin Shah , Zhong Hua , Schneider Robert J.
Published: March 2023

Abstract
Inflammatory breast cancer (IBC) is a highly aggressive form of breast cancer that displays profound cancer stem cell (CSC) and mesenchymal features that promote rapid metastasis. Another hallmark of IBC is high infiltration of M2 tumor-associated (immune-suppressing) macrophages. The molecular mechanism that drives these IBC phenotypes is not well understood. Using patient breast tumor specimens, breast cancer cell lines, and a patient-derived xenograft model of IBC, we demonstrate that IBC strongly expresses IL8 and growth-regulated oncogene (GRO) chemokines that activate STAT3, which promotes development of high levels of CSC-like cells and a mesenchymal phenotype. We also show that IBC expresses high levels of many monocyte recruitment and macrophage polarization factors that attract and differentiate monocytes into tumor-promoting, immune-suppressing M2-like macrophages. The M2 macrophages in turn were found to secrete high levels of IL8 and GRO chemokines, thereby creating a feed-forward chemokine loop that further drives an IBC epithelial-to-mesenchymal transition. Our study uncovers an intricate IBC-initiated autocrine–paracrine signaling network between IBC cells and monocytes that facilitates development of this highly aggressive form of breast cancer.
Significance:
This study uncovers a signaling network in which IBC cells commandeer macrophages to become tumor-promoting, and they in turn drive IBC cells to be more cancer stem-like, mesenchymal, and aggressive.
Data from SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin–Rho GTPase–Hippo Pathways
Authors: Zhang Yan-Li , Li Qing , Yang Xiao-Mei , Fang Fang , Li Jun , Wang Ya-Hui , Yang Qin , Zhu Lei , Nie Hui-Zhen , Zhang Xue-Li , Feng Ming-Xuan , Jiang Shu-Heng , Tian Guang-Ang , Hu Li-Peng , Lee Ho-Young , Lee Su-Jae , Xia Qiang , Zhang Zhi-Gang
Published: March 2023

Abstract
Tumor-associated macrophages (TAM) represent key regulators of the complex interplay between cancer and the immune microenvironment. Matricellular protein SPON2 is essential for recruiting lymphocytes and initiating immune responses. Recent studies have shown that SPON2 has complicated roles in cell migration and tumor progression. Here we report that, in the tumor microenvironment of hepatocellular carcinoma (HCC), SPON2 not only promotes infiltration of M1-like macrophages but also inhibits tumor metastasis. SPON2-α4β1 integrin signaling activated RhoA and Rac1, increased F-actin reorganization, and promoted M1-like macrophage recruitment. F-Actin accumulation also activated the Hippo pathway by suppressing LATS1 phosphorylation, promoting YAP nuclear translocation, and initiating downstream gene expression. However, SPON2-α5β1 integrin signaling inactivated RhoA and prevented F-actin assembly, thereby inhibiting HCC cell migration; the Hippo pathway was not noticeably involved in SPON2-mediated HCC cell migration. In HCC patients, SPON2 levels correlated positively with prognosis. Overall, our findings provide evidence that SPON2 is a critical factor in mediating the immune response against tumor cell growth and migration in HCC.

Significance: Matricellular protein SPON2 acts as an HCC suppressor and utilizes distinct signaling events to perform dual functions in HCC microenvironment.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/9/2305/F1.large.jpg. Cancer Res; 78(9); 2305–17. ©2018 AACR.
Data from CANCERTOOL: A Visualization and Representation Interface to Exploit Cancer Datasets
Authors: Cortazar Ana R. , Torrano Veronica , Martín-Martín Natalia , Caro-Maldonado Alfredo , Camacho Laura , Hermanova Ivana , Guruceaga Elizabeth , Lorenzo-Martín Luis F. , Caloto Ruben , Gomis Roger R. , Apaolaza Iñigo , Quesada Victor , Trka Jan , Gomez-Muñoz Antonio , Vincent Silvestre , Bustelo Xose R. , Planes Francisco J. , Aransay Ana M. , Carracedo Arkaitz
Published: March 2023

