bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism
Authors: Zhang Sheng , Chatterjee Treena , Godoy Carla , Wu Ling , Liu Qingyun J. , Carmon Kendra S.
Published: March 2024

Abstract
Drug resistance continues to be a major obstacle of effective therapy for colorectal cancer, leading to tumor relapse or treatment failure. Cancer stem cells (CSC) or tumor-initiating cells are a subpopulation of tumor cells which retain the capacity for self-renewal and are suggested to be implicated in drug resistance. LGR5 is highly expressed in colorectal cancer and marks CSCs that drive tumor growth and metastasis. LGR5(+) CSCs cells were shown to interconvert with more drug-resistant LGR5(−) cancer cells, and treatment with LGR5-targeted antibody–drug conjugates (ADC) eliminated LGR5(+) tumors, yet a fraction of LGR5(−) tumors eventually recurred. Therefore, it is important to identify mechanisms associated with CSC plasticity and drug resistance in order to develop curative therapies. Here, we show that loss of LGR5 in colon cancer cells enhanced resistance to irinotecan and 5-fluorouracil and increased expression of adhesion G-protein–coupled receptor, GPR56. GPR56 expression was significantly higher in primary colon tumors versus matched normal tissues and correlated with poor survival outcome. GPR56 enhanced drug resistance through upregulation of MDR1 levels via a RhoA-mediated signaling mechanism. Loss of GPR56 led to suppression of tumor growth and increased sensitivity of cancer cells to chemotherapy and monomethyl auristatin E–linked anti–LGR5 ADCs, by reducing MDR1 levels. These findings suggest that upregulation of GPR56 may be a mechanism associated with CSC plasticity by which LGR5(−) cancer cells acquire a more drug-resistant phenotype.
Implications:
Our findings suggest that targeting GPR56 may provide a new strategy for the treatment of colorectal cancer and combatting drug resistance.
Data from Molecular Effects of Stromal-Selective Targeting by uPAR-Retargeted Oncolytic Virus in Breast Cancer
Authors: Jing Yuqi , Chavez Valery , Ban Yuguang , Acquavella Nicolas , El-Ashry Doraya , Pronin Alexey , Chen Xi , Merchan Jaime R.
Published: March 2024

Abstract
The tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MV) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal-selective targeting by uPAR-retargeted MVs were investigated. In vitro infection, virus-induced GFP expression, and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer-associated fibroblasts in a species-specific manner. In a murine fibroblast/human breast cancer 3D coculture model, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. Systemic administration of murine-specific MV-m-uPA in mice bearing human MDA-MB-231 xenografts was associated with a significant delay in tumor progression and improved survival compared with controls. Experiments comparing tumor (MV-h-uPA) versus stromal (MV-m-uPA) versus combined virus targeting showed that tumor and stromal targeting was associated with improved tumor control over the other groups. Correlative studies confirmed in vivo viral targeting of tumor stroma by MV-m-uPA, increased apoptosis, and virus-induced differential regulation of murine stromal genes associated with inflammatory, angiogenesis, and survival pathways, as well as indirect regulation of human cancer pathways, indicating viral-induced modulation of tumor–stroma interactions. These data demonstrate the feasibility of stromal-selective targeting by an oncolytic MV, virus-induced modulation of tumor–stroma pathways, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as antistromal agents.

Implications: The current report demonstrates for the first time the biological, in vitro, and in vivo antitumor and molecular effects of stromal selective targeting by an oncolytic virus. Mol Cancer Res; 15(10); 1410–20. ©2017 AACR.
Data from Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes
Authors: Zhang Li , MacIsaac Kenzie D. , Zhou Ting , Huang Pei-Yu , Xin Chunlin , Dobson Jason R. , Yu Kun , Chiang Derek Y. , Fan Yue , Pelletier Marc , Wang Yan , Jaeger Savina , Krishnamurthy Radhakrishnan Viveksagar , JeBailey Lellean , Skewes-Cox Peter , Zhang Jing , Fang Wenfeng , Huang Yan , Zhao Hongyun , Zhao Yuanyuan , Li En , Peng Bin , Huang Alan , Dranoff Glenn , Hammerman Peter S. , Engelman Jeffrey , Bitter Hans , Zeng Yi-Xin , Yao Yao
Published: March 2024

Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 (CDKN2A) locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens. This genomic analysis was generally concordant with previous studies; however, three subtypes of NPC were identified by differences in immune cell gene expression, prognosis, tumor cell morphology, and genetic characteristics. A gene expression signature of proliferation was poorly prognostic and associated with either higher mutation load or specific EBV gene expression patterns in a subtype-specific manner. Finally, higher levels of stromal tumor-infiltrating lymphocytes associated with good prognosis and lower expression of a WNT and TGFβ pathway activation signature.

