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  • American Association for Cancer Research (AACR)  (28)
  • 1
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    Online Resource
    Abstract 4149: Epidermal growth factor-induced cyclooxygenase-2 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4149-4149
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4149-4149
    Abstract: Epidermal growth factor receptor (EGFR) activation is a major cause of cell metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). However, whether the induction of cyclooxygenase-2 (COX-2) correlates with EGF-enhanced HNSCC metastasis remains unclear. Interestingly, we found that EGF induced COX-2 expression mainly in HNSCC. The tumor cell transformation induced by EGF was repressed with COX-2 knockdown, and this repression was reversed by simultaneously treating the cells with EGF and prostaglandin E2 (PGE2). The down-regulation of COX-2 expression or inhibition of COX-2 activity significantly blocked EGF-enhanced cell migration and invasion, but the addition of PGE2 compensated for this blockage in COX-2-knockdown cells. Interestingly, COX-2 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP3 and fibronectin expression and Rac1/cdc42 activation; this reduction in MMPs and the fibronectin/Rac1/cdc42 axis by the depletion of COX-2 was also rescued when the cells were treated with PGE2. Furthermore, the depletion of fibronectin impeded the COX-2-enhanced binding of HNSCC cells to endothelial cells and tumor cells metastatic seeding of the lungs. These results provide new insight that EGF-induced COX-2 enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of COX-2 expression and activation suggests a potential strategy for the treatment of EGFR-mediated HNSCC metastasis. Citation Format: Jinn-Yuan Hsu, Kwang-Yu Chang, Shang-Hung Chen, Chung-Ta Lee, Sheng-Tsung Chang, Hung-Chi Cheng, Wen-Chang Chang, Ben-Kuen Chen. Epidermal growth factor-induced cyclooxygenase-2 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4149. doi:10.1158/1538-7445.AM2015-4149
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4149
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
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    Abstract A16: Metformin is a potential nontoxic adjuvant to enhance the efficacy of non-PDL1/PD-1 targeting immune therapies
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 4_Supplement ( 2020-04-01), p. A16-A16
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 4_Supplement ( 2020-04-01), p. A16-A16
    Abstract: Investigations into various immunotherapies combined with conventional anticancer drugs are ongoing to increase therapeutic efficacy. However, combination therapy generally increases the risk of side effects. To achieve high efficacy with minimal side effects, nontoxic adjuvants should be identified and appropriate combinations should be designed based on the functional mechanism. In this regard, metformin can be an attractive candidate for immunotherapeutic adjuvants. Metformin is a widely used oral medication for type 2 diabetes (T2D) and has been recognized as a safe and well-tolerated drug through several decades of clinical experience. Interestingly, metformin also exhibits antitumor effects as several case-control studies for T2D patients indicated that metformin reduces the incidence of various cancer types. However, the functions and the detailed mechanism of metformin related to cancer immunity are not fully understood. In this study, we investigated the antitumor effects of metformin in relation to cancer immunity in the tumor microenvironment. Our data showed that AMPK activated by metformin decreases the expression of PD-L1 in the cancer cells, blocking PD-L1’s ability to aid cancer cells in escaping immune surveillance. This is caused by the mechanism in which phosphorylation of PD-L1 at S195 induces an abnormal glycan structure that leads to endoplasmic reticulum-associated degradation. In addition, we have obtained human breast tumor tissues from a previous clinical trial investigating metformin as treatment for breast cancer patients. The data from human tumor tissues also provided strong support to our current conclusion, namely AMPK activated by metformin reduces the level of PD-L1. On the basis of these results, we validated the possibility of metformin as an adjuvant to boost the efficacy of previous immunotherapy without toxicity. Our findings suggest that metformin has strong potential to be used as an adjuvant for immunotherapy. Metformin is expected to have synergistic effect with various non-PDL1/PD-1 targeting immune therapies without additional toxicity. Citation Format: Jong-Ho Cha, Wen-Hao Yang, Weiya Xia, Yongkun Wei, Li-Chuan Chan, Seung-Oe Lim, Chia-Wei Li, Jennifer Hsu, Hung-Ling Wang, Chu-Wei Kuo, Wei-Chao Chang, Sirwan Hadad, Colin Purdie, Aaron McCoy, Jennifer Litton, Elizabeth Mittendorf, Stacy Moulder, William Symmans, Alastair M Thompson, Helen Piwnica-Worms, Chung-Hsuan Chen, Kay-Hooi Khoo, Mien-Chie Hung. Metformin is a potential nontoxic adjuvant to enhance the efficacy of non-PDL1/PD-1 targeting immune therapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A16.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM18-A16
