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学者姓名：卢钟磊
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Abstract ：
Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.
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| GB/T 7714 | Zhuang, Mingzhi , Li, Fengyue , Liang, Hong et al. Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2 [J]. | CELL DEATH & DISEASE , 2024 , 15 (4) . |
| MLA | Zhuang, Mingzhi et al. "Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2" . | CELL DEATH & DISEASE 15 . 4 (2024) . |
| APA | Zhuang, Mingzhi , Li, Fengyue , Liang, Hong , Su, Yongfu , Cheng, Lei , Lin, Bingkai et al. Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2 . | CELL DEATH & DISEASE , 2024 , 15 (4) . |
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Objective: We retrospectively studied cancer mortality and incidence in China from 1990 to 2019, investigated the cancer trends and risk factors, and analyzed the effects of Gross Domestic Product (GDP) on cancer mortality and incidence. Methods: Data was obtained in "Our world in data" in October 2022 to explore mortality rates of different cancers and their trends and the roles of cancer risk factors, including GDP, air pollution, etc. Results: Over the past 30 years, cancer had been China's second leading cause of death. Tracheal, bronchial, and lung cancers, with an annual growth rate of 6.5%, were the most frequently diagnosed cancers. The burden of different cancers changed as the mortality rate of cancer changed. The age-standardized cancer mortality rate had decreased by 19.0%; cancer deaths in all age groups had increased. While the number of cancer deaths in the elderly aged & GE;70 did not increase distinctively, its percentage increased by 52.1% and 1.7% annually. The percentage of patients with new-onset cancer increased by 240% and 8.6% annually. For every USD 1,000 increase in GDP, cancer deaths decreased by 2.3/100,000. Tobacco, meat, and alcohol consumption and BMI had increased and were not conducive to the future control of cancer. Conclusions: We summarized the incidence and mortality of major cancers and their trends in China over the past 30 years and analyzed the effects of GDP and the roles of cancer risk factors. Overall GDP growth and effective control of air pollution reduced cancer mortality, while population aging, smoking, alcohol consumption, BMI increasing, and meat consumption brought challenges for cancer control.
Keyword ：
cancer control cancer control cancer mortality cancer mortality Cancer trends Cancer trends China China GDP GDP risk factor risk factor
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| GB/T 7714 | Wu, Weiwei , Zhang, Ruochen , Jin, Yiming et al. Cancer trends and risk factors in China over the past 30 years (1990-2019) [J]. | JOURNAL OF CANCER , 2023 , 14 (10) : 1935-1945 . |
| MLA | Wu, Weiwei et al. "Cancer trends and risk factors in China over the past 30 years (1990-2019)" . | JOURNAL OF CANCER 14 . 10 (2023) : 1935-1945 . |
| APA | Wu, Weiwei , Zhang, Ruochen , Jin, Yiming , Lu, Yan , Lu, Zhonglei , Li, Tao et al. Cancer trends and risk factors in China over the past 30 years (1990-2019) . | JOURNAL OF CANCER , 2023 , 14 (10) , 1935-1945 . |
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Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERR alpha) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERR alpha in the pyroptosis pathway and glycolytic metabolism.Methods The interaction between ERR alpha and HIF-1 alpha was verified using co-immunoprecipitation. The transcriptional binding sites of ERR alpha and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERR alpha on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERR alpha-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database.Results Triggered by a hypoxic microenvironment, highly expressed ERR alpha could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERR alpha activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERR alpha participated in glycolysis and programmed cell death, which resulted in EC progression.Conclusions ERR alpha inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.