Implications: This study represents the first integrated analysis of mutation, copy number, and gene expression data in NPC and suggests how tumor genetics and EBV infection influence the tumor microenvironment in this disease. These insights should be considered for guiding immunotherapy treatment strategies in this disease. Mol Cancer Res; 15(12); 1722–32. ©2017 AACR.
Data from Targeting TAZ-Driven Human Breast Cancer by Inhibiting a SKP2-p27 Signaling Axis
Authors: Shen He , Yang Nuo , Truskinovsky Alexander , Chen Yanmin , Mussell Ashley L. , Nowak Norma J. , Kobzik Lester , Frangou Costa , Zhang Jianmin
Published: March 2024

Abstract
Deregulated expression of the transcriptional coactivator with PDZ-binding motif (WWTR1/TAZ) is a common feature of basal-like breast cancer (BLBC). Yet, how oncogenic TAZ regulates cell-cycle progression and proliferation in breast cancer remains poorly understood, and whether TAZ is required for tumor maintenance has not been established. Here, using an integrative oncogenomic approach, TAZ-dependent cellular programs essential for tumor growth and progression were identified. Significantly, TAZ-driven tumor cells required sustained TAZ expression, given that its withdrawal impaired both genesis and maintenance of solid tumors. Moreover, temporal inhibition of TAZ diminished the metastatic burden in established macroscopic pulmonary metastases. Mechanistic investigation revealed that TAZ controls distinct gene profiles that determine cancer cell fate through cell-cycle networks, including a specific, causal role for S-phase kinase–associated protein 2 (SKP2) in mediating the neoplastic state. Together, this study elucidates the molecular events that underpin the role of TAZ in BLBC and link to SKP2, a convergent communication node for multiple cancer signaling pathways, as a key downstream effector molecule.
Implications:
Understanding the molecular role of TAZ and its link to SKP2, a signaling convergent point and key regulator in BLBC, represents an important step toward the identification of novel therapeutic targets for TAZ-dependent breast cancer.
Data from Atrophied Thymus, a Tumor Reservoir for Harboring Melanoma Cells
Authors: Sizova Olga , Kuriatnikov Denis , Liu Ying , Su Dong-Ming
Published: March 2024

Abstract
Tumor metastatic relapse is the primary cause for cancer-associated mortality. Metastatic relapse is believed to arise from quantities of tumor cells that are below detectable thresholds, which are able to resist radio/chemotherapy by obtaining a dormant state and hiding in certain organs, i.e., tumor reservoirs. The thymus, a central T-cell immune organ, has been suggested to be a premetastatic tumor reservoir for B-lymphoma cells. However, it remains unknown whether the thymus is able to harbor nonlymphoid solid tumor cells, and whether chemotherapy can thoroughly eliminate cancer cells in the thymus. If chemotherapy is not able to eliminate these cells in the thymus, then what processes allow for this? Melanoma cell–inoculated and genotoxic doxorubicin-treated mouse model systems were used to determine that the thymus, particularly the atrophied thymus, was able to harbor blood stream–circulating melanoma cells. In addition, a chemotherapy-induced DNA-damage response triggered p53 activation in nonmalignant thymic cells, which in turn resulted in thymocyte death and thymic epithelial cell senescence to develop an inflammatory thymic microenvironment. This inflammatory condition induced thymic-harbored minimal tumor cells to acquire a chemoresistant state.

Implications: Here, the thymus serves as a premetastatic reservoir for nonlymphoid solid tumor cells during chemotherapy, which could be a novel target of minimal residual disease in antitumor therapy, thus preventing tumor metastatic relapse. Mol Cancer Res; 16(11); 1652–64. ©2018 AACR.
Data from Pten Regulates Aurora-A and Cooperates with Fbxw7 in Modulating Radiation-Induced Tumor Development
Authors: Kwon Yong-Won , Kim Il-Jin , Wu Di , Lu Jing , Stock William A. , Liu Yueyong , Huang Yurong , Kang Hio Chung , DelRosario Reyno , Jen Kuang-Yu , Perez-Losada Jesus , Wei Guangwei , Balmain Allan , Mao Jian-Hua
Published: March 2024

Abstract
The Aurora-A kinase gene is frequently amplified and/or overexpressed in a variety of human cancers, leading to major efforts to develop therapeutic agents targeting this pathway. Here, we show that Aurora-A is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7 in a process that is regulated by GSK3β. Using a series of truncated Aurora-A proteins and site-directed mutagenesis, we identified distinct FBXW7 and GSK3β-binding sites in Aurora-A. Mutation of critical residues in either site substantially disrupts degradation of Aurora-A. Furthermore, we show that loss of Pten results in the stabilization of Aurora-A by attenuating FBXW7-dependent degradation of Aurora-A through the AKT/GSK3β pathway. Moreover, radiation-induced tumor latency is significantly shortened in Fbxw7+/−Pten+/− mice as compared with either Fbxw7+/− or Pten+/− mice, indicating that Fbxw7 and Pten appear to cooperate in suppressing tumorigenesis. Our results establish a novel posttranslational regulatory network in which the Pten and Fbxw7 pathways appear to converge on the regulation of Aurora-A level. Mol Cancer Res; 10(6); 834–44. ©2012 AACR.
Data from High-Density Lipoprotein Induces Proliferation and Migration of Human Prostate Androgen–Independent Cancer Cells by an ABCA1-Dependent Mechanism
Authors: Sekine Yoshitaka , Demosky Steve J. , Stonik John A. , Furuya Yosuke , Koike Hidekazu , Suzuki Kazuhiro , Remaley Alan T.
Published: March 2024

