bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PDGFRα and β Play Critical Roles in Mediating Foxq1-Driven Breast Cancer Stemness and Chemoresistance
Authors: Meng Fanyan , Speyer Cecilia L. , Zhang Bin , Zhao Yongzhong , Chen Wei , Gorski David H. , Miller Fred R. , Wu Guojun
Published: March 2024

Abstract
Many epithelial–mesenchymal transition (EMT)–promoting transcription factors have been implicated in tumorigenesis and metastasis as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here, we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets. We further show that PDGFRα and β can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRα or β alone. In addition, PDGFRβ is a more potent mediator of Foxq1-promoted stemness traits than PDGFRα. Finally, pharmacologic inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, with potential implications for developing novel therapeutic combinations to treat breast cancer. Cancer Res; 75(3); 584–93. ©2014 AACR.
Data from Cytokine-like Molecule CCDC134 Contributes to CD8+ T-cell Effector Functions in Cancer Immunotherapy
Authors: Huang Jing , Xiao Lin , Gong Xiaoting , Shao Wenwei , Yin Yanhui , Liao Qinyuan , Meng Yang , Zhang Yingmei , Ma Dalong , Qiu Xiaoyan
Published: March 2024

Abstract
CCDC134 is a poorly characterized secreted protein that may act as an immune cytokine. Here, we show that CCDC134 is differentially expressed on resting and activated immune cells and that it promotes CD8+ T-cell activation, proliferation, and cytotoxicity by augmenting expression of the T-cell effector molecules IFNγ, TNFα, granzyme B, and perforin. CCDC134 facilitated infiltration of CD8+ T cells with enhanced cytolytic activity into tumors, demonstrating strong antitumor effects in a CD8+ T-cell–dependent manner. Mechanistically, in CD8+ T cells, exposure to CCDC134 promoted cell proliferation through the JAK3–STAT5 pathway, a classic feature of many cytokines of the common γ-chain (γc) cytokine receptor family. Overall, our results provide evidence that CCDC134 may serve as a member of the γc cytokine family and illustrate its potent antitumor effects by augmenting CD8+ T-cell–mediated immunity. Cancer Res; 74(20); 5734–45. ©2014 AACR.
Data from Novel Methylated Biomarkers and a Robust Assay to Detect Circulating Tumor DNA in Metastatic Breast Cancer
Authors: Fackler Mary Jo , Lopez Bujanda Zoila , Umbricht Christopher , Teo Wei Wen , Cho Soonweng , Zhang Zhe , Visvanathan Kala , Jeter Stacie , Argani Pedram , Wang Chenguang , Lyman Jaclyn P. , de Brot Marina , Ingle James N. , Boughey Judy , McGuire Kandace , King Tari A. , Carey Lisa A. , Cope Leslie , Wolff Antonio C. , Sukumar Saraswati
Published: March 2024

Abstract
The ability to consistently detect cell-free tumor-specific DNA in peripheral blood of patients with metastatic breast cancer provides the opportunity to detect changes in tumor burden and to monitor response to treatment. We developed cMethDNA, a quantitative multiplexed methylation-specific PCR assay for a panel of ten genes, consisting of novel and known breast cancer hypermethylated markers identified by mining our previously reported study of DNA methylation patterns in breast tissue (103 cancer, 21 normal on the Illumina HumanMethylation27 Beadchip) and then validating the 10-gene panel in The Cancer Genome Atlas project breast cancer methylome database. For cMethDNA, a fixed physiologic level (50 copies) of artificially constructed, standard nonhuman reference DNA specific for each gene is introduced in a constant volume of serum (300 μL) before purification of the DNA, facilitating a sensitive, specific, robust, and quantitative assay of tumor DNA, with broad dynamic range. Cancer-specific methylated DNA was detected in training (28 normal, 24 cancer) and test (27 normal, 33 cancer) sets of recurrent stage IV patient sera with a sensitivity of 91% and a specificity of 96% in the test set. In a pilot study, cMethDNA assay faithfully reflected patient response to chemotherapy (N = 29). A core methylation signature present in the primary breast cancer was retained in serum and metastatic tissues collected at autopsy two to 11 years after diagnosis of the disease. Together, our data suggest that the cMethDNA assay can detect advanced breast cancer, and monitor tumor burden and treatment response in women with metastatic breast cancer. Cancer Res; 74(8); 2160–70. ©2014 AACR.
Data from IL-17A Produced by γδ T Cells Promotes Tumor Growth in Hepatocellular Carcinoma
Authors: Ma Shoubao , Cheng Qiao , Cai Yifeng , Gong Huanle , Wu Yan , Yu Xiao , Shi Liyun , Wu Depei , Dong Chen , Liu Haiyan
Published: March 2024