Abstract
With the advent of OMICs technologies, both individual research groups and consortia have spear-headed the characterization of human samples of multiple pathophysiologic origins, resulting in thousands of archived genomes and transcriptomes. Although a variety of web tools are now available to extract information from OMICs data, their utility has been limited by the capacity of nonbioinformatician researchers to exploit the information. To address this problem, we have developed CANCERTOOL, a web-based interface that aims to overcome the major limitations of public transcriptomics dataset analysis for highly prevalent types of cancer (breast, prostate, lung, and colorectal). CANCERTOOL provides rapid and comprehensive visualization of gene expression data for the gene(s) of interest in well-annotated cancer datasets. This visualization is accompanied by generation of reports customized to the interest of the researcher (e.g., editable figures, detailed statistical analyses, and access to raw data for reanalysis). It also carries out gene-to-gene correlations in multiple datasets at the same time or using preset patient groups. Finally, this new tool solves the time-consuming task of performing functional enrichment analysis with gene sets of interest using up to 11 different databases at the same time. Collectively, CANCERTOOL represents a simple and freely accessible interface to interrogate well-annotated datasets and obtain publishable representations that can contribute to refinement and guidance of cancer-related investigations at all levels of hypotheses and design.

Significance: In order to facilitate access of research groups without bioinformatics support to public transcriptomics data, we have developed a free online tool with an easy-to-use interface that allows researchers to obtain quality information in a readily publishable format. Cancer Res; 78(21); 6320–8. ©2018 AACR.
Data from Plk1-Mediated Phosphorylation of TSC1 Enhances the Efficacy of Rapamycin
Authors: Li Zhiguo , Kong Yifan , Song Longzhen , Luo Qian , Liu Jinghui , Shao Chen , Hou Xianzeng , Liu Xiaoqi
Published: March 2023

Abstract
The AKT/TSC/mTOR axis is an important pathway controlling cell growth, survival, and proliferation in response to extracellular cues. Recently, it was reported that AKT activity fluctuates across the cell cycle. However, it remains unclear whether downstream targets of AKT are also regulated by the cell cycle. Here, we report that mTORC1 activity inversely correlates with AKT activity during the cell cycle. Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1/TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation. Tumors derived from cancer cells expressing the TSC1-S467E/S578E mutant exhibited greater sensitivity to rapamycin than those expressing WT TSC1. Collectively, our data support a model in which Plk1, instead of AKT, regulates the TSC/mTORC1 pathway during mitosis, eventually regulating the efficacy of rapamycin.

Significance: This seminal report shows that activation of mTORC1 can be independent of AKT during mitosis. Cancer Res; 78(11); 2864–75. ©2018 AACR.
Data from Silencing of Long Noncoding RNA MIR22HG Triggers Cell Survival/Death Signaling via Oncogenes YBX1, MET, and p21 in Lung Cancer
Authors: Su Wenmei , Feng Shumei , Chen Xiuyuan , Yang Xia , Mao Rui , Guo Chunfang , Wang Zhuwen , Thomas Dafydd G. , Lin Jules , Reddy Rishindra M. , Orringer Mark B. , Chang Andrew C. , Yang Zhixiong , Beer David G. , Chen Guoan
Published: March 2023

Abstract
The long noncoding RNA (lncRNA) MIR22HG has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from RNA-Seq data and report that MIR22HG plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that MIR22HG was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival. MIR22HG bound and stabilized the YBX1 protein. Silencing of MIR22HG triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this MIR22HG network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers. MIR22HG played a tumor-suppressive role as indicated by inhibition of multiple cell cycle–related genes in human primary lung tumors. These data show that MIR22HG has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.

Significance: The lncRNA MIR22HG functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer. Cancer Res; 78(12); 3207–19. ©2018 AACR.
Data from CBP Modulates Sensitivity to Dasatinib in Pre-BCR+ Acute Lymphoblastic Leukemia
Authors: Duque-Afonso Jesús , Lin Chiou-Hong , Han Kyuho , Morgens David W. , Jeng Edwin E. , Weng Ziming , Jeong Johan , Wong Stephen Hon Kit , Zhu Li , Wei Michael C. , Chae Hee-Don , Schrappe Martin , Cario Gunnar , Duyster Justus , Xiao Xiangshu , Sakamoto Kathleen M. , Bassik Michael C. , Cleary Michael L.
Published: March 2023

