bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from miR326 Maturation Is Crucial for VEGF-C–Driven Cortactin Expression and Esophageal Cancer Progression
Authors: Hong Chih-Chen , Chen Pai-Sheng , Chiou Jean , Chiu Ching-Feng , Yang Ching-Yao , Hsiao Michael , Chang Yi-Wen , Yu Yang-Hao , Hung Mien-Chie , Hsu Nai-Wen , Shiah Shine-Gwo , Hsu Nan-Yung , Su Jen-Liang
Published: March 2024

Abstract
Esophageal cancer is an aggressive human malignancy with increasing incidence in the developed world. VEGF-C makes crucial contributions to esophageal cancer progression that are not well understood. Here, we report the discovery of regulatory relationship in esophageal cancers between the expression of VEGF-C and cortactin (CTTN), a regulator of the cortical actin cytoskeleton. Upregulation of CTTN expression by VEGF-C enhanced the invasive properties of esophageal squamous cell carcinoma in vitro and tumor metastasis in vivo. Mechanistic investigations showed that VEGF-C increased CTTN expression by downregulating Dicer-mediated maturation of miR326, thereby relieving the suppressive effect of miR326 on CTTN expression. Clinically, expression of Dicer and miR326 correlated with poor prognosis in patients with esophageal cancer. Our findings offer insights into how VEGF-C enhances the robust invasive and metastatic properties of esophageal cancer, which has potential implications for the development of new biomarkers or therapies in this setting. Cancer Res; 74(21); 6280–90. ©2014 AACR.
Data from Live-Cell Imaging of Invasion and Intravasation in an Artificial Microvessel Platform
Authors: Wong Andrew D. , Searson Peter C.
Published: March 2024

Abstract
Methods to visualize metastasis exist, but additional tools to better define the biologic and physical processes underlying invasion and intravasation are still needed. One difficulty in studying metastasis stems from the complexity of the interface between the tumor microenvironment and the vascular system. Here, we report the development of an investigational platform that positions tumor cells next to an artificial vessel embedded in an extracellular matrix. On this platform, we used live-cell fluorescence microscopy to analyze the complex interplay between metastatic cancer cells and a functional artificial microvessel that was lined with endothelial cells. The platform recapitulated known interactions, and its use demonstrated the capabilities for a systematic study of novel physical and biologic parameters involved in invasion and intravasation. In summary, our work offers an important new tool to advance knowledge about metastasis and candidate antimetastatic therapies. Cancer Res; 74(17); 4937–45. ©2014 AACR.
Data from ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis
Authors: Martinengo Cinzia , Poggio Teresa , Menotti Matteo , Scalzo Maria Stella , Mastini Cristina , Ambrogio Chiara , Pellegrino Elisa , Riera Ludovica , Piva Roberto , Ribatti Domenico , Pastorino Fabio , Perri Patrizia , Ponzoni Mirco , Wang Qi , Voena Claudia , Chiarle Roberto
Published: March 2024

Abstract
Rearrangements involving the anaplastic lymphoma kinase (ALK) gene are defining events in several tumors, including anaplastic large-cell lymphoma (ALCL) and non–small cell lung carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared with other types of T-cell lymphoma or EGFR- and K-RAS–mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC, we found that under hypoxic conditions, ALK directly regulated the abundance of hypoxia-inducible factors (HIF), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF1α and HIF2α in hypoxic conditions required ALK activity and its downstream signaling proteins STAT3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF2α, but not HIF1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF1α and HIF2α. In conclusion, we uncovered an ALK-specific regulation of the hypoxia response across different ALK+ tumor types and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC. Cancer Res; 74(21); 6094–106. ©2014 AACR.
Data from Targeting of miR34a–NOTCH1 Axis Reduced Breast Cancer Stemness and Chemoresistance
Authors: Park Eun Young , Chang EunSun , Lee Eun Ji , Lee Hyun-Woo , Kang Hyeok-Gu , Chun Kyung-Hee , Woo Yu Mi , Kong Hyun Kyung , Ko Je Yeong , Suzuki Hiromu , Song Erwei , Park Jong Hoon
Published: March 2024

Abstract
Human breast cancers include cancer stem cell populations as well as nontumorigenic cancer cells. Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. miRNAs regulate the expression of many target genes; therefore, dysregulation of miRNAs has been associated with the pathogenesis of human diseases, including cancer. However, a role for miRNA dysregulation in stemness and drug resistance has yet to be identified. Members of the miR34 family are reportedly tumor-suppressor miRNAs and are associated with various human cancers. Our results confirm that miR34a expression was downregulated in MCF7/ADR cells compared with MCF7 cells. We hypothesized that this reduction was due to the p53 (TP53) mutation in MCF7/ADR cells. In this study, we found that primary and mature miR34a were suppressed by treatment with p53 RNAi or the dominant-negative p53 mutant in MCF7 cells. Ectopic miR34a expression reduced cancer stem cell properties and increased sensitivity to doxorubicin treatment by directly targeting NOTCH1. Furthermore, tumors from nude mice treated with miR34a were significantly smaller compared with those of mice treated with control lentivirus. Our research suggests that the ectopic expression of miR34a represents a novel therapeutic approach in chemoresistant breast cancer treatment. Cancer Res; 74(24); 7573–82. ©2014 AACR.
Data from AEG-1 Promoter–Mediated Imaging of Prostate Cancer
Authors: Bhatnagar Akrita , Wang Yuchuan , Mease Ronnie C. , Gabrielson Matthew , Sysa Polina , Minn Il , Green Gilbert , Simmons Brian , Gabrielson Kathleen , Sarkar Siddik , Fisher Paul B. , Pomper Martin G.
Published: March 2024