Abstract
Interleukin (IL)-17A is expressed in the tumor microenvironment where it appears to contribute to tumor development, but its precise role in tumor immunity remains controversial. Here, we report mouse genetic evidence that IL-17A is critical for tumor growth. IL-17A–deficient mice exhibited reduced tumor growth, whereas systemic administration of recombinant mouse IL-17A promoted the growth of hepatocellular carcinoma. The tumor-promoting effect of IL-17A was mediated through suppression of antitumor responses, especially CD8+ T-cell responses. Furthermore, we found that IL-17A was produced mainly by Vγ4 γδ T cells, insofar as depleting Vγ4 γδ T cells reduced tumor growth, whereas adoptive transfer of Vγ4 γδ T cells promoted tumor growth. Mechanistic investigations showed that IL-17A induced CXCL5 production by tumor cells to enhance the infiltration of myeloid-derived suppressor cells (MDSC) to tumor sites in a CXCL5/CXCR2–dependent manner. IL-17A also promoted the suppressive activity of MDSC to reinforce suppression of tumoral immunity. Moreover, we found that MDSC could induce IL-17A–producing γδ T cells via production of IL-1β and IL-23. Conversely, IL-17A could also enhance production of IL-1β and IL-23 in MDSC as a positive feedback. Together, our results revealed a novel mechanism involving cross-talk among γδ T cells, MDSCs, and tumor cells through IL-17A production. These findings offer new insights into how IL-17A influences tumor immunity, with potential implications for the development of tumor immunotherapy. Cancer Res; 74(7); 1969–82. ©2014 AACR.
Data from A Sequence Polymorphism in miR-608 Predicts Recurrence after Radiotherapy for Nasopharyngeal Carcinoma
Authors: Zheng Jian , Deng Jieqiong , Xiao Mang , Yang Lei , Zhang Liyuan , You Yonghe , Hu Min , Li Na , Wu Hongchun , Li Wei , Lu Jiachun , Zhou Yifeng
Published: March 2024

Abstract
Nasopharyngeal carcinoma is treated with radiotherapy and other modalities, but there is little information on individual genetic factors to help predict and improve patient outcomes. Single-nucleotide polymorphisms (SNP) in mature microRNA (miRNA) sequences have the potential to exert broad impact as miRNAs target many mRNAs. The aim of this study was to evaluate the effects of SNPs in mature miRNA sequences on clinical outcome in patients with nasopharyngeal carcinoma receiving radiotherapy. In particular, we analyzed associations between seven SNPs and nasopharyngeal carcinoma locoregional recurrence (LRR) in 837 patients from eastern China, validating the findings in an additional 828 patients from southern China. We found that miR-608 rs4919510C>G exhibited a consistent association with LRR in the discovery set [HR, 2.05; 95% confidence interval (CI), 1.35–3.21], the validation set (HR, 2.24; 95% CI, 1.45–3.38), and the combined dataset (HR, 2.08; 95% CI, 1.41–3.26). Biochemical investigations showed that rs4919510C>G affects expression of miR-608 target genes along with nasopharyngeal carcinoma cell growth after irradiation in vivo and in vitro. Notably, X-ray radiation induced more chromatid breaks in lymphocyte cells from rs4919510CC carriers than in those from subjects with other genotypes (P = 0.0024). Our findings reveal rs4919510C>G in miR-608 as a simple marker to predict LRR in patients with radiotherapy-treated nasopharyngeal carcinoma. Cancer Res; 73(16); 5151–62. ©2013 AACR.
Data from Overexpression of the Transcription Factor MEF2D in Hepatocellular Carcinoma Sustains Malignant Character by Suppressing G2–M Transition Genes
Authors: Ma Leina , Liu Jia , Liu Limei , Duan Guangjie , Wang Qingliang , Xu Yanmin , Xia Feng , Shan Juanjuan , Shen Junjie , Yang Zhi , Bie Ping , Cui Youhong , Bian Xiu-Wu , Prieto Jesus , Avila Matías A. , Qian Cheng
Published: March 2024