Keyword ：
Cisplatin resistance Cisplatin resistance Endometrial cancer Endometrial cancer ERR alpha ERR alpha Metabolic reprogramming Metabolic reprogramming Pyroptosis Pyroptosis
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| GB/T 7714 | Su, Pingping , Mao, Xiaodan , Ma, Jincheng et al. ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer [J]. | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH , 2023 , 42 (1) . |
| MLA | Su, Pingping et al. "ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer" . | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 42 . 1 (2023) . |
| APA | Su, Pingping , Mao, Xiaodan , Ma, Jincheng , Huang, Lixiang , Yu, Lirui , Tang, Shuting et al. ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer . | JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH , 2023 , 42 (1) . |
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Advanced prostate cancer, harboring multiple mutations of tumor suppressor genes, is refractory to conventional therapies. Knockout of the Skp2 gene blocks pRb/p53 doubly deficient prostate cancer in mice, which inspired the authors to develop an approach for delivering siRNA that would efficiently silence Skp2 (siSkp2) in vivo. Here, a facile strategy is reported to directly assemble siSkp2 with the natural compound quercetin (Que) into supramolecular nanoparticles (NPs). This carrier-free siSkp2 delivery system could effectively protect siSkp2 from degradation in serum and enhance its cellular internalization. Furthermore, the siSkp2/Que NPs exhibit synergistic effects in Skp2 silencing, because they can degrade the mRNA and protein of Skp2 simultaneously. Indeed, siSkp2/Que NPs remarkably diminish the Skp2 abundance and further inhibit the proliferation and migration of TMU cells (RB1/TP53/KRAS triple mutations) in vitro. The in vivo results further show that i.v. administration of siSkp2/Que NPs efficiently accumulates in tumor sites and strongly inhibits the growth of TMU tumors in nude mice. Importantly, the siSkp2/Que NPs do not induce any abnormality in the treated mice, which suggests satisfactory biocompatibility. Collectively, this study describes a tractable siRNA self-assembled strategy for Skp2 silencing, which might be a promising nanodrug to cure multitherapy-resistant advanced prostate cancer.
Keyword ：
advanced prostate cancer advanced prostate cancer nanodrugs nanodrugs self-assembly self-assembly siRNA delivery siRNA delivery Skp2 Skp2
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| GB/T 7714 | Liang, Hong , Zhang, Fangming , Hong, Yannv et al. Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer [J]. | SMALL , 2022 , 18 (14) . |
| MLA | Liang, Hong et al. "Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer" . | SMALL 18 . 14 (2022) . |
| APA | Liang, Hong , Zhang, Fangming , Hong, Yannv , Wu, Yue , Xie, Huanzhang , Zhang, Chen et al. Synergistic Silencing of Skp2 by siRNA Self-Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer . | SMALL , 2022 , 18 (14) . |
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Loss of neuron homeostasis in the arcuate nucleus (ARC) is responsible for diet-induced-obesity (DIO). We previously reported that loss of Rb1 gene compromised the homeostasis of anorexigenic POMC neurons in ARC and induced obesity in mice. To evaluate the development of DIO, we propose to analyze the transcriptomic alteration of POMC neurons in mice following high fat diet (HFD) feeding. We isolated these neurons from established DIO mice and performed transcriptomic profiling using RNA-seq. In total, 1066 genes (628 upregulated and 438 downregulated) were identified as differentially expressed genes (DEGs). Pathway enrichment analysis with these DEGs further revealed that "cell cycle," "apoptosis," "chemokine signaling," and "sphingo-lipid metabolism" pathways were correlated with DIO development. Moreover, we validated that the pRb protein, a key regulator of "cell cycle pathway," was inactivated by phosphorylation in POMC neurons by HFD feeding. Importantly, the reversal of deregulated cell cycle by stereotaxic delivering of the unphosphorylated pRb.P in ARC significantly meliorated the DIO. Collectively, our study provides insights into the mechanisms related to the loss of homeostasis of POMC neurons in DIO, and suggests pRb phosphorylation as a potential intervention target to treat DIO.