Abstract
We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through a systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single-photon emission computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for noninvasive clinical imaging. Furthermore, the approach compares favorably with accepted and emerging clinical standards, including PET with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer. Cancer Res; 74(20); 5772–81. ©2014 AACR.
Data from Mouse Models of Human Cancer
Authors: Böck Barbara C. , Stein Ulrike , Schmitt Clemens A. , Augustin Hellmut G.
Published: March 2024

Abstract
The Helmholtz Alliance Preclinical Comprehensive Cancer Center (PCCC; www.helmholtz-pccc.de) hosted the “1st International Kloster Seeon Meeting on Mouse Models of Human Cancer” in the Seeon monastery (Germany) from March 8 to 11, 2014. The meeting focused on the development and application of novel mouse models in tumor research and high-throughput technologies to overcome one of the most critical bottlenecks in translational bench-to-bedside tumor biology research. Moreover, the participants discussed basic molecular mechanisms underlying tumor initiation, progression, metastasis, and therapy resistance, which are the prerequisite for the development of novel treatment strategies and clinical applications in cancer therapy. Cancer Res; 74(17); 4671–5. ©2014 AACR.
Data from IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis
Authors: Wang Lin , Zhang Ling-Fei , Wu Jing , Xu Shu-Jun , Xu Yang-Yang , Li Dangsheng , Lou Jia-Tao , Liu Mo-Fang
Published: March 2024

Abstract
Inflammatory stimuli clearly contribute to lung cancer development and progression, but the underlying pathogenic mechanisms are not fully understood. We found that the proinflammatory cytokine IL-1β is dramatically elevated in the serum of patients with non–small cell lung cancer (NSCLC). In vitro studies showed that IL-1β promoted the proliferation and migration of NSCLC cells. Mechanistically, IL-1β acted through the COX2–HIF1α pathway to repress the expression of microRNA-101 (miR-101), a microRNA with an established role in tumor suppression. Lin28B was identified as critical effector target of miR-101 with its repression of Lin28B, a critical aspect of tumor suppression. Overall, IL-1β upregulated Lin28B by downregulating miR-101. Interestingly, cyclooxygenase-2 inhibition by aspirin or celecoxib abrogated IL-1β-mediated repression of miR-101 and IL-1β-mediated activation of Lin28B along with their stimulatory effects on NSCLC cell proliferation and migration. Together, our findings defined an IL-1β–miR-101–Lin28B pathway as a novel regulatory axis of pathogenic inflammatory signaling in NSCLC. Cancer Res; 74(17); 4720–30. ©2014 AACR.
Data from EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation
Authors: Kang Hong-Jun , Park Jun Hong , Chen WeiPing , Kang Soo Im , Moroz Krzysztof , Ladanyi Marc , Lee Sean Bong
Published: March 2024

Abstract
The oncogenic fusion gene EWS–WT1 is the defining chromosomal translocation in desmoplastic small round-cell tumors (DSRCT), a rare but aggressive soft tissue sarcoma with a high rate of mortality. EWS–WT1 functions as an aberrant transcription factor that drives tumorigenesis, but the mechanistic basis for its pathogenic activity is not well understood. To address this question, we created a transgenic mouse strain that permits physiologic expression of EWS–WT1 under the native murine Ews promoter. EWS–WT1 expression led to a dramatic induction of many neuronal genes in embryonic fibroblasts and primary DSRCT, most notably the neural reprogramming factor ASCL1. Mechanistic analyses demonstrated that EWS–WT1 directly bound the proximal promoter of ASCL1, activating its transcription through multiple WT1-responsive elements. Conversely, EWS–WT1 silencing in DSRCT cells reduced ASCL1 expression and cell viability. Notably, exposure of DSRCT cells to neuronal induction media increased neural gene expression and induced neurite-like projections, both of which were abrogated by silencing EWS–WT1. Taken together, our findings reveal that EWS–WT1 can activate neural gene expression and direct partial neural differentiation via ASCL1, suggesting agents that promote neural differentiation might offer a novel therapeutic approach to treat DSRCT. Cancer Res; 74(16); 4526–35. ©2014 AACR.
Data from Targeting EphA3 Inhibits Cancer Growth by Disrupting the Tumor Stromal Microenvironment
Authors: Vail Mary E. , Murone Carmel , Tan April , Hii Linda , Abebe Degu , Janes Peter W. , Lee Fook-Thean , Baer Mark , Palath Varghese , Bebbington Christopher , Yarranton Geoffrey , Llerena Carmen , Garic Slavisa , Abramson David , Cartwright Glenn , Scott Andrew M. , Lackmann Martin
Published: March 2024