Abstract
The underlying molecular pathogenesis in hepatocellular carcinoma remains poorly understood. The transcription factor MEF2D promotes survival in various cell types and it seems to function as an oncogene in leukemia. However, its potential contributions to solid cancers have not been explored. In this study, we investigated MEF2D expression and function in hepatocellular carcinoma, finding that MEF2D elevation in hepatocellular carcinoma clinical specimens was associated with poor prognosis. MEF2D-positive primary hepatocellular carcinoma cells displayed a faster proliferation rate compared with MEF2D-negative cells, and silencing or promoting MEF2D expression in these settings limited or accelerated cell proliferation, respectively. Notably, MEF2D-silencing abolished hepatocellular carcinoma tumorigenicity in mouse xenograft models. Mechanistic investigations revealed that MEF2D-silencing triggered G2–M arrest in a manner associated with direct downregulation of the cell-cycle regulatory genes RPRM, GADD45A, GADD45B, and CDKN1A. Furthermore, we identified MEF2D as an authentic target of miR-122, the reduced expression of which in hepatocellular carcinoma may be responsible for MEF2D upregulation. Together, our results identify MEF2D as a candidate oncogene in hepatocellular carcinoma and a potential target for hepatocellular carcinoma therapy. Cancer Res; 74(5); 1452–62. ©2014 AACR.
Data from TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer
Authors: Levovitz Chaya , Chen Dan , Ivansson Emma , Gyllensten Ulf , Finnigan John P. , Alshawish Sara , Zhang Weijia , Schadt Eric E. , Posner Marshal R. , Genden Eric M. , Boffetta Paolo , Sikora Andrew G.
Published: March 2024

Abstract
Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer. Cancer Res; 74(23); 6833–44. ©2014 AACR.
Data from Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers
Authors: Hata Aaron N. , Yeo Alan , Faber Anthony C. , Lifshits Eugene , Chen Zhao , Cheng Katherine A. , Walton Zandra , Sarosiek Kristopher A. , Letai Anthony , Heist Rebecca S. , Mino-Kenudson Mari , Wong Kwok-Kin , Engelman Jeffrey A.
Published: March 2024

Abstract
Although several groups have demonstrated that concomitant use of MEK and phosphoinositide 3-kinase (PI3K) inhibitors (MEKi/PI3Ki) can induce dramatic tumor regressions in mouse models of KRAS-mutant non–small cell lung cancer (NSCLC), ongoing clinical trials investigating this strategy have been underwhelming to date. While efficacy may be hampered by a narrow therapeutic index, the contribution of biologic heterogeneity in the response of KRAS-mutant NSCLCs to MEKi/PI3Ki has been largely unexplored. In this study, we find that most human KRAS-mutant NSCLC cell lines fail to undergo marked apoptosis in response to MEKi/PI3Ki, which is key for tumor responsiveness in vivo. This heterogeneity of apoptotic response occurs despite relatively uniform induction of growth arrest. Using a targeted short hairpin RNA screen of BCL-2 family members, we identify BIM, PUMA, and BCL-XL as key regulators of the apoptotic response induced by MEKi/PI3Ki, with decreased expression of BIM and PUMA relative to BCL-XL in cell lines with intrinsic resistance. In addition, by modeling adaptive resistance to MEKi/PI3Ki both in vitro and in vivo, we find that, upon the development of resistance, tumors have a diminished apoptotic response due to downregulation of BIM and PUMA. These results suggest that the inability to induce apoptosis may limit the effectiveness of MEKi/PI3Ki for KRAS-mutant NSCLCs by contributing to intrinsic and adaptive resistance to this therapy. Cancer Res; 74(11); 3146–56. ©2014 AACR.
Data from TIGAR Has a Dual Role in Cancer Cell Survival through Regulating Apoptosis and Autophagy
Authors: Xie Jia-Ming , Li Bin , Yu Hong-Pei , Gao Quan-Geng , Li Wei , Wu Hao-Rong , Qin Zheng-Hong
Published: March 2024

