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6. A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Author

Yao, Fan, Deng, Yalan, Zhao, Yang, Mei, Ying, Zhang, Yilei, Liu, Xiaoguang, Martinez, Consuelo, Su, Xiaohua, Rosato, Roberto R, Teng, Hongqi, Hang, Qinglei, Yap, Shannon, Chen, Dahu, Wang, Yumeng, Chen, Mei-Ju May, Zhang, Mutian, Liang, Han, Xie, Dong, Chen, Xin, Zhu, Hao, Chang, Jenny C, You, M James, Sun, Yutong, Gan, Boyi, and Ma, Li

Subjects
Rare Diseases, Biotechnology, Digestive Diseases, Liver Cancer, Liver Disease, Cancer, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, Good Health and Well Being, Animals, Antibodies, Neutralizing, Carcinogenesis, Carcinoma, Hepatocellular, Cell Line, Tumor, Down-Regulation, Ferroptosis, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Leukemia Inhibitory Factor Receptor alpha Subunit, Lipocalin-2, Liver Neoplasms, Male, Mice, Inbred C57BL, NF-kappa B, Piperazines, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Signal Transduction, Sorafenib, Up-Regulation, Xenograft Model Antitumor Assays
Abstract

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Published
2021

7. Sawfly genomes reveal evolutionary acquisitions that fostered the mega-radiation of parasitoid and eusocial Hymenoptera

Author

Oeyen, Jan Philip, Baa-Puyoulet, Patrice, Benoit, Joshua B, Beukeboom, Leo W, Bornberg-Bauer, Erich, Buttstedt, Anja, Calevro, Federica, Cash, Elizabeth I, Chao, Hsu, Charles, Hubert, Chen, Mei-Ju May, Childers, Christopher, Cridge, Andrew G, Dearden, Peter, Dinh, Huyen, Doddapaneni, Harsha Vardhan, Dolan, Amanda, Donath, Alexander, Dowling, Daniel, Dugan, Shannon, Duncan, Elizabeth, Elpidina, Elena N, Friedrich, Markus, Geuverink, Elzemiek, Gibson, Joshua D, Grath, Sonja, Grimmelikhuijzen, Cornelis JP, Große-Wilde, Ewald, Gudobba, Cameron, Han, Yi, Hansson, Bill S, Hauser, Frank, Hughes, Daniel ST, Ioannidis, Panagiotis, Jacquin-Joly, Emmanuelle, Jennings, Emily C, Jones, Jeffery W, Klasberg, Steffen, Lee, Sandra L, Lesný, Peter, Lovegrove, Mackenzie, Martin, Sebastian, Martynov, Alexander G, Mayer, Christoph, Montagné, Nicolas, Moris, Victoria C, Munoz-Torres, Monica, Murali, Shwetha Canchi, Muzny, Donna M, Oppert, Brenda, Parisot, Nicolas, Pauli, Thomas, Peters, Ralph S, Petersen, Malte, Pick, Christian, Persyn, Emma, Podsiadlowski, Lars, Poelchau, Monica F, Provataris, Panagiotis, Qu, Jiaxin, Reijnders, Maarten JMF, von Reumont, Björn Marcus, Rosendale, Andrew J, Simao, Felipe A, Skelly, John, Sotiropoulos, Alexandros G, Stahl, Aaron L, Sumitani, Megumi, Szuter, Elise M, Tidswell, Olivia, Tsitlakidis, Evangelos, Vedder, Lucia, Waterhouse, Robert M, Werren, John H, Wilbrandt, Jeanne, Worley, Kim C, Yamamoto, Daisuke S, van de Zande, Louis, Zdobnov, Evgeny M, Ziesmann, Tanja, Gibbs, Richard A, Richards, Stephen, Hatakeyama, Masatsugu, Misof, Bernhard, and Niehuis, Oliver

Subjects
Human Genome, Genetics, Life Below Water, Amino Acid Sequence, Animals, Conserved Sequence, DNA Transposable Elements, Female, Gene Dosage, Genetic Speciation, Genome, Insect, Glycoproteins, Herbivory, Host-Parasite Interactions, Hymenoptera, Immunity, Insect Proteins, Male, Multigene Family, Receptors, Odorant, Social Behavior, Vision, Ocular, hexamerin, major royal jelly protein, microsynteny, odorant receptor, opsin, phytophagy, Biochemistry and Cell Biology, Evolutionary Biology, Developmental Biology
Abstract