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract 3017: Oct4B mediates hypoxia induced epithelial mesenchymal trans-differentiation of lung cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3017-3017
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3017-3017
    Abstract: Hypoxia, a reduction of normal oxygen levels in cells or tissues, creates a variety of changes in cell metabolism, eliciting a set of genes involved in tissue development and cancer progression. Though Oct4, a homebox transcription factor, is essential for self-renewal of embryonic stem cells, little is known about the functional role of Oct4 in tumorigenesis. In this study, we discovered that hypoxia induces a short isoform of Oct4, termed as Oct4B, in lung cancer through a HIF-2α dependent pathway. Oct4B induced cell proliferation, anchorage-independent growth, and xenograft tumor formation of lung cancer cells, indicating the oncogenic potential of Oct4B. Moreover, ectopic expression of Oct4B in lung cancer cells induced epithelial mesenchymal tans-differentiation (EMT), promoting cell migration and invasion. We observed that Oct4B bound to Slug promoter upon hypoxia stimulation, promoting EMT as well as invasion of lung cancer cells. Thus, our findings provide a novel mechanism of how Oct4B mediates hypoxia signaling to encourage malignancy of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3017. doi:1538-7445.AM2012-3017
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3017
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Glutathione S -Transferase Mu2 Suppresses Cancer Cell Metastasis in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 5 ( 2013-05-01), p. 518-529
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 5 ( 2013-05-01), p. 518-529
    Abstract: Glutathione S-transferase mu2 (GST-M2) is a phase II detoxification enzyme. Low expression of GST-M2 in lung cancers is due to hypermethylation of its promoter. Lung cancer with the GST mu-null genotype is associated with shorter survival. However, a correlation between GST-M2 and important clinical parameters, as well as the migration of GST-M2–defective cells in lung cancer, has not been established. In the present study, we investigate the role of GST-M2 in cell migration and actin disassembly in lung cancer cells. GST-M2 and CCN2 mRNA levels were significantly reduced in non–small cell lung cancer (NSCLC) tumors when compared with matched normal lung tissues in 82 patients with NSCLC. We found that high expressions of both GST-M2 and CCN2 are correlated with favorable survival of patients with lung cancer when compared with similar patients without GST-M2 or CCN2 expression. GST-M2 can induce CCN2 expression by driving the CCN2 proximal promoter. Overexpression of GST-M2 decreases the formation of filopodia, resulting in remodeling of the reorganized cytoskeletons. Overexpression of GST-M2 significantly suppressed cancer cell migration on wound-healing assay. In addition, overexpression of GST-M2 dramatically reduced tumor growth and metastasis in a xenograft mouse model. These data highlight the potential of GST-M2 as a novel tumor suppressor. GST-M2 increases the expression of CCN2 in lung cancer cells, which inhibits cancer cell migration in lung cancer and animal models. Mol Cancer Res; 11(5); 518–29. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-12-0488
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 5
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    ASS1 as a Novel Tumor Suppressor Gene in Myxofibrosarcomas: Aberrant Loss via Epigenetic DNA Methylation Confers Aggressive Phenotypes, Negative Prognostic Impact, and Therapeutic Relevance
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 11 ( 2013-06-01), p. 2861-2872
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 11 ( 2013-06-01), p. 2861-2872
    Abstract: Purpose: The principal goals were to identify and validate targetable metabolic drivers relevant to myxofibrosarcoma pathogenesis using a published transcriptome. Experimental Design: As the most significantly downregulated gene regulating amino acid metabolism, argininosuccinate synthetase (ASS1) was selected for further analysis by methylation-specific PCR, pyrosequencing, and immunohistochemistry of myxofibrosarcoma samples. The roles of ASS1 in tumorigenesis and the therapeutic relevance of the arginine-depriving agent pegylated arginine deiminase (ADI-PEG20) were elucidated in ASS1-deficient myxofibrosarcoma cell lines and xenografts with and without stable ASS1 reexpression. Results: ASS1 promoter hypermethylation was detected in myxofibrosarcoma samples and cell lines and was strongly linked to ASS1 protein deficiency. The latter correlated with increased tumor grade and stage and independently predicted a worse survival. ASS1-deficient cell lines were auxotrophic for arginine and susceptible to ADI-PEG20 treatment, with dose-dependent reductions in cell viability and tumor growth attributable to cell-cycle arrest in the S-phase. ASS1 expression was restored in 2 of 3 ASS1-deficient myxofibrosarcoma cell lines by 5-aza-2′-deoxycytidine, abrogating the inhibitory effect of ADI-PEG20. Conditioned media following ASS1 reexpression attenuated HUVEC tube-forming capability, which was associated with suppression of MMP-9 and an antiangiogenic effect in corresponding myxofibrosarcoma xenografts. In addition to delayed wound closure and fewer invading cells in a Matrigel assay, ASS1 reexpression reduced tumor cell proliferation, induced G1-phase arrest, and downregulated cyclin E with corresponding growth inhibition in soft agar and xenograft assays. Conclusions: Our findings highlight ASS1 as a novel tumor suppressor in myxofibrosarcomas, with loss of expression linked to promoter methylation, clinical aggressiveness, and sensitivity to ADI-PEG20. Clin Cancer Res; 19(11); 2861–72. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-2641