Abstract
The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose- and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127–38. ©2014 AACR.
Data from Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells
Authors: Wang Xiao-kun , He Jie-hua , Xu Jing-hong , Ye Sheng , Wang Fang , Zhang Hui , Huang Zhen-cong , To Kenneth Kin Wah , Fu Li-wu
Published: March 2024

Abstract
Cancer stem cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence that they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ATP-binding cassette subfamily G member 2 (ABCG2) confers chemoresistance to CSCs, where it serves as a potential biomarker and therapeutic target. Here, we show that afatinib, a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4, preferentially eliminated side population cells with CSC character, in both cell lines and patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells, afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA-damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome, or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication. Cancer Res; 74(16); 4431–45. ©2014 AACR.
Data from A Regulatory Loop Involving miR-22, Sp1, and c-Myc Modulates CD147 Expression in Breast Cancer Invasion and Metastasis
Authors: Kong Ling-Min , Liao Cheng-Gong , Zhang Yang , Xu Jing , Li Yu , Huang Wan , Zhang Yi , Bian Huijie , Chen Zhi-Nan
Published: March 2024

Abstract
Breast cancer is the most common cancer in women for which the metastatic process is still poorly understood. CD147 is upregulated in breast cancer and has been associated with tumor progression, but little is known about its regulatory mechanisms. In this study, we demonstrated that CD147 was overexpressed in breast cancer tissues and cell lines, and the high expression correlated with tumor invasion and metastasis. We also found that the transcription factors Sp1 and c-Myc could bind to the CD147 promoter and enhance its expression. The CD147 mRNA has a 748-bp 3′-untranslated region (UTR) with many miRNA target sites, suggesting possible regulation by miRNAs. We discovered that miR-22 repressed CD147 expression by directly targeting the CD147 3′UTR. We also determined that miR-22 could indirectly participate in CD147 modulation by downregulating Sp1 expression. miR-22 could form an autoregulatory loop with Sp1, which repressed miR-22 transcription by binding to the miR-22 promoter. Together with the c-Myc–mediated inhibition of miR-22 expression, our investigation identified a miR-22/Sp1/c-Myc network that regulates CD147 gene transcription. In addition, miR-22 overexpression suppressed breast cancer cell invasion, metastasis, and proliferation by targeting CD147 in vitro and in vivo. Furthermore, we found that miR-22 was significantly downregulated in breast cancer tissues and that its expression was inversely correlated with the tumor–node–metastasis stage and lymphatic metastasis in patients. Our study provides the first evidence that an miR-22/Sp1/c-Myc network regulates CD147 upregulation in breast cancer and that miR-22 represses breast cancer invasive and metastatic capacities. Cancer Res; 74(14); 3764–78. ©2014 AACR.
Data from The Cancer Stem Cell Marker Aldehyde Dehydrogenase Is Required to Maintain a Drug-Tolerant Tumor Cell Subpopulation
Authors: Raha Debasish , Wilson Timothy R. , Peng Jing , Peterson David , Yue Peng , Evangelista Marie , Wilson Catherine , Merchant Mark , Settleman Jeff
Published: March 2024

Abstract
Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug-tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy. Cancer Res; 74(13); 3579–90. ©2014 AACR.
Data from SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C
Authors: Liu Dan , Li Li , Zhang Xiao-Xue , Wan Dong-Yi , Xi Bi-Xin , Hu Zheng , Ding Wen-Cheng , Zhu Da , Wang Xiao-Li , Wang Wei , Feng Zuo-Hua , Wang Hui , Ma Ding , Gao Qing-Lei
Published: March 2024