Abstract
Eph receptor tyrosine kinases are critical for cell–cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow–derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3+/CD90+/Sca1+ mesenchymal/stromal cells with an EphA3 agonist leads to cell contraction, cell–cell segregation, and apoptosis. Treatment of mice with an agonistic α-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. Cancer Res; 74(16); 4470–81. ©2014 AACR.
Data from TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors
Authors: Condelli Valentina , Piscazzi Annamaria , Sisinni Lorenza , Matassa Danilo Swann , Maddalena Francesca , Lettini Giacomo , Simeon Vittorio , Palladino Giuseppe , Amoroso Maria Rosaria , Trino Stefania , Esposito Franca , Landriscina Matteo
Published: March 2024

Abstract
Human BRAF-driven tumors are aggressive malignancies with poor clinical outcome and lack of sensitivity to therapies. TRAP1 is a HSP90 molecular chaperone deregulated in human tumors and responsible for specific features of cancer cells, i.e., protection from apoptosis, drug resistance, metabolic regulation, and protein quality control/ubiquitination. The hypothesis that TRAP1 plays a regulatory function on the BRAF pathway, arising from the observation that BRAF levels are decreased upon TRAP1 interference, was tested in human breast and colorectal carcinoma in vitro and in vivo. This study shows that TRAP1 is involved in the regulation of BRAF synthesis/ubiquitination, without affecting its stability. Indeed, BRAF synthesis is facilitated in a TRAP1-rich background, whereas increased ubiquitination occurs upon disruption of the TRAP1 network that correlates with decreased protein levels. Remarkably, BRAF downstream pathway is modulated by TRAP1 regulatory activity: indeed, TRAP1 silencing induces (i) ERK phosphorylation attenuation, (ii) cell-cycle inhibition with cell accumulation in G0–G1 and G2–M transitions, and (iii) extensive reprogramming of gene expression. Interestingly, a genome-wide profiling of TRAP1-knockdown cells identified cell growth and cell-cycle regulation as the most significant biofunctions controlled by the TRAP1 network. It is worth noting that TRAP1 regulation on BRAF is conserved in human colorectal carcinomas, with the two proteins being frequently coexpressed. Finally, the dual HSP90/TRAP1 inhibitor HSP990 showed activity against the TRAP1 network and high cytostatic potential in BRAF-mutated colorectal carcinoma cells. Therefore, this novel TRAP1 function represents an attractive therapeutic window to target dependency of BRAF-driven tumors on TRAP1 translational/quality control machinery. Cancer Res; 74(22); 6693–704. ©2014 AACR.
Data from AXL Inhibition Sensitizes Mesenchymal Cancer Cells to Antimitotic Drugs
Authors: Wilson Catherine , Ye Xiaofen , Pham Thinh , Lin Eva , Chan Sara , McNamara Erin , Neve Richard M. , Belmont Lisa , Koeppen Hartmut , Yauch Robert L. , Ashkenazi Avi , Settleman Jeff
Published: March 2024

Abstract
Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non–small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory. Cancer Res; 74(20); 5878–90. ©2014 AACR.
Data from PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells
Authors: Kim EunGi , Youn HyeSook , Kwon TaeWoo , Son Beomseok , Kang JiHoon , Yang Hee Jung , Seong Ki Moon , Kim Wanyeon , Youn BuHyun
Published: March 2024

Abstract
The p21-activated Ser/Thr kinase 1 (PAK1) kinase has an essential role in tumorigenesis and cell survival in many cancers, but its regulation is not fully understood. In this study, we showed that in response to irradiation of lung cancer cells, PAK1 was upregulated, tyrosine phosphorylated, and translocated to the nucleus. Tyrosine phosphorylation relied upon JAK2 kinase activity and was essential for PAK1 protein stability and binding to Snail. This radiation-induced JAK2–PAK1–Snail signaling pathway increased epithelial–mesenchymal transition (EMT) by regulating epithelial and mesenchymal cell markers. Notably, JAK2 inhibitors mediated radiosensitization and EMT blockade in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that JAK2 phosphorylates and stabilizes functions of PAK1 that promote EMT and radioresistance in lung cancer cells, with additional implications for the use of JAK2 inhibitors as radiosensitizers in lung cancer treatment. Cancer Res; 74(19); 5520–31. ©2014 AACR.
Data from The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors
Authors: Izumchenko Evgeny , Chang Xiaofei , Michailidi Christina , Kagohara Luciane , Ravi Rajani , Paz Keren , Brait Mariana , Hoque Mohammad O. , Ling Shizhang , Bedi Atul , Sidransky David
Published: March 2024

