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  • American Association for Cancer Research (AACR)  (47)
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  • 1
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 14_Supplement ( 2010-07-15), p. A25-A25
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 14_Supplement ( 2010-07-15), p. A25-A25
    Abstract: Human papillomavirus (HPV) is closely related with many kinds of cancers such as cervical, lung, and skin cancers, etc. HPV 16 showed intratypic variations that were known to differ in oncogenic potential and geographic distribution. This study was designed to analyze sequence variants in oncogenes E6, E7 and L1 of HPV 16 in cervical, lung, and skin cancers in Sichuan, China. Materials from 138 non-malignant controls, 122 cervical cancer patients, 104 lung cancer patients and 104 skin cancer patients were analyzed by PCR and direct sequencing. The infection rates of HPV 16 in cervical, lung, skin cancers were respectively 68.9%, 17.3%, 5.8%. The Asian prototype was the most prevalent variant in cervical cancer in Sichuan (40%). Compared with that detected in cervical cancer, lung and skin cancers showed more monotonous variations, but several mutations on L1 genes existed only in lung or skin cancers such as G6818C, C7011A, and C7017A. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A25.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 2
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 1 ( 2020-01-01), p. 86-103
    Abstract: Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, p. 1
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 13 ( 2018-07-01), p. 3204-3216
    Abstract: Purpose: Hypoxia-inducible factor-2α (HIF2α) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2α activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2α activity and of sorafenib resistance in hypoxic HCC cells. Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2α on hypoxic HCC cells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2α level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells. Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2α and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2α activity by promoting HIF2α nuclear translocation via MAPK pathway. The activation of HIF2α then led to the enhanced activation of VEGF, cyclin D1, and TGFα/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2–specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment. Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2α expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGFα/EGFR pathway. This study highlights the potential of COX-2–specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. Clin Cancer Res; 24(13); 3204–16. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 7, No. 1 ( 2009-01-01), p. 12-22
    Abstract: The gene of SKP2, located on chromosome 5p13, plays a critical role in cell cycle progression, especially at the G1-S transition, putatively through its control of several cell cycle regulator proteins including p27kip1, p21cip1, p57kip2, p130, cyclin E, and c-Myc. Previous studies in this laboratory revealed that gain of chromosome 5p was often seen in esophageal squamous cell carcinoma (ESCC). In the present study, we examined the amplification status and expression level of SKP2 in ESCC and investigated its clinicopathologic significance. Amplification and elevated expression of SKP2 correlated significantly with tumor stage and positive lymph node metastasis (P & lt; 0.05). The SKP2 protein expression level as determined by immunohistochemical staining showed a significant inverse correlation with p27 protein. In vivo assay showed that inhibition of SKP2 expression also decreased tumor growth and lung metastasis of ESCC cells. At the molecular level, knockdown of SKP2 by RNA interference inhibited cell migration and invasion ability. Knockdown of SKP2 expression sensitized cancer cells to anoikis, and a wobble mutant of SKP2 that is resistant to SKP2 small interfering RNA can rescue this effect. Expression level of pAkt decreased after SKP2 knockdown. Treatment of cells with phosphoinositidyl 3-kinase inhibitor (LY294002) and constitutively activator (insulin-like growth factor I) had significant effects on the anoikis of SKP2 RNA interference cells. These results show for the first time that SKP2 is amplified and overexpressed in ESCC. Elevated expression of SKP2 protected cancer cells from anoikis, and this effect was mediated, at least in part, by the phosphoinositidyl 3-kinase-Akt pathway. (Mol Cancer Res 2009;7(1):12–22)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 130-130
    Abstract: E3 ubiquitin ligase CRL4 complex activation requires cullin neddylation. MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, reportedly blocked cullin neddylation and inactivated cullin (CUL)-RING E3 ligases (CRLs). Studies have shown that MLN4924 inhibits cell proliferation and survival. We examined the oncostatic and cytotoxic properties of MLN4924 in ovarian cancer. MLN4924 blocked human cancer cell proliferation in nude mice by inhibiting CpG binding protein CFP1 expression. Loss of CFP1 reduced cell growth, promoted apoptosis, and increased senescence. CFP1-dependent H3K4 trimethylation is necessary to maintain the expression of target genes in ovarian cancer cells. We identified bone marrow stromal cell antigen 2 (BST2) and noggin (NOG) as direct targets of CFP1. Their expression was selectively induced by CFP1 deletion. Furthermore, deletion of NOG and overexpression of BST2 prevented the growth-inhibitory effect of CFP1 loss. Our study further demonstrated that CRL4 inactivation reduced CFP1 transcription and trimethylation on lysine 4 of histone H3, which in turn inhibited cell proliferation and induced apoptosis. Therefore, CRL4 constitutes a druggable target in ovarian cancer. Citation Format: Liu-qing Yang, Han-yin Hu, Yao Han, Heng-Yan Zhu, Xiao-min Wang, Lei Ao, Ying Xu, Xuan Huang, Xuan Che, Li-Zhong Wang, Ya-Bo Jiang, Chun-wei Xu, Shu-Qun Cheng, Michal Heger, Wei-wei Pan. CpG binding protein promotes cell proliferation through H3K4 methylation in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 130.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 24 ( 2022-12-15), p. 5455-5468