Abstract
Lymphatic vessels are one of the major routes for the dissemination of cancer cells. Malignant tumors release growth factors such as VEGF-C to induce lymphangiogenesis, thereby promoting lymph node metastasis. Here, we report that sine oculis homeobox homolog 1 (SIX1), expressed in tumor cells, can promote tumor lymphangiogenesis and lymph node metastasis by coordinating with TGFβ to increase the expression of VEGF-C. Lymphangiogenesis and lymph node metastasis in cervical cancer were closely correlated with higher expression of SIX1 in tumor cells. By enhancing VEGF-C expression in tumor cells, SIX1 could augment the promoting effect of tumor cells on the migration and tube formation of lymphatic endothelial cells (LEC) in vitro and lymphangiogenesis in vivo. SIX1 enhanced TGFβ-induced activation of SMAD2/3 and coordinated with the SMAD pathway to modulate VEGF-C expression. Together, SIX1 and TGFβ induced much higher expression of VEGF-C in tumor cells than each of them alone. Despite its effect in promoting VEGF-C expression, TGFβ could inhibit lymphangiogenesis by directly inhibiting tube formation by LECs. However, the increased production of VEGF-C not only directly promoted migration and tube formation of LECs but also thwarted the inhibitory effect of TGFβ on LECs. That is, tumor cells that expressed high levels of SIX1 could promote lymphangiogenesis and counteract the negative effects of TGFβ on lymphangiogenesis by increasing the expression of VEGF-C. These findings provide new insights into tumor lymphangiogenesis and the various roles of TGFβ signaling in tumor regulation. Our results also suggest that SIX1/TGFβ might be a potential therapeutic target for preventing lymph node metastasis of tumor. Cancer Res; 74(19); 5597–607. ©2014 AACR.
Data from Mycoplasma Hyorhinis Infection Promotes NF-κB–Dependent Migration of Gastric Cancer Cells
Authors: Duan Hongying , Chen Ling , Qu Like , Yang Hua , Song Sonya Wei , Han Yong , Ye Meihua , Chen Wanyuan , He Xianglei , Shou Chengchao
Published: March 2024

Abstract
Chronic infection of Mycoplasma hyorhinis (M. hyorhinis) has been postulated to be associated with several types of cancer, but its effect on patients' survival and host factors mediating its infection remain unclear. Herein, we demonstrated that M. hyorhinis p37 protein expression in gastric cancer tissues predicts poor survival and associates with metastasis. M. hyorhinis infects mammalian cells and promotes gastric cancer cell invasiveness via its membrane protein p37. Synthesized peptide corresponding to the N-terminus of p37 prevents M. hyorhinis infection. Host Annexin A2 (ANXA2) interacts with the N-terminus of p37. In addition, EGFR forms a complex with p37 and ANXA2, and is required for M. hyorhinis–induced phosphorylation and membrane recruitment of ANXA2. M. hyorhinis infection is inhibited by siRNA-mediated knockdown of ANXA2 or EGFR, but is enhanced by expression of ectopic ANXA2 or EGFR. Downstream of ANXA2 and EGFR, the NF-κB pathway is activated and mediates M. hyorhinis–driven cell migration. In conclusion, our study unveils the effect of M. hyorhinis infection on gastric cancer survival and uncovers the mechanisms by which M. hyorhinis infects mammalian cells and promotes cancer cell migration. Cancer Res; 74(20); 5782–94. ©2014 AACR.
Data from Hsp70–Bag3 Interactions Regulate Cancer-Related Signaling Networks
Authors: Colvin Teresa A. , Gabai Vladimir L. , Gong Jianlin , Calderwood Stuart K. , Li Hu , Gummuluru Suryaram , Matchuk Olga N. , Smirnova Svetlana G. , Orlova Nina V. , Zamulaeva Irina A. , Garcia-Marcos Mikel , Li Xiaokai , Young Z.T. , Rauch Jennifer N. , Gestwicki Jason E. , Takayama Shinichi , Sherman Michael Y.
Published: March 2024

Abstract
Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70–Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70–Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70–Bag3 complex may offer an appealing anticancer target. Cancer Res; 74(17); 4731–40. ©2014 AACR.
Data from SA-4-1BBL and Monophosphoryl Lipid A Constitute an Efficacious Combination Adjuvant for Cancer Vaccines
Authors: Srivastava Abhishek K. , Dinc Gunes , Sharma Rajesh K. , Yolcu Esma S. , Zhao Hong , Shirwan Haval
Published: March 2024

