胡国宏
博士 研究员 博士生导师
中国科学院上海营养与健康研究院 中科院肿瘤与微环境重点实验室
1. 转移的微环境调控机制。2. 肿瘤干细胞与转移。3. 肿瘤代谢调控与转移。
个性化签名
- 姓名:胡国宏
- 目前身份:在职研究人员
- 担任导师情况:博士生导师
- 学位:博士
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学术头衔:
博士生导师
- 职称:高级-研究员
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学科领域:
肿瘤学
- 研究兴趣:1. 转移的微环境调控机制。2. 肿瘤干细胞与转移。3. 肿瘤代谢调控与转移。
胡国宏,博士,研究员,博士生导师,中科院肿瘤与微环境重点实验室,肿瘤转移课题组组长。
简历:
2017-至 今 中国科学院上海营养与健康研究院 研究员,院长助理
2009-2016年 中国科学院上海生命科学研究院/上海交通大学医学院健康科学研究所,研究员
2014-2016年 中国科学院上海生命科学研究院/上海交通大学医学院健康科学研究所,副所长
2011-2014年 中国科学院上海生命科学研究院/上海交通大学医学院健康科学研究所,所长助理
2009-2009年 美国普林斯顿大学分子生物系,Associate Research Scholar
2005-2008年 美国普林斯顿大学分子生物系,博士后
2000-2005年 美国罗格斯大学(Rutgers University),分子遗传学,博士
1996-2000年 清华大学,生物科学与技术系,学士
研究方向:
1. 转移的微环境调控机制。肿瘤转移是癌症致死的主要原因。癌细胞对其所处微环境的适应及改造对转移过程有重要影响。我们主要研究癌细胞与转移微环境的互作机制,以及这些互作对肿瘤转移能力、转移的器官特异性、癌细胞的转移休眠/重激活状态的调控作用,并进一步发现有效预测肿瘤转移的分子标志物以及靶向肿瘤-微环境互作的策略。
2. 肿瘤干细胞与转移。肿瘤干细胞一般被认为是癌症发生、抗药及复发的“元凶”,但是肿瘤干细胞与转移的关系尚不清楚。我们主要研究肿瘤干细胞在转移中发挥的作用及调控机制,分析肿瘤干细胞的异质性,不同干细胞亚群的转移及调控,肿瘤干细胞与转移微环境的互作等,以期发现通过靶向肿瘤干细胞抑制转移的方法。
3. 肿瘤代谢调控与转移。肿瘤的Warburg效应已经引起广泛关注。我们主要研究在转移过程中的糖脂代谢调控,包括癌细胞自身的代谢异常模式、代谢微环境对癌细胞转移能力以及转移器官特异性的调控作用等。
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成果阅读
918
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成果数
31
Nucleic Acids Research,2006,34(17):e116
2006年09月01日
Microarray-based analysis of single nucleotide polymorphisms (SNPs) has many applications in large-scale genetic studies. To minimize the influence of experimental variation, microarray data usually need to be processed in different aspects including background subtraction, normalization and low-signal filtering before genotype determination. Although many algorithms are sophisticated for these purposes, biases are still present. In the present paper, new algorithms for SNP microarray data analysis and the software, AccuTyping, developed based on these algorithms are described. The algorithms take advantage of a large number of SNPs included in each assay, and the fact that the top and bottom 20% of SNPs can be safely treated as homozygous after sorting based on their ratios between the signal intensities. These SNPs are then used as controls for color channel normalization and background subtraction. Genotype calls are made based on the logarithms of signal intensity ratios using two cutoff values, which were determined after training the program with a dataset of ∼160 000 genotypes and validated by non-microarray methods. AccuTyping was used to determine >300 000 genotypes of DNA and sperm samples. The accuracy was shown to be >99%. AccuTyping can be downloaded from http://www2.umdnj.edu/lilabweb/publications/AccuTyping.html.