Abstract
Dasatinib is a multi-tyrosine kinase inhibitor approved for treatment of Ph+ acute lymphoblastic leukemia (ALL), but its efficacy is limited by resistance. Recent preclinical studies suggest that dasatinib may be a candidate therapy in additional ALL subtypes including pre-BCR+ ALL. Here we utilized shRNA library screening and global transcriptomic analysis to identify several novel genes and pathways that may enhance dasatinib efficacy or mitigate potential resistance in human pre-BCR+ ALL. Depletion of the transcriptional coactivator CBP increased dasatinib sensitivity by downregulating transcription of the pre-BCR signaling pathway previously associated with dasatinib sensitivity. Acquired resistance was due, in part, to upregulation of alternative pathways including WNT through a mechanism, suggesting transcriptional plasticity. Small molecules that disrupt CBP interactions with the CREB KID domain or β-catenin showed promising preclinical efficacy in combination with dasatinib. These findings highlight novel modulators of sensitivity to targeted therapies in human pre-BCR+ ALL, which can be reversed by small-molecule inhibitors. They also identify promising therapeutic approaches to ameliorate dasatinib sensitivity and prevent resistance in ALL.

Significance: These findings reveal mechanisms that modulate sensitivity to dasatinib and suggest therapeutic strategies to improve the outcome of patients with acute lymphoblastic leukemia.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/22/6497/F1.large.jpg. Cancer Res; 78(22); 6497–508. ©2018 AACR.
Data from Mcl-1 Phosphorylation without Degradation Mediates Sensitivity to HDAC Inhibitors by Liberating BH3-Only Proteins
Authors: Tong Jingshan , Zheng Xingnan , Tan Xiao , Fletcher Rochelle , Nikolovska-Coleska Zaneta , Yu Jian , Zhang Lin
Published: March 2023

Abstract
Mcl-1, a prosurvival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anticancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. In this study, we show in colon cancer cells that histone deacetylase inhibitors (HDACi) induce GSK3β-dependent Mcl-1 phosphorylation, but not degradation or downregulation. The in vitro and in vivo anticancer effects of HDACi were dependent on Mcl-1 phosphorylation and were blocked by genetic knock-in of a Mcl-1 phosphorylation site mutant. Phosphorylation-dead Mcl-1 maintained cell survival by binding and sequestering BH3-only Bcl-2 family proteins PUMA, Bim, and Noxa, which were upregulated and necessary for apoptosis induction by HDACi. Resistance to HDACi mediated by phosphorylation-dead Mcl-1 was reversed by small-molecule Mcl-1 inhibitors that liberated BH3-only proteins. These results demonstrate a critical role of Mcl-1 phosphorylation in mediating HDACi sensitivity through a novel and degradation-independent mechanism. These results provide new mechanistic insights on how Mcl-1 maintains cancer cell survival and suggest that Mcl-1–targeting agents are broadly useful for overcoming therapeutic resistance in cancer cells.

Significance: These findings present a novel degradation–independent function of Mcl-1 phosphorylation in anticancer therapy that could be useful for developing new Mcl-1–targeting agents to overcome therapeutic resistance. Cancer Res; 78(16); 4704–15. ©2018 AACR.
Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes
Authors: Wang Sophia S. , Carrington Mary , Berndt Sonja I. , Slager Susan L. , Bracci Paige M. , Voutsinas Jenna , Cerhan James R. , Smedby Karin E. , Hjalgrim Henrik , Vijai Joseph , Morton Lindsay M. , Vermeulen Roel , Paltiel Ora , Vajdic Claire M. , Linet Martha S. , Nieters Alexandra , de Sanjose Silvia , Cozen Wendy , Brown Elizabeth E. , Turner Jennifer , Spinelli John J. , Zheng Tongzhang , Birmann Brenda M. , Flowers Christopher R. , Becker Nikolaus , Holly Elizabeth A. , Kane Eleanor , Weisenburger Dennis , Maynadie Marc , Cocco Pierluigi , Albanes Demetrius , Weinstein Stephanie J. , Teras Lauren R. , Diver W. Ryan , Lax Stephanie J. , Travis Ruth C. , Kaaks Rudolph , Riboli Elio , Benavente Yolanda , Brennan Paul , McKay James , Delfau-Larue Marie-Hélène , Link Brian K. , Magnani Corrado , Ennas Maria Grazia , Latte Giancarlo , Feldman Andrew L. , Doo Nicole Wong , Giles Graham G. , Southey Melissa C. , Milne Roger L. , Offit Kenneth , Musinsky Jacob , Arslan Alan A. , Purdue Mark P. , Adami Hans-Olov , Melbye Mads , Glimelius Bengt , Conde Lucia , Camp Nicola J. , Glenn Martha , Curtin Karen , Clavel Jacqueline , Monnereau Alain , Cox David G. , Ghesquières Hervé , Salles Gilles , Bofetta Paulo , Foretova Lenka , Staines Anthony , Davis Scott , Severson Richard K. , Lan Qing , Brooks-Wilson Angela , Smith Martyn T. , Roman Eve , Kricker Anne , Zhang Yawei , Kraft Peter , Chanock Stephen J. , Rothman Nathaniel , Hartge Patricia , Skibola Christine F.
Published: March 2023