Abstract
Vaccines based on tumor-associated antigens (TAA) have limited therapeutic efficacy due to their weak immunogenic nature and the various immune evasion mechanisms active in advanced tumors. In an effort to overcome these limitations, we evaluated a combination of the T-cell costimulatory molecule SA-4-1BBL with the TLR4 agonist monophosphoryl lipid A (MPL) as a novel vaccine adjuvant system. In the TC-1 mouse allograft model of human papilloma virus (HPV)-induced cancer, a single administration of this combination adjuvant with HPV E7 protein caused tumor rejection in all tumor-bearing mice. On its own, SA-4-1BBL outperformed MPL in this setting. Against established tumors, two vaccinations were sufficient to elicit rejection in the majority of mice. In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced dendritic cell activation, CD8+ T-cell function, and an increased intratumoral ratio of CD8+ T effector cells to CD4+FoxP3+ T regulatory cells. Unexpectedly, use of MPL on its own was associated with unfavorable intratumoral ratios of these T-cell populations, resulting in suboptimal efficacy. The efficacy of MPL monotherapy was restored by depletion of T regulatory cells, whereas eliminating CD8+ T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFNγ played a critical role in supporting the therapeutic effect of SA-4-1BBL/MPL. Taken together, our results offer a preclinical proof of concept for the use of a powerful new adjuvant system for TAA-based cancer vaccines. Cancer Res; 74(22); 6441–51. ©2014 AACR.
Data from Notch Signaling Drives Stemness and Tumorigenicity of Esophageal Adenocarcinoma
Authors: Wang Zhiqiang , Da Silva Thiago G. , Jin Ke , Han Xiaoqing , Ranganathan Prathibha , Zhu Xiaoxia , Sanchez-Mejias Avencia , Bai Feng , Li Bin , Fei Dennis Liang , Weaver Kelly , Carpio Rodrigo Vasquez-Del , Moscowitz Anna E. , Koshenkov Vadim P. , Sanchez Lilly , Sparling Lynne , Pei Xin-Hai , Franceschi Dido , Ribeiro Afonso , Robbins David J. , Livingstone Alan S. , Capobianco Anthony J.
Published: March 2024

Abstract
Esophageal adenocarcinoma ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the Western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal adenocarcinoma and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient-derived xenograft models, we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patient's ultrasound-assisted endoscopic–derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating esophageal adenocarcinoma, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in esophageal adenocarcinoma treatment. Cancer Res; 74(21); 6364–74. ©2014 AACR.
Data from ABCB5 Maintains Melanoma-Initiating Cells through a Proinflammatory Cytokine Signaling Circuit
Authors: Wilson Brian J. , Saab Karim R. , Ma Jie , Schatton Tobias , Pütz Pablo , Zhan Qian , Murphy George F. , Gasser Martin , Waaga-Gasser Ana Maria , Frank Natasha Y. , Frank Markus H.
Published: March 2024

Abstract
The drug efflux transporter ABCB5 identifies cancer stem–like cells (CSC) in diverse human malignancies, where its expression is associated with clinical disease progression and tumor recurrence. ABCB5 confers therapeutic resistance, but other functions in tumorigenesis independent of drug efflux have not been described that might help explain why it is so broadly overexpressed in human cancer. Here we show that in melanoma-initiating cells, ABCB5 controls IL1β secretion, which serves to maintain slow cycling, chemoresistant cells through an IL1β/IL8/CXCR1 cytokine signaling circuit. This CSC maintenance circuit involved reciprocal paracrine interactions with ABCB5-negative cancer cell populations. ABCB5 blockade induced cellular differentiation, reversed resistance to multiple chemotherapeutic agents, and impaired tumor growth in vivo. Together, our results defined a novel function for ABCB5 in CSC maintenance and tumor growth. Cancer Res; 74(15); 4196–207. ©2014 AACR.
Data from A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets
Authors: Taguchi Ayumu , Taylor Allen D. , Rodriguez Jaime , Çeliktaş Müge , Liu Hui , Ma Xiaotu , Zhang Qing , Wong Chee-Hong , Chin Alice , Girard Luc , Behrens Carmen , Lam Wan L. , Lam Stephen , Minna John D. , Wistuba Ignacio I. , Gazdar Adi F. , Hanash Samir M.
Published: March 2024