Keyword ：
Diet-induced obesity (DIO) Diet-induced obesity (DIO) High-fat-diet (HFD) High-fat-diet (HFD) Neuron homeostasis Neuron homeostasis POMC neuron POMC neuron pRb phosphorylation pRb phosphorylation
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| GB/T 7714 | Lyu, Peng , Huang, Zhishun , Feng, Qingjun et al. Unveiling the transcriptome alteration of POMC neuron in diet-induced obesity [J]. | EXPERIMENTAL CELL RESEARCH , 2020 , 389 (1) . |
| MLA | Lyu, Peng et al. "Unveiling the transcriptome alteration of POMC neuron in diet-induced obesity" . | EXPERIMENTAL CELL RESEARCH 389 . 1 (2020) . |
| APA | Lyu, Peng , Huang, Zhishun , Feng, Qingjun , Su, Yongfu , Zheng, Mengying , Hong, Yannv et al. Unveiling the transcriptome alteration of POMC neuron in diet-induced obesity . | EXPERIMENTAL CELL RESEARCH , 2020 , 389 (1) . |
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近年来,因肥胖症所造成的社会问题和医疗负担越发严重.肥胖主要是由于机体能量的摄入与消耗不平衡所致,而中枢神经系统以及相关神经元在机体能量代谢平衡的调控中发挥着重要作用.下丘脑弓状核含有抑食性阿黑皮素原(Proopiomelanocortin,POMC)神经元和促食性神经肽Y(Neuropeptid Y,NPY)/刺鼠相关蛋白(Agouti-related protein,AgRP)神经元,是调控机体摄食行为的主要神经元.研究显示,高脂饮食会诱导POMC神经元中的Rb蛋白发生磷酸化修饰并失活,导致POMC神经元从静息状态重新进入细胞周期循环,进而迅速转向细胞凋亡.高脂饮食也会引起神经元再生抑制,并诱导炎症发生和神经元损伤,使神经元稳态失衡,引发瘦素抵抗,最终导致肥胖症的发生.文中就神经元稳态失衡以及肥胖症等疾病之间的关系进行了综述,希望能为饮食诱导肥胖症等疾病的治疗和预防提供新的方向和思路.
Keyword ：
神经元稳态失衡 神经元稳态失衡 肥胖症 肥胖症 高脂饮食 高脂饮食
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| GB/T 7714 | 黄智舜 , 郑梦盈 , 冯庆君 et al. 神经元稳态失衡和饮食诱导肥胖症的相关性研究进展 [J]. | 生物工程学报 , 2019 , 35 (8) : 1433-1440 . |
| MLA | 黄智舜 et al. "神经元稳态失衡和饮食诱导肥胖症的相关性研究进展" . | 生物工程学报 35 . 8 (2019) : 1433-1440 . |
| APA | 黄智舜 , 郑梦盈 , 冯庆君 , 洪燕女 , 卢钟磊 . 神经元稳态失衡和饮食诱导肥胖症的相关性研究进展 . | 生物工程学报 , 2019 , 35 (8) , 1433-1440 . |
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When obesity is caused by consumption of a high-fat diet, the tumor suppressor pRb is phosphoinactivated in the neurons of the mediobasal hypothalamus, a brain area critical for energy-balance regulation. However, the functional relevance of pRb phosphoinactivation in the mediobasal hypothalamus to diet-induced obesity remains unknown. Here, we show that inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice. Expressing an unphosphorylable pRb nonselectively in the mediobasal hypothalamus or conditionally in anorexigenic POMC neurons inhibits diet-induced obesity. Intracerebroventricular delivery of US Food and Drug Administration-approved (FDA-approved) cyclin-dependent kinase 4 (CDK4) inhibitor abemaciclib inhibits pRb phosphorylation in the mediobasal hypothalamus and prevents diet-induced obesity. Oral administration of abemaciclib at doses approved for human use reduces fat mass in diet-induced obese mice by increasing lipid oxidation without significantly reducing lean mass. With analysis of recent literature identifying CDK4 as the most abundantly expressed neuronal CDK in the mediobasal hypothalamus, our work uncovers CDK4 as the major kinase for hypothalamic pRb phosphoinactivation and a highly effective central antiobesity target. As three CDK4/6 inhibitors have recently received FDA approval for life-long breast cancer therapy, our study provides a preclinical basis for their expedient repurposing for obesity management.