Abstract
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.

Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.
Data from Mouse Homolog of the Human TP53 R337H Mutation Reveals Its Role in Tumorigenesis
Authors: Park Ji-Hoon , Li Jie , Starost Matthew F. , Liu Chengyu , Zhuang Jie , Chen Jichun , Achatz Maria I. , Kang Ju-Gyeong , Wang Ping-yuan , Savage Sharon A. , Hwang Paul M.
Published: March 2023

Abstract
Inheritance of germline mutations in the tumor suppressor gene TP53 causes Li-Fraumeni syndrome (LFS), a cancer predisposition disorder. The arginine to histidine substitution at amino acid position 337 of p53 (R337H) is a founder mutation highly prevalent in southern and southeastern Brazil and is considered an LFS mutation. Although this mutation is of significant clinical interest, its role in tumorigenesis using animal models has not been described. Here, we generate a knockin mouse model containing the homologous R337H mutation (mouse R334H). De novo tumorigenesis was not significantly increased in either heterozygous (p53334R/H) or homozygous (p53334H/H) p53 R334H knockin mice compared with wild-type mice. However, susceptibility to diethylnitrosamine (DEN)-induced liver carcinogenesis was increased in a mutant allele dose-dependent manner. In parallel, p53334H/H mice exposed to DEN exhibited increased DNA damage but decreased cell-cycle regulation in the liver. Oligomerization of p53, which is required for transactivation of target genes, was reduced in R334H liver, consistent with its decreased nuclear activity compared with wild-type. By modeling a TP53 mutation in mice that has relatively weak cancer penetrance, this study provides in vivo evidence that the human R337H mutation can compromise p53 activity and promote tumorigenesis.

Significance: A germline mutation in the oligomerization domain of p53 decreases its transactivation potential and renders mice susceptible to carcinogen-induced liver tumorigenesis. Cancer Res; 78(18); 5375–83. ©2018 AACR.
Data from Analysis of Over 140,000 European Descendants Identifies Genetically Predicted Blood Protein Biomarkers Associated with Prostate Cancer Risk
Authors: Wu Lang , Shu Xiang , Bao Jiandong , Guo Xingyi , Kote-Jarai Zsofia , Haiman Christopher A. , Eeles Rosalind A. , Zheng Wei
Published: March 2023

Abstract
Several blood protein biomarkers have been associated with prostate cancer risk. However, most studies assessed only a small number of biomarkers and/or included a small sample size. To identify novel protein biomarkers of prostate cancer risk, we studied 79,194 cases and 61,112 controls of European ancestry, included in the PRACTICAL/ELLIPSE consortia, using genetic instruments of protein quantitative trait loci for 1,478 plasma proteins. A total of 31 proteins were associated with prostate cancer risk including proteins encoded by GSTP1, whose methylation level was shown previously to be associated with prostate cancer risk, and MSMB, SPINT2, IGF2R, and CTSS, which were previously implicated as potential target genes of prostate cancer risk variants identified in genome-wide association studies. A total of 18 proteins inversely correlated and 13 positively correlated with prostate cancer risk. For 28 of the identified proteins, gene somatic changes of short indels, splice site, nonsense, or missense mutations were detected in patients with prostate cancer in The Cancer Genome Atlas. Pathway enrichment analysis showed that relevant genes were significantly enriched in cancer-related pathways. In conclusion, this study identifies 31 candidates of protein biomarkers for prostate cancer risk and provides new insights into the biology and genetics of prostate tumorigenesis.
Significance:
Integration of genomics and proteomics data identifies biomarkers associated with prostate cancer risk.
Data from Cholesterol Induces Epithelial-to-Mesenchymal Transition of Prostate Cancer Cells by Suppressing Degradation of EGFR through APMAP
Authors: Jiang Siyuan , Wang Xuetong , Song Dalong , Liu XiaoJun , Gu Yinmin , Xu Zhiyuan , Wang Xiaodong , Zhang Xiaolu , Ye Qinong , Tong Zhou , Yan BingXue , Yu Jie , Chen Yunzhao , Sun Minxuan , Wang Yang , Gao Shan
Published: March 2023