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
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    Abstract 2199: SOX1 functions as a tumor suppressor through antagonizing WNT/β-catenin signaling pathway in hepatocellular carcinoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2199-2199
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2199-2199
    Abstract: Oncogenic activation of the Wnt/β-catenin signaling pathway is common in hepatocellular carcinoma (HCC). Aberrant hypermethylation of tumor suppressor genes in their promoter regions is frequently found in human cancers. Our previous works have demonstrated that SOX1 gene was hypermethylated in HCCs as well as cervical and ovarian cancers. A growing number of papers suggest that SOX family proteins, such as SOX9, SOX17, SOX4 and SOX2, serve as either tumor suppressors or oncoproteins through manipulating Wnt signaling pathway in different types of cancer. However the molecular mechanism is not well understood. In this study, we established an inducible system to overexpress SOX1 in HCC cell lines and checked whether SOX1 have tumor suppressor function in vitro and in vivo. We found that overexpression of SOX1 could inhibit cell proliferation and colony formation in HCC cells and suppress tumor growth in xenograft mice. Next we used GST pull-down, co-immunoprecipitation (co-IP), immunocytochemistry and luciferase reporter assay to study whether SOX1 could interact with β-catenin to regulate Wnt/β-catenin signaling. Our data showed that SOX1 is physically associated with β-catenin/ TCF complex and could inhibit the TCF-dependent transcriptional activity. Furthermore, SOX1 was co-localized with β-catenin in nucleus by confocal microscopy. These results suggest that SOX1 functions as a tumor suppressor through interfering Wnt/β-catenin signaling in HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2011-2199
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2199
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 3359: JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3359-3359
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3359-3359
    Abstract: JMJD5, a JmjC-domain containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxia-induced cell proliferation. JMJD5 interacts directly with PKM2, pyruvate kinase M2, to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes HIF-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α are all recruited to the HRE (hypoxia response element) site in the LDHA and PKM2 loci, and mediates the recruitment of the latter two proteins. Our data uncovers a new mechanism whereby PKM2 can be regulated by factor-binding induced homo/hetero-oligomeric restructuring, paving the way to cell metabolic reprogram. Citation Format: Hung-Jung Wang, Ya-Ju Hsieh, Wen-Chi Cheng, Chun-Pu Lin, Yu-Shan Lin, So-Fang Yang, Chung-Ching Chen, Yoshihiro Izumiya, Jau-Song Yu, Hsing-Jien Kung, Wen-Ching Wang. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3359. doi:10.1158/1538-7445.AM2014-3359
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3359
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract B186: ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B186-B186
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B186-B186
    Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers and is also a leading cause of cancer-related deaths worldwide. Until now, treatments for HCC remain limited, especially for the shortage of promising systemic therapies to replace systemic chemotherapy. Sorafenib, the first drug applied in targeted therapy for HCC, was approved and drew considerable attention. However, the efficacy and side effects of sorafenib are still unsatisfied, which make sorafenib far from ideal for treatment of HCC. Thus, developing novel therapeutics for HCC is necessary. A novel compound, ITRI-2531, is developed to improve the efficacy from sorafenib. ITRI-2531 shows cytotoxicity in HCC cell lines (Huh-7 and PLC/PRF/5) and patient-derived HCC tissue cell lines. In studies of kinase activities, ITRI-2531 suppresses the phosphorylation of MEK and ERK in PLC/PRF/5 cells and shows inhibition of multiple kinases (FLT3, FLT4, PDGFRA, PGDFRB, and VEGFR2) in KINOMEscanTM study. In in vivo studies, oral treatment of ITRI-2531 repressed subcutaneous Huh-7 and PLC/PRF/5 tumor growth in severe combined immunodeficient (SCID) mice and shows better efficacy than sorafinib. Moreover, ITRI-2531 prolongs the survival of SCID mice with orthotopic patient-derived xenograft tumor and suppresses alpha-fetoprotein in serum. On the other hand, ITRI-2531 also has good pharmacokinetic profiles. According to these results, we believe that ITRI-2531 warrants further evaluation as a new anti-HCC drug. Citation Format: Tsung-Keng Kuo, On Lee, Mai-Wei Lin, Li-Zong Lin, Chun-Min Liu, Tai-ju Hsieh, Chun-Chung Wang, Shyh-Horng Lin, Chia-Ni Chang, Hui-Chun Hsu, Nien-Tzu Chou, Chin-Pen Lai, Chih-Hung Chen, Chia-Mu Tu, Shih-Ta Chen, Yuan-Jang Tsai, Chih-Peng Liu, Jenn-Tsang Hwang, Jui-Wen Huang, Yen-Chun Chen, Chrong-Shiong Hwang, Hsiang-Wen Tseng. ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B186.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-B186