Abstract
Androgen deprivation therapy for prostate cancer leads to a significant increase of high-density lipoprotein (HDL), which is generally viewed as beneficial, particularly for cardiovascular disease, but the effect of HDL on prostate cancer is unknown. In this study, we investigated the effect of HDL on prostate cancer cell proliferation, migration, intracellular cholesterol levels, and the role of cholesterol transporters, namely ABCA1, ABCG1, and SR-BI in these processes. HDL induced cell proliferation and migration of the androgen-independent PC-3 and DU145 cells by a mechanism involving extracellular signal-regulated kinase (ERK) 1/2 and Akt, but had no effect on the androgen-dependent LNCaP cell, which did not express ABCA1 unlike the other cell lines. Treatment with HDL did not significantly alter the cholesterol content of the cell lines. Knockdown of ABCA1 but not ABCG1 or SR-BI by small interfering RNA (siRNA) inhibited HDL-induced cell proliferation, migration, and ERK1/2 and Akt signal transduction in PC-3 cells. Moreover, after treatment of LNCaP cells with charcoal-stripped fetal bovine serum, ABCA1 was induced ∼10-fold, enabling HDL to induce ERK1/2 activation, whereas small interfering RNA knockdown of ABCA1 inhibited HDL-induced ERK1/2 activation. Simvastatin, which inhibited ABCA1 expression in PC-3 and DU145 cells, attenuated HDL-induced PC-3 and DU145 cell proliferation, migration, and ERK1/2 and Akt phosphorylation. In human prostate biopsy samples, ABCA1 mRNA expression was ∼2-fold higher in the androgen deprivation therapy group than in subjects with benign prostatic hyperplasia or pretreatment prostate cancer groups. In summary, these results suggest that HDL by an ABCA1-dependent mechanism can mediate signal transduction, leading to increased proliferation and migration of prostate cancer cells. Mol Cancer Res; 8(9); 1284–94. ©2010 AACR.
Data from Enhanced Susceptibility to Chemical Induction of Ovarian Tumors in Mice with a Germ Line p53 Mutation
Authors: Wang Yian , Zhang Zhongqiu , Lu Yan , Yao Ruisheng , Jia Dongmei , Wen Weidong , LaRegina Marie , Crist Keith , Lubet Ronald , You Ming
Published: March 2024

Abstract
Mice with a germ line p53 mutation (p53Ala135Val/wt) display increased susceptibility to lung, skin, and colon carcinogenesis. Here, we show that p53Ala135Val/wt mice developed ovarian tumors significantly more rapidly than their wild-type littermates after 7,12-dimethylbenz(a)anthracene (DMBA) treatment. Approximately 50% of the ovarian tumors in p53wt/wt mice and 23% in p53Ala135Val/wt mice are adenocarcinomas and the remaining tumors were adenocarcinoma mixed with sarcoma or ovarian sarcomas. All of the p53Ala135Val/wt mice had died of ovarian tumors 25 weeks after the initial DMBA treatment, whereas >50% of p53wt/wt mice were still alive. These mice not only have a shortened tumor latency but also closely resemble a subset of human ovarian tumors containing the p53 mutation. Microarray and GenMAPP analyses revealed that the mutant p53 (Ala135Val) affected several cellular processes, including the cell cycle, apoptosis, and Wnt pathways. These findings indicate that a germ line p53 mutation significantly enhanced DMBA-induced ovarian tumor development and progression. (Mol Cancer Res 2008;6(1):99–109)
Data from Hu/Mu ProtIn Oligonucleotide Microarray: Dual-Species Array for Profiling Protease and Protease Inhibitor Gene Expression in Tumors and Their Microenvironment
Authors: Schwartz Donald R. , Moin Kamiar , Yao Bin , Matrisian Lynn M. , Coussens Lisa M. , Bugge Thomas H. , Fingleton Barbara , Acuff Heath B. , Sinnamon Mark , Nassar Hind , Platts Adrian E. , Krawetz Stephen A. , Linebaugh Bruce E. , Sloane Bonnie F.
Published: March 2024

Abstract
Proteolysis is a critical regulatory mechanism for a wide variety of physiologic and pathologic processes. To assist in the identification of proteases, their endogenous inhibitors, and proteins that interact with proteases or proteolytic pathways in biological tissues, a dual-species oligonucleotide microarray has been developed in conjunction with Affymetrix. The Hu/Mu ProtIn microarray contains 516 and 456 probe sets that survey human and mouse genes of interest (proteases, protease inhibitors, or interactors), respectively. To investigate the performance of the array, gene expression profiles were analyzed in pure mouse and human samples (reference RNA; normal and tumor cell lines/tissues) and orthotopically implanted xenografts of human A549 lung and MDA-MB-231 breast carcinomas. Relative gene expression and “present-call” P values were determined for each probe set using dChip and MAS5 software, respectively. Despite the high level of sequence identity of mouse and human protease/inhibitor orthologues and the theoretical potential for cross-hybridization of some of the probes, >95% of the “present calls” (P < 0.01) resulted from same-species hybridizations (e.g., human transcripts to human probe sets). To further assess the performance of the microarray, differential gene expression and false discovery rate analyses were carried out on human or mouse sample groups, and data processing methods to optimize performance of the mouse and human probe sets were identified. The Hu/Mu ProtIn microarray is a valuable discovery tool for the identification of components of human and murine proteolytic pathways in health and disease and has particular utility in the determination of cellular origins of proteases and protease inhibitors in xenograft models of human cancer. (Mol Cancer Res 2007;5(5):443–54)
Data from EMT-Derived Alterations in Glutamine Metabolism Sensitize Mesenchymal Breast Cells to mTOR Inhibition
Authors: Karvelsson Sigurdur Trausti , Sigurdsson Arnar , Seip Kotryna , Grinde Maria Tunset , Wang Qiong , Johannsson Freyr , Mælandsmo Gunhild Mari , Moestue Siver Andreas , Rolfsson Ottar , Halldorsson Skarphedinn
Published: March 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process with strong implications in cancer progression. Understanding the metabolic alterations associated with EMT may open new avenues of treatment and prevention. Here we used 13C carbon analogs of glucose and glutamine to examine differences in their utilization within central carbon and lipid metabolism following EMT in breast epithelial cell lines. We found that there are inherent differences in metabolic profiles before and after EMT. We observed EMT-dependent re-routing of the TCA-cycle, characterized by increased mitochondrial IDH2-mediated reductive carboxylation of glutamine to lipid biosynthesis with a concomitant lowering of glycolytic rates and glutamine-dependent glutathione (GSH) generation. Using weighted correlation network analysis, we identified cancer drugs whose efficacy against the NCI-60 Human Tumor Cell Line panel is significantly associated with GSH abundance and confirmed these in vitro. We report that EMT-linked alterations in GSH synthesis modulate the sensitivity of breast epithelial cells to mTOR inhibitors.
Implications:
EMT in breast cells causes an increased demand for glutamine for fatty acid biosynthesis, altering its contribution to glutathione biosynthesis, which sensitizes the cells to mTOR inhibitors.
Data from An IFNγ/STAT1/JMJD3 Axis Induces ZEB1 Expression and Promotes Aggressiveness in Lung Adenocarcinoma
Authors: Yang Jianjian , Wang Xue , Huang Bing , Liu Rong , Xiong Hui , Ye Fan , Zeng Chenxi , Fu Xiangning , Li Lequn
Published: March 2024