Abstract
Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells.
Significance:
This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT.
Data from ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis
Authors: Lu Yun-Xin , Ju Huai-Qiang , Liu Ze-Xian , Chen Dong-Liang , Wang Yun , Zhao Qi , Wu Qi-Nian , Zeng Zhao-lei , Qiu Hai-Bo , Hu Pei-Shan , Wang Zhi-Qiang , Zhang Dong-Sheng , Wang Feng , Xu Rui-Hua
Published: March 2023

Abstract
Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo. Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft–based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis.

Significance: These findings reveal the role of malic enzyme in growth and metastasis.

Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg. Cancer Res; 78(8); 1972–85. ©2018 AACR.
Data from Inhibition of ATM Increases Interferon Signaling and Sensitizes Pancreatic Cancer to Immune Checkpoint Blockade Therapy
Authors: Zhang Qiang , Green Michael D. , Lang Xueting , Lazarus Jenny , Parsels Joshua D. , Wei Shuang , Parsels Leslie A. , Shi Jiaqi , Ramnath Nithya , Wahl Daniel R. , Pasca di Magliano Marina , Frankel Timothy L. , Kryczek Ilona , Lei Yu L. , Lawrence Theodore S. , Zou Weiping , Morgan Meredith A.
Published: March 2023

Abstract
Combinatorial strategies are needed to overcome the resistance of pancreatic cancer to immune checkpoint blockade (ICB). DNA damage activates the innate immune response and improves ICB efficacy. Because ATM is an apical kinase in the radiation-induced DNA damage response, we investigated the effects of ATM inhibition and radiation on pancreatic tumor immunogenicity. ATM was inhibited through pharmacologic and genetic strategies in human and murine pancreatic cancer models both in vitro and in vivo. Tumor immunogenicity was evaluated after ATM inhibition alone and in combination with radiation by assessing TBK1 and Type I interferon (T1IFN) signaling as well as tumor growth following PD-L1/PD-1 checkpoint inhibition. Inhibition of ATM increased tumoral T1IFN expression in a cGAS/STING-independent, but TBK1- and SRC-dependent, manner. The combination of ATM inhibition with radiation further enhanced TBK1 activity, T1IFN production, and antigen presentation. Furthermore, ATM silencing increased PD-L1 expression and increased the sensitivity of pancreatic tumors to PD-L1–blocking antibody in association with increased tumoral CD8+ T cells and established immune memory. In patient pancreatic tumors, low ATM expression inversely correlated with PD-L1 expression. Taken together, these results demonstrate that the efficacy of ICB in pancreatic cancer is enhanced by ATM inhibition and further potentiated by radiation as a function of increased tumoral immunogenicity, underscoring the potential of ATM inhibition in combination with ICB and radiation as an efficacious treatment strategy for pancreatic cancer.
Significance:
This study demonstrates that ATM inhibition induces a T1IFN-mediated innate immune response in pancreatic cancer that is further enhanced by radiation and leads to increased sensitivity to anti–PD-L1 therapy.

See related commentary by Gutiontov and Weichselbaum, p. 3815
Data from The Cdk2–c-Myc–miR-571 Axis Regulates DNA Replication and Genomic Stability by Targeting Geminin
Authors: Zhang Yi , Li Zhuqing , Hao Qiang , Tan Wei , Sun Jing , Li Jing , Chen Chi-wei , Li Zongzhu , Meng Yunxiao , Zhou Yuan , Han Zhiyong , Pei Huadong , DePamphilis Melvin L. , Zhu Wenge
Published: March 2023