Abstract
Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared with other nontumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications. Cancer Res; 74(17); 4694–705. ©2014 AACR.
Data from CtBP2 Modulates the Androgen Receptor to Promote Prostate Cancer Progression
Authors: Takayama Ken-ichi , Suzuki Takashi , Fujimura Tetsuya , Urano Tomohiko , Takahashi Satoru , Homma Yukio , Inoue Satoshi
Published: March 2024

Abstract
The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal–binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling. Cancer Res; 74(22); 6542–53. ©2014 AACR.
Data from mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress
Authors: Li Jing , Shin Sejeong , Sun Yang , Yoon Sang-Oh , Li Chenggang , Zhang Erik , Yu Jane , Zhang Jianming , Blenis John
Published: March 2024

Abstract
mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816–27. ©2016 AACR.
Data from Androgen Receptor Is the Key Transcriptional Mediator of the Tumor Suppressor SPOP in Prostate Cancer
Authors: Geng Chuandong , Rajapakshe Kimal , Shah Shrijal S. , Shou John , Eedunuri Vijay Kumar , Foley Christopher , Fiskus Warren , Rajendran Mahitha , Chew Sue Anne , Zimmermann Martin , Bond Richard , He Bin , Coarfa Cristian , Mitsiades Nicholas
Published: March 2024

Abstract
Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3–mediated effects, SPOP also exerts SRC-3–independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma–associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP. Cancer Res; 74(19); 5631–43. ©2014 AACR.
Data from miRNA-128 Suppresses Prostate Cancer by Inhibiting BMI-1 to Inhibit Tumor-Initiating Cells
Authors: Jin Min , Zhang Tao , Liu Can , Badeaux Mark A. , Liu Bigang , Liu Ruifang , Jeter Collene , Chen Xin , Vlassov Alexander V. , Tang Dean G.
Published: March 2024

Abstract
microRNA-128 (miR128) is reduced in prostate cancer relative to normal/benign prostate tissues, but causal roles are obscure. Here we show that exogenously introduced miR128 suppresses tumor regeneration in multiple prostate cancer xenograft models. Cancer stem–like cell (CSC)–associated properties were blocked, including holoclone and sphere formation as well as clonogenic survival. Using a miR128 sensor to distinguish cells on the basis of miR128 expression, we found that miR128-lo cells possessed higher clonal, clonogenic, and tumorigenic activities than miR128-hi cells. miR128 targets the stem cell regulatory factors BMI-1, NANOG, and TGFBR1, the expression of which we found to vary inversely with miR128 expression in prostate cancer stem/progenitor cell populations. In particular, we defined BMI-1 as a direct and functionally relevant target of miR128 in prostate cancer cells, where these genes were reciprocally expressed and exhibited opposing biological functions. Our results define a tumor suppressor function for miR128 in prostate cancer by limiting CSC properties mediated by BMI-1 and other central stem cell regulators, with potential implications for prostate cancer gene therapy. Cancer Res; 74(15); 4183–95. ©2014 AACR.
Data from Dsh Homolog DVL3 Mediates Resistance to IGFIR Inhibition by Regulating IGF-RAS Signaling
Authors: Gao Shan , Bajrami Ilirjana , Verrill Clare , Kigozi Asha , Ouaret Djamila , Aleksic Tamara , Asher Ruth , Han Cheng , Allen Paul , Bailey Deborah , Feller Stephan , Kashima Takeshi , Athanasou Nicholas , Blay Jean-Yves , Schmitz Sandra , Machiels Jean-Pascal , Upile Nav , Jones Terry M. , Thalmann George , Ashraf Shazad Q. , Wilding Jennifer L. , Bodmer Walter F. , Middleton Mark R. , Ashworth Alan , Lord Christopher J. , Macaulay Valentine M.
Published: March 2024