Abstract
Active IFNγ signaling is a common feature of tumors responding to PD-1 checkpoint blockade. IFNγ exhibits both anti- and protumor activities. Here, we show that the treatment of lung adenocarcinoma cells with IFNγ led to a rapid increase of ZEB1 expression and a significant change in epithelial-to-mesenchymal transition (EMT)-associated gene expression pattern. Moreover, functional analyses show that IFNγ promoted cell migration in vitro and metastasis in vivo. We demonstrate that ZEB1 is required for IFNγ-promoted EMT, cell migration, and metastasis, as RNAi-mediated knockdown of ZEB1 abrogated EMT, cell migration, and metastasis induced by IFNγ. We show that IFNγ induced upregulation of JMJD3 significantly reduced H3K27 trimethylation in the promoter of the ZEB1 gene, which led to activation of ZEB1 gene transcription. IFNγ-induced JMJD3 expression was JAK1/2-STAT1 dependent. Inhibition of JMJD3 abrogated IFNγ-induced ZEB1 expression. IFNγ-induced ZEB1 also reduced miR-200 expression. Downregulation of ZEB1 increased miR-200 expression, which led to a reduction of PD-L1 expression induced by IFNγ. It is worth noting that knockdown of ZEB1 did not affect IFNγ-mediated antiproliferation and induction of CXCL9 and CXCL10. Thus, downregulation of ZEB1 may prevent the protumor activity of IFNγ while retaining its antitumor function. This study expands our understanding of IFNγ-mediated signaling and helps to identify therapeutic targets to improve current immunotherapies.
Implications:
IFNγ increases ZEB1 expression in a STAT1-JMJD3 dependent manner, and consequently promotes cancer cell aggressiveness. This study provides a potential target to minimize the procancer effect of IFNγ while preserving its antitumor function.
Data from Epstein-Barr Virus Induces Lymphangiogenesis and Lympth Node Metastasis via Upregulation of VEGF-C in Nasopharyngeal Carcinoma
Authors: Li Deng-Ke , Chen Xing-Rui , Wang Li-Na , Wang Jia-Hong , Wen Yue-Ting , Zhou Zi-Ying , Li Ji-Ke , Liu Jing-Xian , Cai Lin-Bo , Zhong Shui-Sheng , Lyu Xiao-Ming , Damola Faleti Oluwasijibomi , Li Min-Ying , Zhang Jing-Jing , Zeng Yu-Mei , Wang Qian-Li , Zhang Qian-Bing , Lyu Hao , Fu Xiao-Yan , Wang Wei , Li Xin , Huang Zhong-Xi , Yao Kai-Tai
Published: March 2024

Abstract
Lymphatic metastasis is a common clinical symptom in nasopharyngeal carcinoma (NPC), the most common Epstein-Barr virus (EBV)-associated head and neck malignancy. However, the effect of EBV on NPC lymph node (LN) metastasis is still unclear. In this study, we demonstrated that EBV infection is strongly associated with advanced clinical N stage and lymphangiogenesis of NPC. We found that NPC cells infected with EBV promote LN metastasis by inducing cancer-associated lymphangiogenesis, whereas these changes were abolished upon clearance of EBV genomes. Mechanistically, EBV-induced VEGF-C contributed to lymphangiogenesis and LN metastasis, and PHLPP1, a target of miR-BART15, partially contributed to AKT/HIF1a hyperactivity and subsequent VEGF-C transcriptional activation. In addition, administration of anti-VEGF-C antibody or HIF1α inhibitors attenuated the lymphangiogenesis and LN metastasis induced by EBV. Finally, we verified the clinical significance of this prometastatic EBV/VEGF-C axis by determining the expression of PHLPP1, AKT, HIF1a, and VEGF-C in NPC specimens with and without EBV. These results uncover a reasonable mechanism for the EBV-modulated LN metastasis microenvironment in NPC, indicating that EBV is a potential therapeutic target for NPC with lymphatic metastasis.
Implications:
This research demonstrates that EBV induces lymphangiogenesis in NPC by regulating PHLPP1/p-AKT/HIF1a/VEGF-C, providing a new therapeutic target for NPC with lymphatic metastasis.
Data from LncIHAT Is Induced by Hypoxia-Inducible Factor 1 and Promotes Breast Cancer Progression
Authors: Chen Lin , Bao Lei , Niu Yanling , Wang Jennifer E. , Kumar Ashwani , Xing Chao , Wang Yingfei , Luo Weibo
Published: March 2024