Abstract
DNA rereplication leads to genomic instability and has been implicated in the pathology of a variety of human cancers. Eukaryotic DNA replication is tightly controlled to ensure it occurs only once during each cell cycle. Geminin is a critical component of this control, it prevents DNA rereplication from occurring during S, G2, and early M phases by preventing MCM helicases from forming prereplication complexes. Geminin is targeted for degradation by the anaphase-promoting complex (APC/C) from anaphase through G1-phase, however, accumulating evidence indicates that Geminin is downregulated in late S-phase due to an unknown mechanism. Here, we used a high-throughput screen to identify miRNAs that can induce excess DNA replication and found that miR-571 could reduce the protein level of Geminin in late S-phase independent of the APC/C. Furthermore, miR-571 regulated efficient DNA replication and S-phase cell-cycle progression. Strikingly, c-Myc suppressed miR-571 expression by binding directly to the miR-571 promoter. At the beginning of S-phase, Cdk2 phosphorylated c-Myc at Serine 62, promoting its association with the miR-571 promoter region. Collectively, we identify miR-571 as the first miRNA that prevents aberrant DNA replication and the Cdk2–c-Myc–miR-571 axis as a new pathway for regulating DNA replication, cell cycle, and genomic stability in cancer cells.
Significance:
These findings identify a novel regulatory mechanism that is critical for maintaining genome integrity by regulating DNA replication and cell-cycle progression.
Data from DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing
Authors: Xing Songge , Li Zhaoyong , Ma Wenhao , He Xiaoping , Shen Shengqi , Wei Haoran , Li Shi-Ting , Shu Ying , Sun Linchong , Zhong Xiuying , Huangfu Yuhao , Su Lanhong , Feng Junru , Zhang Xiaozhang , Gao Ping , Jia Wei-Dong , Zhang Huafeng
Published: March 2023

Abstract
DIS3-like 3′-5′ exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing.
Significance:
These findings establish the role and mechanism of the 3′-5′ exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.
Data from Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging
Authors: Ray Kevin J. , Simard Manon A. , Larkin James R. , Coates James , Kinchesh Paul , Smart Sean C. , Higgins Geoff S. , Chappell Michael A. , Sibson Nicola R.
Published: March 2023

Abstract
Abnormal pH is a common feature of malignant tumors and has been associated clinically with suboptimal outcomes. Amide proton transfer magnetic resonance imaging (APT MRI) holds promise as a means to noninvasively measure tumor pH, yet multiple factors collectively make quantification of tumor pH from APT MRI data challenging. The purpose of this study was to improve our understanding of the biophysical sources of altered APT MRI signals in tumors. Combining in vivo APT MRI measurements with ex vivo histological measurements of protein concentration in a rat model of brain metastasis, we determined that the proportion of APT MRI signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumor pH. In a mouse model of hypopharyngeal squamous cell carcinoma (FaDu), APT MRI showed that a reduction in tumor hypoxia was associated with a shift in tumor pH. The results of this study extend our understanding of APT MRI data and may enable the use of APT MRI to infer the pH of individual patients' tumors as either a biomarker for therapy stratification or as a measure of therapeutic response in clinical settings.
Significance:
These findings advance our understanding of amide proton transfer magnetic resonance imaging (APT MRI) of tumors and may improve the interpretation of APT MRI in clinical settings.
Data from Quantification and Localization of Protein–RNA Interactions in Patient-Derived Archival Tumor Tissue
Authors: Blanchard Emmeline L. , Argyropoulou Danae , Zurla Chiara , Bhosle Sushma M. , Vanover Daryll , Santangelo Philip J.
Published: March 2023

Abstract
Abnormal post-transcriptional regulation induced by alterations of mRNA–protein interactions is critical during tumorigenesis and cancer progression and is a hallmark of cancer cells. A more thorough understanding is needed to develop treatments and foresee outcomes. Cellular and mouse tumor models are insufficient for vigorous investigation as they lack consistency and translatability to humans. Moreover, to date, studies in human tumor tissue are predominately limited to expression analysis of proteins and mRNA, which do not necessarily provide information about the frequency of mRNA–protein interactions. Here, we demonstrate novel optimization of a method that is based on FISH and proximity ligation techniques to quantify mRNA interactions with RNA-binding proteins relevant for tumorigenesis and cancer progression in archival patient-derived tumor tissue. This method was validated for multiple mRNA-protein pairs in several cellular models and in multiple types of archival human tumor samples. Furthermore, this approach allowed high-throughput analysis of mRNA–protein interactions across a wide range of tumor types and stages through tumor microarrays. This method is quantitative, specific, and sensitive for detecting interactions and their localization at both the individual cell and whole-tissue scales with single interaction sensitivity. This work presents an important tool in investigating post-transcriptional regulation in cancer on a high-throughput scale, with great potential for translatability into any applications where mRNA–protein interactions are of interest.
Significance:
This work presents an approach to sensitively, specifically, and quantitatively detect and localize native mRNA and protein interactions for analysis of abnormal post-transcriptional regulation in patient-derived archival tumor samples.
Data from Hypermethylation of SHISA3 Promotes Nasopharyngeal Carcinoma Metastasis by Reducing SGSM1 Stability
Authors: Zhang Jian , Li Ying-Qin , Guo Rui , Wang Ya-Qin , Zhang Pan-Pan , Tang Xin-Ran , Wen Xin , Hong Xiao-Hong , Lei Yuan , He Qing-Mei , Yang Xiao-Jing , Sun Ying , Ma Jun , Liu Na
Published: March 2023