The tremendous diversity of Hymenoptera is commonly attributed to the evolution of parasitoidism in the last common ancestor of parasitoid sawflies (Orussidae) and wasp-waisted Hymenoptera (Apocrita). However, Apocrita and Orussidae differ dramatically in their species richness, indicating that the diversification of Apocrita was promoted by additional traits. These traits have remained elusive due to a paucity of sawfly genome sequences, in particular those of parasitoid sawflies. Here, we present comparative analyses of draft genomes of the primarily phytophagous sawfly Athalia rosae and the parasitoid sawfly Orussus abietinus. Our analyses revealed that the ancestral hymenopteran genome exhibited traits that were previously considered unique to eusocial Apocrita (e.g., low transposable element content and activity) and a wider gene repertoire than previously thought (e.g., genes for CO2 detection). Moreover, we discovered that Apocrita evolved a significantly larger array of odorant receptors than sawflies, which could be relevant to the remarkable diversification of Apocrita by enabling efficient detection and reliable identification of hosts.

Published
2020

8. Molecular evolutionary trends and feeding ecology diversification in the Hemiptera, anchored by the milkweed bug genome

Author

Panfilio, Kristen A, Vargas Jentzsch, Iris M, Benoit, Joshua B, Erezyilmaz, Deniz, Suzuki, Yuichiro, Colella, Stefano, Robertson, Hugh M, Poelchau, Monica F, Waterhouse, Robert M, Ioannidis, Panagiotis, Weirauch, Matthew T, Hughes, Daniel ST, Murali, Shwetha C, Werren, John H, Jacobs, Chris GC, Duncan, Elizabeth J, Armisén, David, Vreede, Barbara MI, Baa-Puyoulet, Patrice, Berger, Chloé S, Chang, Chun-che, Chao, Hsu, Chen, Mei-Ju M, Chen, Yen-Ta, Childers, Christopher P, Chipman, Ariel D, Cridge, Andrew G, Crumière, Antonin JJ, Dearden, Peter K, Didion, Elise M, Dinh, Huyen, Doddapaneni, Harsha Vardhan, Dolan, Amanda, Dugan, Shannon, Extavour, Cassandra G, Febvay, Gérard, Friedrich, Markus, Ginzburg, Neta, Han, Yi, Heger, Peter, Holmes, Christopher J, Horn, Thorsten, Hsiao, Yi-min, Jennings, Emily C, Johnston, J Spencer, Jones, Tamsin E, Jones, Jeffery W, Khila, Abderrahman, Koelzer, Stefan, Kovacova, Viera, Leask, Megan, Lee, Sandra L, Lee, Chien-Yueh, Lovegrove, Mackenzie R, Lu, Hsiao-ling, Lu, Yong, Moore, Patricia J, Munoz-Torres, Monica C, Muzny, Donna M, Palli, Subba R, Parisot, Nicolas, Pick, Leslie, Porter, Megan L, Qu, Jiaxin, Refki, Peter N, Richter, Rose, Rivera-Pomar, Rolando, Rosendale, Andrew J, Roth, Siegfried, Sachs, Lena, Santos, M Emília, Seibert, Jan, Sghaier, Essia, Shukla, Jayendra N, Stancliffe, Richard J, Tidswell, Olivia, Traverso, Lucila, van der Zee, Maurijn, Viala, Séverine, Worley, Kim C, Zdobnov, Evgeny M, Gibbs, Richard A, and Richards, Stephen