Abstract
Although specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial–mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here, we show that during transforming growth factor β (TGFβ)–mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of the mitogen-inducible gene 6 (MIG6), a negative regulator of EGFR. The MIG6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of MIG6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild-type EGFR showed that the tumor MIG6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ–miR200–MIG6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of MIG6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs. Cancer Res; 74(14); 3995–4005. ©2014 AACR.
Data from SCP Phosphatases Suppress Renal Cell Carcinoma by Stabilizing PML and Inhibiting mTOR/HIF Signaling
Authors: Lin Yu-Ching , Lu Li-Ting , Chen Hsin-Yi , Duan Xueyan , Lin Xia , Feng Xin-Hua , Tang Ming-Jer , Chen Ruey-Hwa
Published: March 2024

Abstract
The tumor-suppressor protein promyelocytic leukemia (PML) is aberrantly degraded in multiple types of human cancers through mechanisms that are incompletely understood. Here, we show that the phosphatase SCP1 and its isoforms SCP2/3 dephosphorylate PML at S518, thereby blocking PML ubiquitination and degradation mediated by the prolyl isomerase Pin1 and the ubiquitin ligase KLHL20. Clinically, SCP1 and SCP3 are downregulated in clear cell renal cell carcinoma (ccRCC) and these events correlated with PMLS518 phosphorylation, PML turnover, and high-grade tumors. Restoring SCP1-mediated PML stabilization not only inhibited malignant features of ccRCC, including proliferation, migration, invasion, tumor growth, and tumor angiogenesis, but also suppressed the mTOR–HIF pathway. Furthermore, blocking PML degradation in ccRCC by SCP1 overexpression or Pin1 inhibition enhanced the tumor-suppressive effects of the mTOR inhibitor temsirolimus. Taken together, our results define a novel pathway of PML degradation in ccRCC that involves SCP downregulation, revealing contributions of this pathway to ccRCC progression and offering a mechanistic rationale for combination therapies that jointly target PML degradation and mTOR inhibition for ccRCC treatment. Cancer Res; 74(23); 6935–46. ©2014 AACR.
Data from Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression
Authors: Guéry Leslie , Dubrot Juan , Lippens Carla , Brighouse Dale , Malinge Pauline , Irla Magali , Pot Caroline , Reith Walter , Waldburger Jean-Marc , Hugues Stéphanie
Published: March 2024

Abstract
Plasmacytoid dendritic cells (pDC) rapidly and massively produce type I IFN and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing T-cell responses. Moreover, antigen (Ag)-presenting pDCs directly regulate T-cell differentiation. Depending on the immune environment, pDCs exhibit either tolerogenic or immunogenic properties. Here, we show that CpG-activated pDCs promote efficient Th17 differentiation. Indeed, Th17 responses are defective in mice selectively lacking MHCII on pDCs upon antigenic challenge. Importantly, in those mice, the frequency of Th17 cells infiltrating solid tumors is impaired. As a result, the recruitment of infiltrating leukocytes in tumors, including tumor-specific cytotoxic T lymphocytes (CTL), is altered and results in increased tumor growth. Importantly, following immunization with tumor Ag and CpG-B, MHCII-restricted Ag presentation by pDCs promotes the differentiation of antitumor Th17 cells that induce intratumor CTL recruitment and subsequent regression of established tumors. Our results highlight a new role for Ag presenting activated pDCs in promoting the development of Th17 cells and impacting on antitumor immunity. Cancer Res; 74(22); 6430–40. ©2014 AACR.
Data from A Small-Molecule Modulator of the Tumor-Suppressor miR34a Inhibits the Growth of Hepatocellular Carcinoma
Authors: Xiao Zhangang , Li Chi Han , Chan Stephen L. , Xu Feiyue , Feng Lu , Wang Yan , Jiang Jian-Dong , Sung Joseph J.Y. , Cheng Christopher H.K. , Chen Yangchao
Published: March 2024

Abstract
Small molecules that restore the expression of growth-inhibitory microRNAs (miRNA) downregulated in tumors may have potential as anticancer agents. miR34a functions as a tumor suppressor and is downregulated or silenced commonly in a variety of human cancers, including hepatocellular carcinoma (HCC). In this study, we used an HCC cell–based miR34a luciferase reporter system to screen for miR34a modulators that could exert anticancer activity. One compound identified as a lead candidate, termed Rubone, was identified through its ability to specifically upregulate miR34a in HCC cells. Rubone activated miR34a expression in HCC cells with wild-type or mutated p53 but not in cells with p53 deletions. Notably, Rubone lacked growth-inhibitory effects on nontumorigenic human hepatocytes. In a mouse xenograft model of HCC, Rubone dramatically inhibited tumor growth, exhibiting stronger anti-HCC activity than sorafenib both in vitro and in vivo. Mechanistic investigations showed that Rubone decreased expression of cyclin D1, Bcl-2, and other miR34a target genes and that it enhanced the occupancy of p53 on the miR34a promoter. Taken together, our results offer a preclinical proof of concept for Rubone as a lead candidate for further investigation as a new class of HCC therapeutic based on restoration of miR34a tumor-suppressor function. Cancer Res; 74(21); 6236–47. ©2014 AACR.
Data from PCTAIRE1 Phosphorylates p27 and Regulates Mitosis in Cancer Cells
Authors: Yanagi Teruki , Krajewska Maryla , Matsuzawa Shu-ichi , Reed John C.
Published: March 2024