Abstract
Hypoxia induces thousands of mRNAs and miRNAs to mediate tumor malignancy. However, hypoxia-induced long noncoding RNA (lncRNA) transcriptome and their role in triple-negative breast cancer (TNBC) have not been defined. Here we identified hypoxia-induced lncRNA transcriptome in two human TNBC cell lines by whole transcriptome sequencing. AC093818.1 was one of 26 validated lncRNAs and abundantly expressed in TNBC in vitro and in vivo. 5′- and 3′-rapid amplification of cDNA ends assays revealed that the isoform 2 was a dominant AC093818.1 transcript in TNBC cells and thus referred to as lncIHAT (lncRNA induced by hypoxia and abundant in TNBC). Hypoxia-inducible factor 1 (HIF1) but not HIF2 bound to the hypoxia response element at the promoter of lncIHAT to activate its transcription in hypoxic TNBC cells. LncIHAT promoted TNBC cell survival in vitro and tumor growth and lung metastasis in mice. Mechanistically, lncIHAT was required for the expression of its proximal neighboring oncogenic genes PDK1 and ITGA6 in TNBC cells and tumors. Reexpression of PDK1 and ITGA6 rescued survival and growth of lncIHAT knockdown TNBC cells in vitro. Collectively, these findings uncovered lncIHAT as a new hypoxia-induced oncogenic cis-acting lncRNA in TNBC.
Implications:
This study systematically identified hypoxia-induced lncRNA transcriptome in TNBC and sheds light on multiple layers of regulatory mechanisms of gene expression under hypoxia.
Data from SOHLH2 Suppresses Angiogenesis by Downregulating HIF1α Expression in Breast Cancer
Authors: Cui Weiwei , Xiao Yunling , Zhang Ruihong , Zhao Na , Zhang Xianghong , Wang Fuwu , Liu Yang , Zhang Xiaoli , Hao Jing
Published: March 2024

Abstract
SOHLH2 has been demonstrated the downregulation in various cancers and the involvement in tumor growth and metastasis. However, the function of SOHLH2 on tumor angiogenesis and the underlying molecular mechanisms have not been interrogated. IHC staining results revealed that SOHLH2 was negatively associated with microvessel density (MVD), tumor size, histology grade, and metastasis. Overexpression of SOHLH2 inhibited the angiogenic behavior of human umbilical vein endothelial cells (HUVEC) by a tumor cell–mediated paracrine signal, while knockdown of SOHLH2 promoted HUVEC angiogenic behavior. Ectopic SOHLH2 expression remarkably suppressed tumor growth and MVD in xenograft tumors, downregulated the expression of hypoxia inducible factor-1 alpha (HIF1α)-mediated proangiogenic genes in vivo and in vitro, while knockdown of SOHLH2 had an opposite result. Furthermore, we found that upregulation of HIF1α reversed SOHLH2-induced suppression of breast cancer angiogenesis, while KC7F2, the inhibitor of HIF1α, could attenuate the promotion of angiogenesis by SOHLH2 silencing. Using Chromatin immunoprecipitation and luciferase reporter assays, we validated that SOHLH2 could directly bind to HIF1α promoter and repress its transcriptional activity. Collectively, SOHLH2 suppresses breast cancer angiogenesis by downregulating HIF1α transcription and may be a potential biomarker for anti-angiogenesis therapy.
Implications:
SOHLH2 directly represses HIF1α–mediated angiogenesis and serves as an important inhibitor of angiogenesis in breast cancer.
Data from KRAS Mutants Upregulate Integrin β4 to Promote Invasion and Metastasis in Colorectal Cancer
Authors: Choi Seo-Hyun , Kim Jin K. , Chen Chin-Tung , Wu Chao , Marco Michael R. , Barriga Francisco M. , O'Rourke Kevin , Pelossof Raphael , Qu Xuan , Chang Qing , de Stanchina Elisa , Shia Jinru , Smith J. Joshua , Sanchez-Vega Francisco , Garcia-Aguilar Julio
Published: March 2024

Abstract
KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6β4 through ERK/MEK signaling. Knocking-out integrin β4 (ITGB4) specifically depleted the expression of integrin α6β4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6β4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate.
Implications:
Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.
Data from Mitochondrial Aconitase ACO2 Links Iron Homeostasis with Tumorigenicity in Non–Small Cell Lung Cancer
Authors: Mirhadi Shideh , Zhang Wen , Pham Nhu-An , Karimzadeh Fereshteh , Pintilie Melania , Tong Jiefei , Taylor Paul , Krieger Jonathan , Pitcher Bethany , Sykes Jenna , Wybenga-Groot Leanne , Fladd Christopher , Xu Jing , Wang Tao , Cabanero Michael , Li Ming , Weiss Jessica , Sakashita Shingo , Zaslaver Olga , Yu Man , Caudy Amy A. , St-Pierre Julie , Hawkins Cynthia , Kislinger Thomas , Liu Geoffrey , Shepherd Frances A. , Tsao Ming-Sound , Moran Michael F.
Published: March 2024