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 9
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    High Serum Iron Is Associated with Increased Cancer Risk
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 22 ( 2014-11-15), p. 6589-6597
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 22 ( 2014-11-15), p. 6589-6597
    Abstract: Epidemiologic studies linking high serum iron with cancer risks are limited and inconclusive, despite evidence implicating body iron in human carcinogenesis. A cohort of 309,443 adults in Taiwan who had no history of cancer had serum iron levels tested at the time of recruitment (1997–2008). Initially measured iron levels were associated with subsequent cancer risk by linking individuals with the National Cancer Registry and National Death File. HRs were calculated by the Cox model. One third of males (35%) and one fifth of females (18%) had high serum iron (≥120 μg/dL), which was associated with a 25% increase in risk for incidence of all cancers [HR, 1.25; 95% confidence interval (CI), 1.16–1.35] and with a 39% increase in risk for mortality from all cancers (HR, 1.39; 95% CI, 1.23–1.57). The relationship between serum iron and cancer risk was a J-shaped one, with higher cancer risk at both ends, either at lower than 60 μg/dL or higher than 120 μg/dL. At the higher end, cancer risk increased by 4% for every 10 μg/dL increment above 80 μg/dL, showing a dose–response relationship, with 60 to 79 μg/dL as a reference level. In a sensitivity analysis, the increases in risk were still observed after the first 5 years of cancer cases were excluded. Liver cancer risk was increased in HBV (−) non-hepatitis B carrier (3-fold) and HBV (+) hepatitis B carrier (24-fold). Lifestyle risks such as smoking, drinking, or inactivity interacted synergistically with high serum iron and significantly increased the cancer risks. The liver (HR, 2.49; 95% CI, 1.97–3.16) and the breast (HR, 1.31; 95% CI, 1.01–1.70) were the two major cancer sites where significant cancer risks were observed for serum iron either ≥120 μg/dL or ≥140 μg/dL, respectively. This study reveals that high serum iron is both a common disorder and a marker of increased risk for several cancers. Cancer Res; 74(22); 6589–97. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0360
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    ASPM Activates Hedgehog and Wnt Signaling to Promote Small Cell Lung Cancer Stemness and Progression
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 6 ( 2023-03-15), p. 830-844
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 6 ( 2023-03-15), p. 830-844
    Abstract: Small cell lung cancer (SCLC) is among the most aggressive and lethal human malignancies. Most patients with SCLC who initially respond to chemotherapy develop disease relapse. Therefore, there is a pressing need to identify novel driver mechanisms of SCLC progression to unlock treatment strategies to improve patient prognosis. SCLC cells comprise subsets of cells possessing progenitor or stem cell properties, while the underlying regulatory pathways remain elusive. Here, we identified the isoform 1 of the neurogenesis-associated protein ASPM (ASPM-I1) as a prominently upregulated stemness-associated gene during the self-renewal of SCLC cells. The expression of ASPM-I1 was found to be upregulated in SCLC cells and tissues, correlated with poor patient prognosis, and indispensable for SCLC stemness and tumorigenesis. A reporter array screening identified multiple developmental signaling pathways, including Hedgehog (Hh) and Wnt pathways, whose activity in SCLC cells depended upon ASPM-I1 expression. Mechanistically, ASPM-I1 stabilized the Hh transcriptional factor GLI1 at the protein level through a unique exon-18–encoded region by competing with the E3 ligases β-TrCP and CUL3. In parallel, ASPM-I1 sustains the transcription of the Hh pathway transmembrane regulator SMO through the Wnt−DVL3−β-catenin signaling axis. Functional studies verified that the ASPM-I1–regulated Hh and Wnt activities significantly contributed to SCLC aggressiveness in vivo. Consistently, the expression of ASPM-I1 positively correlated with GLI1 and stemness markers in SCLC tissues. This study illuminates an ASPM-I1–mediated regulatory module that drives tumor stemness and progression in SCLC, providing an exploitable diagnostic and therapeutic target. Significance: ASPM promotes SCLC stemness and aggressiveness by stabilizing the expression of GLI1, DVL3, and SMO, representing a novel regulatory hub of Hh and Wnt signaling and targetable vulnerability.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-2496
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 410466-3
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