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The Journal of Biological Chemistry,2008,283():14910-1491
2008年04月14日
MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in which step(s) of the multistep metastatic cascade these miRNAs play a defined functional role. To study the functional importance of miRNAs in epithelial-mesenchymal transition (EMT), a process thought to initiate metastasis by enhancing the motility of tumor cells, we used a well established in vitro EMT assay: transforming growth factor-β-induced EMT in NMuMG murine mammary epithelial cells. We found that members of the miR-200 family, organized as two clusters in the genome, were repressed during EMT. Overexpression of each miRNA individually or as clusters in NMuMG cells hindered EMT by enhancing E-cadherin expression through direct targeting of ZEB1 and ZEB2, which encode transcriptional repressors of E-cadherin. In the 4TO7 mouse carcinoma cell line, which expresses low levels of endogenous E-cadherin and displays a mesenchymal phenotype, ectopic expression of the miR-200 family miRNAs significantly increased E-cadherin expression and altered cell morphology to an epithelial phenotype. Furthermore, ectopic expression of each miR-200 miRNA cluster significantly reduced the in vitro motility of 4TO7 cells in migration assays. These results suggested that loss of expression of the miR-200 family members may play a critical role in the repression of E-cadherin by ZEB1 and ZEB2 during EMT, thereby enhancing migration and invasion during cancer progression.
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【期刊论文】A highly sensitive and specific system for large-scale gene expression profiling
BMC Genomics ,2008,9():9
2008年01月10日
Background Rapid progress in the field of gene expression-based molecular network integration has generated strong demand on enhancing the sensitivity and data accuracy of experimental systems. To meet the need, a high-throughput gene profiling system of high specificity and sensitivity has been developed. Results By using specially designed primers, the new system amplifies sequences in neighboring exons separated by big introns so that mRNA sequences may be effectively discriminated from other highly related sequences including their genes, unprocessed transcripts, pseudogenes and pseudogene transcripts. Probes used for microarray detection consist of sequences in the two neighboring exons amplified by the primers. In conjunction with a newly developed high-throughput multiplex amplification system and highly simplified experimental procedures, the system can be used to analyze >1,000 mRNA species in a single assay. It may also be used for gene expression profiling of very few (n = 100) or single cells. Highly reproducible results were obtained from duplicate samples with the same number of cells, and from those with a small number (100) and a large number (10,000) of cells. The specificity of the system was demonstrated by comparing results from a breast cancer cell line, MCF-7, and an ovarian cancer cell line, NCI/ADR-RES, and by using genomic DNA as starting material. Conclusion Our approach may greatly facilitate the analysis of combinatorial expression of known genes in many important applications, especially when the amount of RNA is limited.
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Genes & Dev.,2009,23():1882-1894
2009年07月16日
Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor α (TGFα) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer.
EGFR bone metastasis breast cancer metalloprotease osteoclastogenesis
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Cancer Cell,2009,15(1):胡国宏
2009年01月06日
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.
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【期刊论文】From Breast to the Brain: Unraveling the Puzzle of Metastasis Organotropism
Journal of Molecular Cell Biology,2009,1(1):3–5
2009年07月24日
Metastatic colonization of different target organs is a highly selective process that depends on specialized properties of tumor cells. In a recent Nature paper, Massagué and colleagues built on their earlier success in functional genomic analysis of breast cancer metastasis to bone and lung and reported the identification of breast cancer brain metastasis genes, highlighting the importance of the stromal environment in the development of organ-specific metastasis.