Abstract
The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non–small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumors. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas upregulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumor growth in vivo. High level ACO2 increased iron response element binding protein 1 (IRP1) and the intracellular labile iron pool. Impaired cellular proliferation associated with high level ACO2 was reversed by treatment of cells with an iron chelator, whereas increased cell proliferation associated with low level ACO2 was suppressed by treatment of cells with iron. Expression of CDGSH iron-sulfur (FeS) domain-containing protein 1 [CISD1; also known as mitoNEET (mNT)] was modulated by ACO2 expression level and inhibition of mNT by RNA interference or by treatment of cells with pioglitazone also increased iron and cell death. Hence, ACO2 is identified as a regulator of iron homeostasis and mNT is implicated as a target in aggressive NSCLC.
Implications:
FeS cluster–associated proteins including ACO2, mNT (encoded by CISD1), and IRP1 (encoded by ACO1) are part of an “ACO2–Iron Axis” that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC.
Data from Proliferation and Self-Renewal Are Differentially Sensitive to NRASG12V Oncogene Levels in an Acute Myeloid Leukemia Cell Line
Authors: Kurata Morito , Antony Marie Lue , Noble-Orcutt Klara E. , Rathe Susan K. , Lee Yoonkyu , Furuno Hidehiro , Ishibashi Sachiko , Ikeda Masumi , Yamamoto Kouhei , Kitagawa Masanobu , Largaespada David A. , Sachs Zohar
Published: March 2024

Abstract
NRAS proteins are central regulators of proliferation, survival, and self-renewal in leukemia. Previous work demonstrated that the effects of oncogenic NRAS in mediating proliferation and self-renewal are mutually exclusive within leukemia subpopulations and that levels of oncogenic NRAS vary between highly proliferative and self-renewing leukemia subpopulations. These findings suggest that NRAS activity levels may be important determinants of leukemic behavior. To define how oncogenic NRAS levels affect these functions, we genetically engineered an acute myeloid leukemia (AML) cell line, THP-1, to express variable levels of NRASG12V. We replaced the endogenous NRASG12D gene with a tetracycline-inducible and dose-responsive NRASG12V transgene. Cells lacking NRASG12V oncoprotein were cell-cycle arrested. Intermediate levels of NRASG12V induced maximal proliferation; higher levels led to attenuated proliferation, increased G1 arrest, senescence markers, and maximal self-renewal capacity. Higher levels of the oncoprotein also induced self-renewal and mitochondrial genes. We used mass cytometry (CyTOF) to define the downstream signaling events that mediate these differential effects. Not surprisingly, we found that the levels of such canonical RAS-effectors as pERK and p4EBP1 correlated with NRASG12V levels. β-Catenin, a mediator of self-renewal, also correlated with NRASG12V levels. These signaling intermediates may mediate the differential effects of NRASG12V in leukemia biology. Together, these data reveal that oncogenic NRAS levels are important determinants of leukemic behavior explaining heterogeneity in phenotypes within a clone. This system provides a new model to study RAS oncogene addiction and RAS-induced self-renewal in AML.
Implications:
Different levels of activated NRAS may exert distinct effects on proliferation and self-renewal.
Data from Comprehensive Viral Genotyping Reveals Prognostic Viral Phylogenetic Groups in HPV16-Associated Squamous Cell Carcinoma of the Oropharynx
Authors: Schrank Travis P. , Landess Lee , Stepp Wesley H. , Rehmani Hina , Weir William H. , Lenze Nicholas , Lal Asim , Wu Di , Kothari Aditi , Hackman Trevor G. , Sheth Siddharth , Patel Shetal , Jefferys Stuart R. , Issaeva Natalia , Yarbrough Wendell G.
Published: March 2024

Abstract
Human papillomavirus–positive (HPV+) squamous cell carcinoma of the oropharynx (OPSCC) is the most prevalent HPV-associated malignancy in the United States and is primarily caused by HPV subtype 16 (HPV16). Favorable treatment outcomes have led to increasing interest in treatment deescalation to reduce treatment-related morbidity. Prognostic biomarkers are needed to identify appropriately low-risk patients for reduced treatment intensity. Targeted DNA sequencing including all HPV16 open reading frames was performed on tumors from 104 patients with HPV16+ OPSCC treated at a single center. Genotypes closely related to the HPV16-A1 reference were associated with increased numbers of somatic copy-number variants in the human genome and poor recurrence-free survival (RFS). Genotypes divergent from HPV16-A1 were associated with favorable RFS. These findings were independent of tobacco smoke exposure. Total RNA sequencing was performed on a second independent cohort of 89 HPV16+ OPSCC cases. HPV16 genotypes divergent from HPV16-A1 were again validated in this independent cohort, to be prognostic of improved RFS in patients with moderate (less than 30 pack-years) or low (no more than 10 pack-years) of tobacco smoke exposure. In summary, we show in two independent cohorts that viral sequence divergence from the HPV16-A1 reference is correlated with improved RFS in patients with moderate or low tobacco smoke exposure.
Implications:
HPV16 genotype is a potential biomarker that could be easily adopted to guide therapeutic decision-making related to deescalation therapy.
Data from Tumor Microenvironment Acidity Triggers Lipid Accumulation in Liver Cancer via SCD1 Activation
Authors: Ding Ming , Zhang Shuwei , Guo Yajuan , Yao Jingjing , Shen Qinghong , Huang Min , Chen Wenbo , Yu Shaofang , Zheng Yaqiu , Lin Yuefang , Yan Wenxin , Liu Zhongqiu , Su Tao , Lu Linlin
Published: March 2024