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| GB/T 7714 | Iqbal, Niloy Jafar , Lu, Zhonglei , Liu, Shun Mei et al. Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity [J]. | JCI INSIGHT , 2018 , 3 (17) . |
| MLA | Iqbal, Niloy Jafar et al. "Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity" . | JCI INSIGHT 3 . 17 (2018) . |
| APA | Iqbal, Niloy Jafar , Lu, Zhonglei , Liu, Shun Mei , Schwartz, Gary J. , Chua, Streamson, Jr. , Zhu, Liang . Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity . | JCI INSIGHT , 2018 , 3 (17) . |
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SCFSkp2/Cks1 ubiquitinates Thr187-phosphorylated p27 for degradation. Overexpression of Skp2 coupled with underexpression of p27 are frequent characteristics of cancer cells. When the role of SCFSkp2/Cksl - mediated p27 ubiquitination in cancer was specifically tested by p27 Thr187-to-Ala knockin (p27T187A KI), it was found dispensable for Kras(G12D)-induced lung tumorigenesis but essential for Rbl-deficient pituitary tumorigenesis. Here we identify pRb and p53 doubly deficient (DKO) prostate tumorigenesis as a context in which p27 ubiquitination by SCFSkp2/Cks1 is required for p27 downregulation. p27 protein accumulated in prostate when p27T187A KI mice underwent DKO prostate tumorigenesis. p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells). p27T187A KI activated an E2F1-p73-apoptosis axis in DKO prostate tumorigenesis, slowed disease progression and significantly extended survival. Querying co-occurrence relationships among RB1, TP53, PTEN, NKX3-1 and MYC in TCGA of prostate cancer identified co-inactivation of RB1 and TP53 as the only statistically significant co-occurrences in metastatic castration-resistant prostate cancer (mCRPC). Together, our study identifies Skp2/Cks1 pocket inhibitors as potential therapeutics for mCRPC. Procedures for establishing mCRPC organoid cultures from contemporary patients were recently established. An Skp2/Cks1 pocket inhibitor preferentially collapsed DKO prostate tumor organoids over AADKO organoids, which spontaneously disintegrated over time when DKO prostate tumor organoids grew larger, setting the stage to translate mouse model findings to precision medicine in the clinic on the organoid platform.
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| GB/T 7714 | Zhao, H. , Lu, Z. , Bauzon, F. et al. p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer [J]. | ONCOGENE , 2017 , 36 (1) : 60-70 . |
| MLA | Zhao, H. et al. "p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer" . | ONCOGENE 36 . 1 (2017) : 60-70 . |
| APA | Zhao, H. , Lu, Z. , Bauzon, F. , Fu, H. , Cui, J. , Locker, J. et al. p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer . | ONCOGENE , 2017 , 36 (1) , 60-70 . |
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Exo70是胞外分泌复合体Exocyst的关键亚基,可通过参与Exocyst复合体或自身聚合促进细胞迁移.我们在研究中发现,Exo70自身形成二聚体的能力显著强于与Exocyst其它7个亚基的结合,提示Exo70二聚化的重要作用.进一步构建Exo70缺失突变体,并通过一系列免疫共沉淀实验确定了Exo70形成二聚体的关键位置是位于氨基酸31～35与505～509的两段同样的序列SLEKS.进而利用这两个序列的缺失突变体,通过transwell迁移实验,证实这两段SLEKS序列在Exo70二聚化及乳腺癌细胞迁移过程中的关键作用.以上结果为Exo70独立于Exocyst复合体功能之外的新功能研究提供了依据,也为乳腺癌及其转移的治疗提供潜在的靶点.
Keyword ：
Exo70蛋白 Exo70蛋白 乳腺癌 乳腺癌 二聚化序列 二聚化序列 迁移 迁移
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| GB/T 7714 | 陈雄 , 侯积环 , 占艳艳 et al. Exo70二聚化的关键序列及其在乳腺癌细胞迁移过程中的作用 [J]. | 基因组学与应用生物学 , 2016 , 35 (10) : 2533-2538 . |
| MLA | 陈雄 et al. "Exo70二聚化的关键序列及其在乳腺癌细胞迁移过程中的作用" . | 基因组学与应用生物学 35 . 10 (2016) : 2533-2538 . |
| APA | 陈雄 , 侯积环 , 占艳艳 , 卢钟磊 . Exo70二聚化的关键序列及其在乳腺癌细胞迁移过程中的作用 . | 基因组学与应用生物学 , 2016 , 35 (10) , 2533-2538 . |
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