    Abstract: Development of B-cell lymphoma 2 (BCL-2)–specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein–protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575). Experimental Design: Computational modeling was used to design “lead” compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models. Results: Lisaftoclax selectively binds BCL-2 (Ki & lt; 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo. Conclusions: These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2–selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 14 ( 2019-07-15), p. 3542-3556
    Abstract: Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in colorectal carcinoma. SATB2-AS1 suppressed colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of colorectal carcinoma. Significance: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress colorectal cancer progression. See related commentary by Li, p. 3536
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Discovery Vol. 12, No. 12 ( 2022-12-02), p. 2820-2837
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 12, No. 12 ( 2022-12-02), p. 2820-2837
    Abstract: Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. Significance: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 17 ( 2019-09-01), p. 5407-5421
    Abstract: As a main rate-limiting subunit of the 2-oxoglutarate dehydrogenase multienzyme complex, oxoglutarate dehydrogenase like (OGDHL) is involved in the tricarboxylic acid cycle, and frequently downregulated in human carcinoma and suppresses tumor growth. However, little is known about the role of OGDHL in human cancer, especially pancreatic cancer. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by OGDHL modulating pancreatic cancer progression. Experimental Design: The expression and functional analysis of OGDHL, miR-214, and TWIST1 in human pancreatic cancer tissues, cell lines, and xenograft tumor model were investigated. The correlations between OGDHL and those markers were analyzed. Results: OGDHL was downregulated in human pancreatic cancer and predicted poor prognosis. OGDHL overexpression inhibited migration and invasion of pancreatic cancer cells and suppressed pancreatic cancer tumor growth. OGDHL was shown to be negatively regulated by miR-214. TWIST1 upregulation induced miR-214 expression in pancreatic cancer. OGDHL suppressed TWIST1 expression through promoting ubiquitin-mediated proteasomal degradation of HIF1α and regulating AKT pathways. A combination of OGDHL downregulation and TWIST1 and miR-214 overexpression predicted worse prognosis in patients with pancreatic cancer. Conclusions: We demonstrated the prognostic value of OGDHL, miR-214, and TWIST1 in pancreatic cancer, and elucidated a novel pathway in OGDHL-regulated inhibition of pancreatic cancer tumorigenesis and metastasis. These findings may lead to new targeted therapy for pancreatic cancer through regulating OGDHL, miR-214, and TWIST1.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3273-3273
    Abstract: In China, more than 80% of the esophageal cancer occurs in farmer village, and most of the esophageal cancer patients die at village home. Therefore, the cause of death for esophageal cancer patients has not been well characterized. The present study was thus undertaken to determine the causes of death in patients with esophageal squamous cell carcinoma (ESCC) to provide more information for further prevention and accurate treatment after ESCC diagnosed. All the 8,838 ESCC patients with a detailed cause of death in this study were derived from the ESCC database (1973-2015) in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University, China. All the patients were categorized by age ( & lt;50 years and≥50 years), gender (male and female) and pathological stage (early, middle and later stage). Chi-Square test was used to analyze the differences in different groups. The results demonstrated that, of the 8,838 died ESCC patients, there were 5,713 males (64.6%) with a mean age of 60.95±9.43 and 3,125 females (35.4%) with a mean age of 61.95±9.47. Notably, 69.5% of the patients died within five years after diagnosis, and the 1-, 3- and 5-year death after diagnosis for these died ESCC patients were 1622 (18.4%), 2960 (33.5%) and 1557 (17.6%), respectively. Overall, the major cause of death for ESCC was due to ESCC recurrence and metastasis (8500, 96.1%), and followed by cardiovascular disease (121, 1.4%), different infections (68, 0.8%), second cancer (52, 0.6%), accident (25, 0.3%), suicide (22, 0.2%), and uncertain cause (50, 0.6%). Furthermore, the major cause of death in males and females was similar (p & gt;0.05) and the cause of death by ESCC recurrence and metastasis, cardiovascular disease, different infections, second cancer, accident, suicide and uncertain cause was 96% (5485) 1.5% (84), 0.8% (44), 0.6% (34), 0.3% (18), 0.2% (16), 0.6% (32), respectively in males and 96.5% (3015), 1.1% (37), 0.8% (24) 0.6% (18), 0.2% (7), 0.2% (6) and 0.6% (18), respectively in females. The present results demonstrate that recurrence and metastasis are the major cause of death both in male and female for ESCC (96%). It is noteworthy that there are 0.2 percent of the ESCC patients have suicide which call for more attention of psychotherapy on cancer patients. [Supported by the Science and Technology Major Projects of Henan Province of China (161100311300), and Correspondence to: Li Dong Wang, the National Key Research and Development Program of China and Correspondence to: Li Dong Wang. Email: ldwang2007@126.com] Note: This abstract was not presented at the meeting. Citation Format: Xiang Yang Zhang, Jian Po Wang, Rui Ping Xu, Ya Qin Hou, Xiu Jian Chen, Ai Li Li, Xi Chen, Shuang Yin Han, Wei Xing Zhao, Li Sun, Min Wang, Wen Ting Fu, Li Dong Wang. Analysis of causes of death in patients with esophageal squamous cell carcinoma in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2017-3273
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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