Abstract
Altered DNA methylation is a key feature of cancer, and aberrant methylation is important in nasopharyngeal carcinoma (NPC) development. However, the methylation mechanisms underlying metastasis of NPC remain unclear. Analyzing data from public databases and conducting our own experiments, we report here that promoter hypermethylation of SHISA3 is common and contributes to the downregulation of this gene in many types of tumors, including NPC. SHISA3 suppressed NPC cell invasion and metastasis in vitro and in vivo by impeding the E3 ubiquitin ligase tripartite motif containing 21 (TRIM21)–mediated ubiquitination and degradation small G protein signaling modulator 1 (SGSM1) and by inhibiting the MAPK pathway activation. Silencing SGSM1 abrogated the inhibitory effect of SHISA3 on NPC cell migration and invasion. This newly identified SHISA3–TRIM21–SGSM1 axis could be a novel therapeutic target in NPC.
Significance:
These findings highlight the mechanism by which a newly identified tumor suppressor SHISA3 suppresses invasion and metastasis of nasopharyngeal carcinoma.
Data from N6-Methyladenosine Modulates Nonsense-Mediated mRNA Decay in Human Glioblastoma
Authors: Li Fuxi , Yi Yang , Miao Yanyan , Long Wenyong , Long Teng , Chen Siyun , Cheng Weisheng , Zou Changye , Zheng Yueyuan , Wu Xingui , Ding Junjun , Zhu Kaiyu , Chen Delin , Xu Qiongcong , Wang Jinkai , Liu Qing , Zhi Feng , Ren Jian , Cao Qi , Zhao Wei
Published: March 2023

Abstract
The N6-methyladenosine (m6A) modification influences various mRNA metabolic events and tumorigenesis, however, its functions in nonsense-mediated mRNA decay (NMD) and whether NMD detects induced carcinogenesis pathways remain undefined. Here, we showed that the m6A methyltransferase METTL3 sustained its oncogenic role by modulating NMD of splicing factors and alternative splicing isoform switches in glioblastoma (GBM). Methylated RNA immunoprecipitation-seq (MeRIP-seq) analyses showed that m6A modification peaks were enriched at metabolic pathway–related transcripts in glioma stem cells (GSC) compared with neural progenitor cells. In addition, the clinical aggressiveness of malignant gliomas was associated with elevated expression of METTL3. Furthermore, silencing METTL3 or overexpressing dominant-negative mutant METTL3 suppressed the growth and self-renewal of GSCs. Integrated transcriptome and MeRIP-seq analyses revealed that downregulating the expression of METTL3 decreased m6A modification levels of serine- and arginine-rich splicing factors (SRSF), which led to YTHDC1-dependent NMD of SRSF transcripts and decreased SRSF protein expression. Reduced expression of SRSFs led to larger changes in alternative splicing isoform switches. Importantly, the phenotypes mediated by METTL3 deficiency could be rescued by downregulating BCL-X or NCOR2 isoforms. Overall, these results establish a novel function of m6A in modulating NMD and uncover the mechanism by which METTL3 promotes GBM tumor growth and progression.
Significance:
These findings establish the oncogenic role of m6A writer METTL3 in glioblastoma stem cells.
Data from Assessment of Tumor Redox Status through (S)-4-(3-[18F]fluoropropyl)-L-Glutamic Acid PET Imaging of System xc− Activity
Authors: McCormick Patrick N. , Greenwood Hannah E. , Glaser Matthias , Maddocks Oliver D.K. , Gendron Thibault , Sander Kerstin , Gowrishankar Gayatri , Hoehne Aileen , Zhang Tong , Shuhendler Adam J. , Lewis David Y. , Berndt Mathias , Koglin Norman , Lythgoe Mark F. , Gambhir Sanjiv S. , Årstad Erik , Witney Timothy H.
Published: March 2023

Abstract
The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc− maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc−-specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.
Significance:
[18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.