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【期刊论文】The Multifaceted Role of MTDH/AEG-1 in Cancer Progression
Clin Cancer Res,2009,15(18):5615–20
2009年09月01日
Cancer is the result of the progressive acquisition of multiple malignant traits through the accumulation of genetic or epigenetic alterations. Recent studies have established a functional role of MTDH (Metadherin)/AEG-1 (Astrocyte Elevated Gene 1) in several crucial aspects of tumor progression, including transformation, evasion of apoptosis, invasion, metastasis, and chemoresistance. Overexpression of MTDH/AEG-1 is frequently observed in melanoma, glioma, neuroblastoma, and carcinomas of breast, prostate, liver, and esophagus and is correlated with poor clinical outcomes. MTDH/AEG-1 functions as a downstream mediator of the transforming activity of oncogenic Ha-Ras and c-Myc. Furthermore, MTDH/AEG-1 overexpression activates the PI3K/Akt, nuclear factor κB (NFκB), and Wnt/β-catenin signaling pathways to stimulate proliferation, invasion, cell survival, and chemoresistance. The lung-homing domain of MTDH/AEG-1 also mediates the adhesion of tumor cells to the vasculature of distant organs and promotes metastasis. These findings suggest that therapeutic targeting of MTDH/AEG-1 may simultaneously suppress tumor growth, block metastasis, and enhance the efficacy of chemotherapeutic treatments.
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Cancer Res,2010,70(10):3905–14
2010年05月01日
Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis, invasion, and metastasis. However, a comparative analysis of the potentially distinct functions of hypoxia in primary tumor growth and organ-specific metastasis has not been reported. Here, we show distinct hypoxia kinetics in tumors generated by the MDA-MB-231 breast cancer sublines with characteristically different primary tumor growth rates and organotropic metastasis potentials. Hypoxia-induced angiogenesis promotes both primary tumor growth and lung metastasis but is nonessential for bone metastasis. Microarray profiling revealed that hypoxia enhances the expression of a significant number of genes in the lung metastasis signature, but only activates a few bone metastasis genes, among which DUSP1 was functionally validated in this study. Despite the different mechanisms by which hypoxia promotes organ-specific metastasis, inhibition of HIF-1α with a dominant-negative form of HIF-1α or 2-methoxyestradiol reduced metastasis to both lung and bone. Consistent with the extensive functional overlap of hypoxia in promoting primary tumor growth and lung metastasis, a 45-gene hypoxia response signature efficiently stratifies breast cancer patients with low or high risks of lung metastasis, but not for bone metastasis. Our study shows distinct functions of hypoxia in regulating angiogenesis and metastasis in different organ microenvironments and establishes HIF-1α as a promising target for controlling organotropic metastasis of breast cancer.
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Adv Funct Mater,2011,21(13):2488-2495
2011年05月05日
The utilization of upconverting nanophosphors (UCNP) for photodynamic therapy (PDT) has gained significant interests due to its ability to convert deep‐penetrating near‐infra red (NIR) light (i.e., 978 nm) to visible light. Previous attempts to co‐localize UCNPs with photosensitizers suffer from low photosensitizer loading and problems with nanoparticle aggregation. Here, the preparation of a novel composite nanoparticle formulation comprising 100 nm β−NaYF4:Yb3+,Er3+ UCNPs, and meso‐tetraphenyl porphine (TPP) photosensitizer, stabilized by biocompatible poly(ethylene glycol‐block‐(dl)lactic acid) block copolymers (PEG‐b‐PLA) is presented. A photosensitizer loading of 10 wt% with respect to UCNP crystal was achieved via the Flash NanoPrecipitation (FNP) process. A sterically stabilizing PEG layer on the composite nanoparticle surface prevents nanoparticle aggregation and ensures nanoparticle stability in water, PBS buffer, and culture medium containing serum proteins, resulting in nanoparticle suitable for in vivo applications. Based on in vitro studies utilizing HeLa cervical cancer cell lines, the composite nanoparticles are shown to exhibit low dark toxicity and efficient cancer cell‐killing activity upon NIR excitation. Exposure with 134 W cm−2 of 978 nm light for 45 min resulted in 75% HeLa cell death. This is the first quantification of the cell‐killing capabilities of the UCNP/TPP composite nanoparticles formulated for photodynamic therapy.
upconverting nanophosphors, self‐assembly, photodynamic therapy, tetraphenyl porphines, block copolymers, nanoparticles.,
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Nature Medicine,2011,17():1101–1108
2011年08月07日
Although the role of miR-200s in regulating E-cadherin expression and epithelial-to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin–dependent epithelial traits and Sec23a-mediated tumor cell secretome.
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