Abstract
PCTAIRE1 is distant relative of the cyclin-dependent kinase family that has been implicated in spermatogenesis and neuronal development, but it has not been studied in cancer. Here, we report that PCTAIRE1 is expressed in prostate, breast, and cervical cancer cells, where its RNAi-mediated silencing causes growth inhibition with aberrant mitosis due to defects in centrosome dynamics. PCTAIRE1 was not similarly involved in proliferation of nontransformed cells, including diploid human IMR-90 fibroblasts. Through yeast two-hybrid screening, we identified tumor suppressor p27 as a PCTAIRE1 interactor. In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells. In a mouse xenograft model of PPC1 prostate cancer, conditional silencing of PCTAIRE1 restored p27 protein expression and suppressed tumor growth. Mechanistic studies in HeLa cells showed that PCTAIRE1 phosphorylates p27 during the S and M phases of the cell cycle. Notably, p27 silencing was sufficient to rescue cells from mitotic arrest caused by PCTAIRE1 silencing. Clinically, PCTAIRE1 was highly expressed in primary breast and prostate tumors compared with adjacent normal epithelial tissues. Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target. Cancer Res; 74(20); 5795–807. ©2014 AACR.
Data from H3K9 Histone Methyltransferase, KMT1E/SETDB1, Cooperates with the SMAD2/3 Pathway to Suppress Lung Cancer Metastasis
Authors: Wu Pei-Chun , Lu Jeng-Wei , Yang Jer-Yen , Lin I-Hsuan , Ou Da-Liang , Lin Yu-Hsiang , Chou Kuan-Hsien , Huang Wen-Feng , Wang Wan-Ping , Huang Yih-Leh , Hsu Chiun , Lin Liang-In , Lin Yueh-Min , Shen C.-K. James , Tzeng Tsai-Yu
Published: March 2024

Abstract
Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells. Restoring KMT1E expression in this setting suppressed filopodia formation, migration, and invasive behavior. Conversely, loss of KMT1E in lung cancer cells with limited metastatic potential promoted migration in vitro and restored metastatic prowess in vivo. Mechanistic investigations indicated that KMT1E cooperates with the TGFβ-regulated complex SMAD2/3 to repress metastasis through ANXA2. Together, our findings defined an essential role for the KMT1E/SMAD2/3 repressor complex in TGFβ-mediated lung cancer metastasis. Cancer Res; 74(24); 7333–43. ©2014 AACR.
Data from Microenvironment-Derived HGF Overcomes Genetically Determined Sensitivity to Anti-MET Drugs
Authors: Pennacchietti Selma , Cazzanti Manuela , Bertotti Andrea , Rideout William M. , Han May , Gyuris Jeno , Perera Timothy , Comoglio Paolo M. , Trusolino Livio , Michieli Paolo
Published: March 2024

Abstract
Cell-based drug screenings indicate that tumors displaying c-MET gene amplification are “addicted” to MET signaling and therefore are very sensitive to MET-targeted agents. However, these screenings were conducted in the absence of the MET ligand, hepatocyte growth factor (HGF), which is abundant in the tumor microenvironment. Sensitivity of six MET-addicted human tumor cells to three MET kinase inhibitors (JNJ-38877605, PHA-665752, crizotinib) and one antagonistic anti-MET antibody (DN30 Fab) was analyzed in the absence or presence of HGF, in a stroma–tumor coculture system, and by combining anti-MET drugs with an HGF neutralizing antibody (ficlatuzumab) in human HGF knock-in mice bearing c-MET–amplified tumors. In all models examined, HGF promoted resistance to MET-targeted agents, affecting both their potency and efficacy. HGF-induced resistance was due to restoration of physiologic GAB1–mediated PI3K activation that compensated for loss of aberrant HER3-dependent PI3K signaling. Ficlatuzumab restored sensitivity to MET-targeted agents in coculture systems and overcame resistance to JNJ-38877605, crizotinib, and DN30 Fab in human HGF knock-in mice. These data suggest that c-MET–amplified tumor cells—which normally exhibit ligand-independent, constitutive MET activation—become dependent on HGF for survival upon pharmacologic MET inhibition. Because HGF is frequently overexpressed in human cancer, this mechanism may represent a major cause of resistance to anti-MET therapies. The ability of ficlatuzumab to overcome HGF-mediated resistance generates proof of principle that vertical inhibition of both a tyrosine kinase receptor and its ligand can be therapeutically beneficial and opens new perspectives for the treatment of MET-dependent tumors. Cancer Res; 74(22); 6598–609. ©2014 AACR.
Data from IL15RA Drives Antagonistic Mechanisms of Cancer Development and Immune Control in Lymphocyte-Enriched Triple-Negative Breast Cancers
Authors: Marra Pierfrancesco , Mathew Sumi , Grigoriadis Anita , Wu Yin , Kyle-Cezar Fernanda , Watkins Johnathan , Rashid Mamunur , De Rinaldis Emanuele , Hessey Sonya , Gazinska Patrycja , Hayday Adrian , Tutt Andrew
Published: March 2024