Abstract
Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK–ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor–bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc–Grb2–SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition. Cancer Res; 74(20); 5866–77. ©2014 AACR.
Data from Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19
Authors: Zhou Mei , Wang Xueyan , Phung Van , Lindhout Darrin A. , Mondal Kalyani , Hsu Jer-Yuan , Yang Hong , Humphrey Mark , Ding Xunshan , Arora Taruna , Learned R. Marc , DePaoli Alex M. , Tian Hui , Ling Lei
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19–FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer. Cancer Res; 74(12); 3306–16. ©2014 AACR.
Data from A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition
Authors: Carmona F. Javier , Davalos Veronica , Vidal Enrique , Gomez Antonio , Heyn Holger , Hashimoto Yutaka , Vizoso Miguel , Martinez-Cardus Anna , Sayols Sergi , Ferreira Humberto J. , Sánchez-Mut Jose V. , Morán Sebastián , Margelí Mireia , Castella Eva , Berdasco Maria , Stefansson Olafur A. , Eyfjord Jorunn E. , Gonzalez-Suarez Eva , Dopazo Joaquín , Orozco Modesto , Gut Ivo G. , Esteller Manel
Published: March 2024

Abstract
Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells, and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition. The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of Madin–Darby canine kidney cells undergoing EMT and translated the identified differentially methylated regions to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples. Cancer Res; 74(19); 5608–19. ©2014 AACR.
Data from Modeling Lung Cancer Evolution and Preclinical Response by Orthotopic Mouse Allografts
Authors: Ambrogio Chiara , Carmona Francisco J. , Vidal August , Falcone Mattia , Nieto Patricia , Romero Octavio A. , Puertas Sara , Vizoso Miguel , Nadal Ernest , Poggio Teresa , Sánchez-Céspedes Montserrat , Esteller Manel , Mulero Francisca , Voena Claudia , Chiarle Roberto , Barbacid Mariano , Santamaría David , Villanueva Alberto
Published: March 2024

Abstract
Cancer evolution is a process that is still poorly understood because of the lack of versatile in vivo longitudinal studies. By generating murine non–small cell lung cancer (NSCLC) orthoallobanks and paired primary cell lines, we provide a detailed description of an in vivo, time-dependent cancer malignization process. We identify the acquisition of metastatic dissemination potential, the selection of co-driver mutations, and the appearance of naturally occurring intratumor heterogeneity, thus recapitulating the stochastic nature of human cancer development. This approach combines the robustness of genetically engineered cancer models with the flexibility of allograft methodology. We have applied this tool for the preclinical evaluation of therapeutic approaches. This system can be implemented to improve the design of future treatments for patients with NSCLC. Cancer Res; 74(21); 5978–88. ©2014 AACR.
Data from Globo-H Ceramide Shed from Cancer Cells Triggers Translin-Associated Factor X-Dependent Angiogenesis
Authors: Cheng Jing-Yan , Wang Sheng-Hung , Lin Juway , Tsai Yi-Chien , Yu John , Wu Jen-Chine , Hung Jung-Tung , Lin Jin-Jin , Wu Yih-Yiing , Yeh Kun-Tu , Yu Alice L.
Published: March 2024

Abstract
Tumor angiogenesis is a critical element of cancer progression, and strategies for its selective blockade are still sought. Here, we examine the angiogenic effects of Globo-H ceramide (GHCer), the most prevalent glycolipid in a majority of epithelial cancers and one that acts as an immune checkpoint. Here, we report that GHCer becomes incorporated into endothelial cells through the absorption of microvesicles shed from tumor cells. In endothelial cells, GHCer addition induces migration, tube formation, and intracellular Ca2+ mobilization in vitro and angiogenesis in vivo. Breast cancer cells expressing high levels of GHCer displayed relatively greater tumorigenicity and angiogenesis compared with cells expressing low levels of Globo-H. Clincally, GHCer+ breast cancer specimens contained higher vessel density than GHCer− breast cancer specimens. Mechanistic investigations linked the angiogenic effects of GHCer to its endocytosis and binding to TRAX, with consequent release of PLCβ1 from TRAX to trigger Ca2+ mobilization. Together, our findings highlight the importance of GHC as a target for cancer therapy by providing new information on its key role in tumor angiogenesis. Cancer Res; 74(23); 6856–66. ©2014 AACR.