See related commentary by Lee et al., p. 701
Data from miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells
Authors: Mukohyama Junko , Isobe Taichi , Hu Qingjiang , Hayashi Takanori , Watanabe Takashi , Maeda Masao , Yanagi Hisano , Qian Xin , Yamashita Kimihiro , Minami Hironobu , Mimori Koshi , Sahoo Debashis , Kakeji Yoshihiro , Suzuki Akira , Dalerba Piero , Shimono Yohei
Published: March 2023

Abstract
miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the “cancer stem cell” (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM+/CD44+ cancer cells (enriched in CSCs) and EpCAM+/CD44neg cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM+/CD44+ cancer cells. High levels of miR-221 expression were associated with Lgr5+ cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) in vitro. Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity in vitro and substantially reduced the tumorigenic capacity of CSC populations from PDX lines in vivo. Finally, the most abundant splicing isoform of the human Quaking (QKI) gene, QKI-5, was identified as a functional target of miR-221; overexpression of miR-221–reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity in vitro and tumorigenic capacity of colorectal carcinoma PDX cells in vivo. Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer.
Significance:
These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer.
Data from Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion
Authors: Liu Yi , Deguchi Yasunori , Tian Rui , Wei Daoyan , Wu Ling , Chen Weidong , Xu Weiguo , Xu Min , Liu Fuyao , Gao Shen , Jaoude Jonathan C. , Chrieki Sarah P. , Moussalli Micheline J. , Gagea Mihai , Morris Jeffrey , Broaddus Russell R. , Zuo Xiangsheng , Shureiqi Imad
Published: March 2023

Abstract
APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer–invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness.
Significance:
These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis.
Data from MEK Inhibition Modulates Cytokine Response to Mediate Therapeutic Efficacy in Lung Cancer
Authors: Xie Mengyu , Zheng Hong , Madan-Lala Ranjna , Dai Wenjie , Gimbrone Nicholas T. , Chen Zhihua , Kinose Fumi , Blackstone Sarah A. , Smalley Keiran S.M. , Cress W. Douglas , Haura Eric B. , Rix Uwe , Beg Amer A.
Published: March 2023

Abstract
Activating mutations in BRAF, a key mediator of RAS signaling, are present in approximately 50% of melanoma patients. Pharmacologic inhibition of BRAF or the downstream MAP kinase MEK is highly effective in treating BRAF-mutant melanoma. In contrast, RAS pathway inhibitors have been less effective in treating epithelial malignancies, such as lung cancer. Here, we show that treatment of melanoma patients with BRAF and MEK inhibitors (MEKi) activated tumor NF-κB activity. MEKi potentiated the response to TNFα, a potent activator of NF-κB. In both melanoma and lung cancer cells, MEKi increased cell-surface expression of TNFα receptor 1 (TNFR1), which enhanced NF-κB activation and augmented expression of genes regulated by TNFα and IFNγ. Screening of 289 targeted agents for the ability to increase TNFα and IFNγ target gene expression demonstrated that this was a general activity of inhibitors of MEK and ERK kinases. Treatment with MEKi led to acquisition of a novel vulnerability to TNFα and IFNγ-induced apoptosis in lung cancer cells that were refractory to MEKi killing and augmented cell-cycle arrest. Abolishing the expression of TNFR1 on lung cancer cells impaired the antitumor efficacy of MEKi, whereas the administration of TNFα and IFNγ in MEKi-treated mice enhanced the antitumor response. Furthermore, immunotherapeutics known to induce expression of these cytokines synergized with MEKi in eradicating tumors. These findings define a novel cytokine response modulatory function of MEKi that can be therapeutically exploited.
Significance:
Lung cancer cells are rendered sensitive to MEK inhibitors by TNFα and IFNγ, providing a strong mechanistic rationale for combining immunotherapeutics, such as checkpoint blockers, with MEK inhibitor therapy for lung cancer.

See related commentary by Havel, p. 5699