Abstract
Despite its aggressive nature, triple-negative breast cancer (TNBC) often exhibits leucocyte infiltrations that correlate with favorable prognosis. In this study, we offer an explanation for this apparent conundrum by defining TNBC cell subsets that overexpress the IL15 immune receptor IL15RA. This receptor usually forms a heterotrimer with the IL2 receptors IL2RB and IL2RG, which regulates the proliferation and differentiation of cytotoxic T cells and NK cells. However, unlike IL15RA, the IL2RB and IL2RG receptors are not upregulated in basal-like TNBC breast cancer cells that express IL15RA. Mechanistic investigations indicated that IL15RA signaling activated JAK1, STAT1, STAT2, AKT, PRAS40, and ERK1/2 in the absence of IL2RB and IL2RG, whereas neither STAT5 nor JAK2 were activated. RNAi-mediated attenuation of IL15RA established its role in cell growth, apoptosis, and migration, whereas expression of the IL15 cytokine in IL15RA-expressing cells stimulated an autocrine signaling cascade that promoted cell proliferation and migration and blocked apoptosis. Notably, coexpression of IL15RA and IL15 was also sufficient to activate peripheral blood mononuclear cells upon coculture in a paracrine signaling manner. Overall, our findings offer a mechanistic explanation for the paradoxical association of some high-grade breast tumors with better survival outcomes, due to engagement of the immune stroma. Cancer Res; 74(17); 4908–21. ©2014 AACR.
Data from CD66+ Cells in Cervical Precancers Are Partially Differentiated Progenitors with Neoplastic Traits
Authors: Pattabiraman Chitra , Hong Shiyuan , Gunasekharan Vignesh K. , Pranatharthi Annapurna , Bajaj Jeevisha , Srivastava Sweta , Krishnamurthy H. , Ammothumkandy Aswathy , Giri Venkat G. , Laimins Laimonis A. , Krishna Sudhir
Published: March 2024

Abstract
Cervical cancers, a malignancy associated with oncogenic papilloma viruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66+ cells have previously been identified as a tumor-propagating subset in cervical cancers. We investigated the existence, differentiation state, and neoplastic potential of CD66+ cells in a precancer cell line harboring HPV31b episomes. The gene expression profile of CD66high cells overlaps with differentiated keratinocytes, neoplastic mesenchymal transition, cells of the squamocolumnar junction, and cervical cancer cell line–derived spheroids. There is elevated expression of DNMT1, Notch1, and the viral gene product E1⁁E4 in CD66high cells. Thus, CD66high cells, in the absence of differentiating signals, express higher levels of key regulators of keratinocytes stemness, differentiation, and the viral life cycle, respectively. We also find a striking association of neoplastic traits, including migration, invasion, and colony formation, in soft agar with CD66high cells. These properties and a distinct G2–M–enriched cell-cycle profile are conserved in cells from cervical cancers. Principally, using a precancerous cell line, we propose that CD66high cells have an intermediate differentiation state, with a cellular milieu connected with both viral replication and neoplastic potential, and validate some key features in precancer lesions. Such pathophysiologically relevant systems for defining cellular changes in the early phases of the disease process provide both mechanistic insight and potential therapeutic strategies. Collectively, our data provide a rationale for exploring novel therapeutic targets in CD66+ subsets during cancer progression. Cancer Res; 74(22); 6682–92. ©2014 AACR.
Data from Selenium Suppresses Leukemia through the Action of Endogenous Eicosanoids
Authors: Gandhi Ujjawal H. , Kaushal Naveen , Hegde Shailaja , Finch Emily R. , Kudva Avinash K. , Kennett Mary J. , Jordan Craig T. , Paulson Robert F. , Prabhu K. Sandeep
Published: March 2024