Abstract
Acidification is recognized as the predominant characteristic of the tumor microenvironment (TME) and contributes to tumor progression. However, the mechanism of extracellular acidic TME directly influences intercellular pathologic responses remains unclear. Meanwhile, acidic TME is mainly ascribed to aberrant metabolism of lipids and glucose, but whether and how acidity affects metabolic reprogramming, especially for lipid metabolism, is still unknown. We found that lipid was significantly accumulated in liver cancer cells when exposed to acidic TME. Moreover, proteomic analysis showed that differentially expressed proteins were mainly clustered into fatty acid pathways. Subsequently, we found that acidification increased the expression of SCD1 by activating PI3K/AKT signaling pathway. Interestingly, we found that SCD1 directly bound to PPARα in the acidic TME, which vanished after 2-day reverse incubation in pH 7.4 medium, implying extracellular acidosis might influence intercellular function by mediating the binding affinity between SCD1 and PPARα under different pH gradients. In summary, our data revealed that acidosis could significantly trigger fatty acid synthesis to promote liver tumorigenesis by upregulating SCD1 in a PI3K/AKT activation dependent manner and simultaneously promote SCD1 binding to PPARα. Our study not only provides direct mechanistic evidence to support the vital role of acidosis in lipid metabolic reprogramming, but also provides novel insights for determining the binding affinity of functional proteins as a molecular mechanism to better understand the role of the acidic TME in tumor development.
Implications:
The acidic TME contributes to lipid accumulation in liver cancer by activating the PI3K/AKT signaling pathway and promoting SCD1–PPARα binding.
Data from Inactivation of AR/TMPRSS2-ERG/Wnt Signaling Networks Attenuates the Aggressive Behavior of Prostate Cancer Cells
Authors: Li Yiwei , Kong Dejuan , Wang Zhiwei , Ahmad Aamir , Bao Bin , Padhye Subhash , Sarkar Fazlul H.
Published: March 2024

Abstract
The development of prostate cancer and its progression to castrate-resistant prostate cancer (CRPC) after antiandrogen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human prostate cancers overexpress ERG (v-ets avian erythroblastosis virus E26 oncogene related gene) due to AR-regulated TMPRSS2-ERG fusion gene. However, the reported roles of TMPRSS2-ERG fusion in cancer progression are not clear. In this study, we investigated the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network for studying the aggressive behavior of prostate cancer cells and further assessed the effects of BR-DIM and CDF [natural agents-derived synthetic formulation and analogue of 3,3′-diindolylmethane (DIM) and curcumin, respectively, with improved bioavailability] on the regulation of AR/TMPRSS2-ERG/Wnt signaling. We found that activation of AR resulted in the induction of ERG expression through TMPRSS2-ERG fusion. Moreover, we found that ERG overexpression and nuclear translocation activated the activity of Wnt signaling. Furthermore, forced overexpression of ERG promoted invasive capacity of prostate cancer cells. More important, we found that BR-DIM and CDF inhibited the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network, leading to the inactivation of Wnt signaling consistent with inhibition of prostate cancer cell invasion. In addition, BR-DIM and CDF inhibited proliferation of prostate cancer cells and induced apoptotic cell death. On the basis of our findings, we conclude that because BR-DIM and CDF downregulate multiple signaling pathways including AR/TMPRSS2-ERG/Wnt signaling, these agents could be useful for designing novel strategies for the prevention and/or treatment of prostate cancer. Cancer Prev Res; 4(9); 1495–506. ©2011 AACR.
Data from Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study
Authors: Saba Nabil F. , Hurwitz Selwyn J. , Kono Scott A. , Yang Chung S. , Zhao Yang , Chen Zhengjia , Sica Gabe , Müller Susan , Moreno-Williams Rachel , Lewis Melinda , Grist William , Chen Amy Y. , Moore Charles E. , Owonikoko Taofeek K. , Ramalingam Suresh , Beitler Jonathan J. , Nannapaneni Sreenivas , Shin Hyung Ju C. , Grandis Jennifer R. , Khuri Fadlo R. , Chen Zhuo Georgia , Shin Dong M.
Published: March 2024