Abstract
Eradicating cancer stem-like cells (CSC) may be essential to fully eradicate cancer. Metabolic changes in CSC could hold a key to their targeting. Here, we report that the dietary micronutrient selenium can trigger apoptosis of CSC derived from chronic or acute myelogenous leukemias when administered at supraphysiologic but nontoxic doses. In leukemia CSC, selenium treatment activated ATM-p53–dependent apoptosis accompanied by increased intracellular levels of reactive oxygen species. Importantly, the same treatment did not trigger apoptosis in hematopoietic stem cells. Serial transplantation studies with BCR–ABL-expressing CSC revealed that the selenium status in mice was a key determinant of CSC survival. Selenium action relied upon the endogenous production of the cyclooxygenase-derived prostaglandins Δ12-PGJ2 and 15d-PGJ2. Accordingly, nonsteroidal anti-inflammatory drugs and NADPH oxidase inhibitors abrogated the ability of selenium to trigger apoptosis in leukemia CSC. Our results reveal how selenium-dependent modulation of arachidonic acid metabolism can be directed to trigger apoptosis of primary human and murine CSC in leukemia. Cancer Res; 74(14); 3890–901. ©2014 AACR.
Data from IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress
Authors: Shimizu Takatsune , Sugihara Eiji , Yamaguchi-Iwai Sayaka , Tamaki Sakura , Koyama Yuko , Kamel Walied , Ueki Arisa , Ishikawa Tomoki , Chiyoda Tatsuyuki , Osuka Satoru , Onishi Nobuyuki , Ikeda Hiroko , Kamei Junzo , Matsuo Koichi , Fukuchi Yumi , Nagai Toshihiro , Toguchida Junya , Toyama Yoshiaki , Muto Akihiro , Saya Hideyuki
Published: March 2024

Abstract
Osteosarcoma is a malignant bone tumor in children and adolescents characterized by intrinsic therapeutic resistance. The IGF2 is expressed at elevated levels in osteosarcoma after treatment with chemotherapy, prompting an examination of its functional contributions to resistance. We found that continuous exposure to IGF2 or insulin in the absence of serum created a dormant growth state in osteosarcoma cells that conferred resistance to various chemotherapeutic drugs in vitro. Mechanistic investigations revealed that this dormant state correlated with downregulation of downstream signaling by the IGF1 receptor, heightened cell survival, enhanced autophagy, and the presence of extracellular glutamine. Notably, inhibiting autophagy or depleting glutamine was sufficient to increase chemotherapeutic sensitivity in osteosarcoma xenografts in mice. Clinically, we confirmed that IGF expression levels were elevated in human osteosarcoma specimens from patients who received chemotherapy. Together, our results suggest that activation of IGF or insulin signaling preserves the survival of osteosarcoma cells under chemotherapeutic stress, providing a drug-resistant population that may engender minimal residual disease. Attenuating this survival mechanism may help overcome therapeutic resistance in osteosarcoma. Cancer Res; 74(22); 6531–41. ©2014 AACR.
Data from Inhibiting DX2-p14/ARF Interaction Exerts Antitumor Effects in Lung Cancer and Delays Tumor Progression
Authors: Oh Ah-Young , Jung Youn Sang , Kim Jiseon , Lee Jee-Hyun , Cho Jung-Hyun , Chun Ho-Young , Park Soyoung , Park Hyunchul , Lim Sikeun , Ha Nam-Chul , Park Jong Sook , Park Choon-Sik , Song Gyu-Yong , Park Bum-Joon
Published: March 2024

Abstract
The aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) splice variant designated DX2 is induced by cigarette smoke carcinogens and is often detected in human lung cancer specimens. However, the function of DX2 in lung carcinogenesis is obscure. In this study, we found that DX2 expression was induced by oncogenes in human lung cancer tissues and cells. DX2 prevented oncogene-induced apoptosis and senescence and promoted drug resistance by directly binding to and inhibiting p14/ARF. Through chemical screening, we identified SLCB050, a novel compound that blocks the interaction between DX2 and p14/ARF in vitro and in vivo. SLCB050 reduced the viability of human lung cancer cells, especially small cell lung cancer cells, in a p14/ARF-dependent manner. Moreover, in a mouse model of K-Ras–driven lung tumorigenesis, ectopic expression of DX2 induced small cell and non–small cell lung cancers, both of which could be suppressed by SLCB050 treatment. Taken together, our findings show how DX2 promotes lung cancer progression and how its activity may be thwarted as a strategy to treat patients with lung cancers exhibiting elevated DX2 levels. Cancer Res; 76(16); 4791–804. ©2016 AACR.
Data from Vaccine-Elicited CD8+ T Cells Cure Mesothelioma by Overcoming Tumor-Induced Immunosuppressive Environment
Authors: Tan Zhiwu , Zhou Jingying , Cheung Allen K.L. , Yu Zhe , Cheung Ka-Wai , Liang Jianguo , Wang Haibo , Lee Boon Kiat , Man Kwan , Liu Li , Yuen Kwok-Yung , Chen Zhiwei
Published: March 2024

Abstract
Eradicating malignant tumors by vaccine-elicited host immunity remains a major medical challenge. To date, correlates of immune protection remain unknown for malignant mesothelioma. In this study, we demonstrated that antigen-specific CD8+ T-cell immune response correlates with the elimination of malignant mesothelioma by a model PD-1–based DNA vaccine. Unlike the nonprotective tumor antigen WT1-based DNA vaccines, the model vaccine showed complete and long-lasting protection against lethal mesothelioma challenge in immunocompetent BALB/c mice. Furthermore, it remained highly immunogenic in tumor-bearing animals and led to therapeutic cure of preexisting mesothelioma. T-cell depletion and adoptive transfer experiments revealed that vaccine-elicited CD8+ T cells conferred to the protective efficacy in a dose-dependent way. Also, these CD8+ T cells functioned by releasing inflammatory IFNγ and TNFα in the vicinity of target cells as well as by initiating TRAIL-directed tumor cell apoptosis. Importantly, repeated DNA vaccinations, a major advantage over live-vectored vaccines with issues of preexisting immunity, achieve an active functional state, not only preventing the rise of exhausted PD-1+ and Tim-3+ CD8+ T cells but also suppressing tumor-induced myeloid-derived suppressive cells and Treg cells, with the frequency of antigen-specific CD8+ T cells inversely correlating with tumor mass. Our results provide new insights into quantitative and qualitative requirements of vaccine-elicited functional CD8+ T cells in cancer prevention and immunotherapy. Cancer Res; 74(21); 6010–21. ©2014 AACR.
Data from SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer
Authors: Ming Mei , Han Weinong , Zhao Baozhong , Sundaresan Nagalingam R. , Deng Chu-Xia , Gupta Mahesh P. , He Yu-Ying
Published: March 2024

Abstract
SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. Cancer Res; 74(20); 5925–33. ©2014 AACR.
Data from RABL6A Promotes G1–S Phase Progression and Pancreatic Neuroendocrine Tumor Cell Proliferation in an Rb1-Dependent Manner
Authors: Hagen Jussara , Muniz Viviane P. , Falls Kelly C. , Reed Sara M. , Taghiyev Agshin F. , Quelle Frederick W. , Gourronc Francoise A. , Klingelhutz Aloysius J. , Major Heather J. , Askeland Ryan W. , Sherman Scott K. , O'Dorisio Thomas M. , Bellizzi Andrew M. , Howe James R. , Darbro Benjamin W. , Quelle Dawn E.
Published: March 2024

Abstract
Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients. Cancer Res; 74(22); 6661–70. ©2014 AACR.
Data from MicroRNA100 Inhibits Self-Renewal of Breast Cancer Stem–like Cells and Breast Tumor Development
Authors: Deng Lu , Shang Li , Bai Shoumin , Chen Ji , He Xueyan , Martin-Trevino Rachel , Chen Shanshan , Li Xiao-yan , Meng Xiaojie , Yu Bin , Wang Xiaolin , Liu Yajing , McDermott Sean P. , Ariazi Alexa E. , Ginestier Christophe , Ibarra Ingrid , Ke Jia , Luther Tahra , Clouthier Shawn G. , Xu Liang , Shan Ge , Song Erwei , Yao Herui , Hannon Gregory J. , Weiss Stephen J. , Wicha Max S. , Liu Suling
Published: March 2024

Abstract
miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem–like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation. Cancer Res; 74(22); 6648–60. ©2014 AACR.
Data from RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth
Authors: Glanzer Jason G. , Liu Shengqin , Wang Ling , Mosel Adam , Peng Aimin , Oakley Greg G.
Published: March 2024

Abstract
The ATR/Chk1 pathway is a critical surveillance network that maintains genomic integrity during DNA replication by stabilizing the replication forks during normal replication to avoid replication stress. One of the many differences between normal cells and cancer cells is the amount of replication stress that occurs during replication. Cancer cells with activated oncogenes generate increased levels of replication stress. This creates an increased dependency on the ATR/Chk1 pathway in cancer cells and opens up an opportunity to preferentially kill cancer cells by inhibiting this pathway. In support of this idea, we have identified a small molecule termed HAMNO ((1Z)-1-[(2-hydroxyanilino)methylidene]naphthalen-2-one), a novel protein interaction inhibitor of replication protein A (RPA), a protein involved in the ATR/Chk1 pathway. HAMNO selectively binds the N-terminal domain of RPA70, effectively inhibiting critical RPA protein interactions that rely on this domain. HAMNO inhibits both ATR autophosphorylation and phosphorylation of RPA32 Ser33 by ATR. By itself, HAMNO treatment creates DNA replication stress in cancer cells that are already experiencing replication stress, but not in normal cells, and it acts synergistically with etoposide to kill cancer cells in vitro and slow tumor growth in vivo. Thus, HAMNO illustrates how RPA inhibitors represent candidate therapeutics for cancer treatment, providing disease selectivity in cancer cells by targeting their differential response to replication stress. Cancer Res; 74(18); 5165–72. ©2014 AACR.