Abstract
Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated. Cancer Prev Res; 7(3); 283–91. ©2013 AACR.
Data from Prediction of Recurrence and Survival in Hepatocellular Carcinoma Based on Two Cox Models Mainly Determined by FoxP3+ Regulatory T Cells
Authors: Lin Sheng-Zhang , Chen Kang-Jie , Xu Zhi-Yuan , Chen Hui , Zhou Lin , Xie Hai-Yang , Zheng Shu-Sen
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis and limited methods to predict patient survival. Immune cells infiltrating tumors is known to impact clinical outcome. Here, we investigated the prognostic significance of immune infiltration within the tumor microenvironment in 245 specimens from two independent cohorts by immunohistochemical analyses. A Cox regression model was constructed using a training cohort and validated in an independent cohort. The diagnostic accuracy was evaluated by receiver operating characteristic curve. The activation, function, and chemotaxis of intratumoral regulatory T cells (Treg) were analyzed using flow cytometry, quantitative PCR, and chemotaxis assay. We identified that the proportion of FoxP3+ cells within tumors is negatively associated with patient prognosis, whereas the proportion of interleukin (IL)-17+ cell and the number of trypase+ cells are positive predictor. The two Cox models, composed of independent predictors in multivariate analysis, provided a high diagnostic accuracy of prognosis for patients with HCC. The proportion of FoxP3+ cells showed the most significant predictive power, with the highest Cox score in the two models. Furthermore, we found Tregs from tumor with high FoxP3+ proportion were more active and powerful than the counterparts from tumor with low FoxP3+ proportion. In conclusion, two Cox models are established that have considerable clinical value in predicting tumor recurrence and survival of patients with HCC, respectively. In the both models, the proportion of Tregs among CD4+ T cells plays a central role. Cancer Prev Res; 6(6); 594–602. ©2013 AACR.
Data from Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation
Authors: Chen Wenxing , Luo Yan , Liu Lei , Zhou Hongyu , Xu Baoshan , Han Xiuzhen , Shen Tao , Liu Zhijun , Lu Yin , Huang Shile
Published: March 2024

Abstract
Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G1-G0 phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I– or 10% fetal bovine serum–stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent. Cancer Prev Res; 3(8); 1015–25. ©2010 AACR.
Data from Epigenetic DNA Methylation of Antioxidative Stress Regulator NRF2 in Human Prostate Cancer
Authors: Khor Tin Oo , Fuentes Francisco , Shu Limin , Paredes-Gonzalez Ximena , Yang Anne Yuqing , Liu Yue , Smiraglia Dominic J. , Yegnasubramanian Srinivasan , Nelson William G. , Kong Ah-Ng Tony
Published: March 2024

Abstract
Epigenetic control of NRF2, a master regulator of many critical antioxidative stress defense genes in human prostate cancer (CaP), is unknown. Our previous animal study found decreased Nrf2 expression through promoter CpG methylation/histone modifications during prostate cancer progression in TRAMP mice. In this study, we evaluated CpG methylation of human NRF2 promoter in 27 clinical prostate cancer samples and in LNCaP cells using MAQMA analysis and bisulfite genomic DNA sequencing. Prostate cancer tissue microarray (TMA) containing normal and prostate cancer tissues was studied by immunohistochemistry. Luciferase reporter assay using specific human NRF2 DNA promoter segments and chromatin immunoprecipitation (ChIP) assay against histone modifying proteins were performed in LNCaP cells. Three specific CpG sites in the NRF2 promoter were found to be hypermethylated in clinical prostate cancer samples (BPHNRF2 promoter. LNCaP cells treated with 5-aza/TSA restored the expression of NRF2 and NRF2 downstream target genes, decreased expression levels of DNMT and HDAC proteins, and ChIP assays showed increased RNA Pol II and H3Ac with a concomitant decrease in H3K9me3, MBD2, and MeCP2 at CpG sites of human NRF2 promoter. Taken together, these findings suggest that epigenetic modification may contribute to the regulation of transcription activity of NRF2, which could be used as prevention and treatment target of human prostate cancer. Cancer Prev Res; 7(12); 1186–97. ©2014 AACR.
Data from Abdominal Obesity, Independent from Caloric Intake, Accounts for the Development of Intestinal Tumors in Apc1638N/+ Female Mice
Authors: Huffman Derek M. , Augenlicht Leonard H. , Zhang Xueying , Lofrese John J. , Atzmon Gil , Chamberland John P. , Mantzoros Christos S.
Published: March 2024

Abstract
To determine whether visceral fat (VF), independent of other confounders, is causally linked to intestinal tumorigenesis, we surgically removed visceral fat in Apc1638/N+ mice. At 15 weeks of age, male and female Apc1638/N+ mice were randomized to one of three groups: ad libitum, visceral fat removal (VF-) and ad libitum fed, or caloric restriction, and were studied for effects on tumorigenesis and survival. As compared with ad libitum, VF− and caloric restriction reduced macroadenomas to a similar extent (P < 0.05), but only caloric restriction significantly improved survival (P < 0.05). Given that a significant group × gender interaction was observed, we next examined males and females separately. In females, macroadenomas were markedly attenuated by VF− (1.33 ± 0.23 mean ± SE; P < 0.05), but not by caloric restriction (2.35 ± 0.25; P = 0.71), as compared with ad libitum (2.50 ± 0.34). In males, however, caloric restriction (1.71 ± 0.26; P < 0.01), but not VF− (2.94 ± 0.42; P = 0.29), reduced macroadenomas, as compared with ad libitum males (3.47 ± 0.30). In females, both VF− (P = 0.05) and caloric restriction (P < 0.01) improved survival, but not in male mice (P = 0.15). The benefits observed with caloric restriction were consistent with favorable metabolic adaptations, but protection conferred in VF− females was despite lower adiponectin levels (P < 0.05), and failure to reduce body mass, total adiposity, glucose, insulin, leptin, and chemokine (C–X–C motif) ligand 1 (CXCL-1) levels. In conclusion, these data provide the first causal evidence linking visceral fat to intestinal cancer risk, and suggest that factors, other than known metabolic mediators, may impact tumor development. Furthermore, these data emphasize that strategies designed to deplete visceral fat stores in humans should be considered in the prevention of intestinal cancer. Cancer Prev Res; 6(3); 177–87. ©2012 AACR.