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, Amino Acid Sequence, Animals, CYS2-HIS2 Zinc Fingers, Evolution, Molecular, Feeding Behavior, Gene Dosage, Gene Expression Profiling, Gene Transfer, Horizontal, Genes, Homeobox, Genome, Insect, Hemiptera, Pigmentation, Smell, Transcription Factors, Evolution of development, Gene family evolution, Gene structure, Lateral gene transfer, Phytophagy, RNAi, Transcription factors, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundThe Hemiptera (aphids, cicadas, and true bugs) are a key insect order, with high diversity for feeding ecology and excellent experimental tractability for molecular genetics. Building upon recent sequencing of hemipteran pests such as phloem-feeding aphids and blood-feeding bed bugs, we present the genome sequence and comparative analyses centered on the milkweed bug Oncopeltus fasciatus, a seed feeder of the family Lygaeidae.ResultsThe 926-Mb Oncopeltus genome is well represented by the current assembly and official gene set. We use our genomic and RNA-seq data not only to characterize the protein-coding gene repertoire and perform isoform-specific RNAi, but also to elucidate patterns of molecular evolution and physiology. We find ongoing, lineage-specific expansion and diversification of repressive C2H2 zinc finger proteins. The discovery of intron gain and turnover specific to the Hemiptera also prompted the evaluation of lineage and genome size as predictors of gene structure evolution. Furthermore, we identify enzymatic gains and losses that correlate with feeding biology, particularly for reductions associated with derived, fluid nutrition feeding.ConclusionsWith the milkweed bug, we now have a critical mass of sequenced species for a hemimetabolous insect order and close outgroup to the Holometabola, substantially improving the diversity of insect genomics. We thereby define commonalities among the Hemiptera and delve into how hemipteran genomes reflect distinct feeding ecologies. Given Oncopeltus's strength as an experimental model, these new sequence resources bolster the foundation for molecular research and highlight technical considerations for the analysis of medium-sized invertebrate genomes.

Published
2019

12. Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets

Author

Fujita, Masashi, Chen, Mei-Ju May, Siwak, Doris Rieko, Sasagawa, Shota, Oosawa-Tatsuguchi, Ayako, Arihiro, Koji, Ono, Atsushi, Miura, Ryoichi, Maejima, Kazuhiro, Aikata, Hiroshi, Ueno, Masaki, Hayami, Shinya, Yamaue, Hiroki, Chayama, Kazuaki, Lee, Ju-Seog, Lu, Yiling, Mills, Gordon B., Liang, Han, Nishizuka, Satoshi S., and Nakagawa, Hidewaki

Published
2022
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13. A model species for agricultural pest genomics: the genome of the Colorado potato beetle, Leptinotarsa decemlineata (Coleoptera: Chrysomelidae).

Author

Schoville, Sean D, Chen, Yolanda H, Andersson, Martin N, Benoit, Joshua B, Bhandari, Anita, Bowsher, Julia H, Brevik, Kristian, Cappelle, Kaat, Chen, Mei-Ju M, Childers, Anna K, Childers, Christopher, Christiaens, Olivier, Clements, Justin, Didion, Elise M, Elpidina, Elena N, Engsontia, Patamarerk, Friedrich, Markus, García-Robles, Inmaculada, Gibbs, Richard A, Goswami, Chandan, Grapputo, Alessandro, Gruden, Kristina, Grynberg, Marcin, Henrissat, Bernard, Jennings, Emily C, Jones, Jeffery W, Kalsi, Megha, Khan, Sher A, Kumar, Abhishek, Li, Fei, Lombard, Vincent, Ma, Xingzhou, Martynov, Alexander, Miller, Nicholas J, Mitchell, Robert F, Munoz-Torres, Monica, Muszewska, Anna, Oppert, Brenda, Palli, Subba Reddy, Panfilio, Kristen A, Pauchet, Yannick, Perkin, Lindsey C, Petek, Marko, Poelchau, Monica F, Record, Éric, Rinehart, Joseph P, Robertson, Hugh M, Rosendale, Andrew J, Ruiz-Arroyo, Victor M, Smagghe, Guy, Szendrei, Zsofia, Thomas, Gregg WC, Torson, Alex S, Vargas Jentzsch, Iris M, Weirauch, Matthew T, Yates, Ashley D, Yocum, George D, Yoon, June-Sun, and Richards, Stephen

Subjects
Animals, Insect Proteins, Transcription Factors, DNA Transposable Elements, Genetics, Population, Genomics, Pest Control, Biological, Evolution, Molecular, Phylogeny, Gene Expression Regulation, RNA Interference, Insecticide Resistance, Multigene Family, Agriculture, Female, Male, Solanum tuberosum, Genome, Insect, Host-Parasite Interactions, Genetic Variation, Molecular Sequence Annotation, Coleoptera, Genetics, Population, Pest Control, Biological, Evolution, Molecular, Genome, Insect, Biochemistry and Cell Biology, Other Physical Sciences
Abstract

The Colorado potato beetle is one of the most challenging agricultural pests to manage. It has shown a spectacular ability to adapt to a variety of solanaceaeous plants and variable climates during its global invasion, and, notably, to rapidly evolve insecticide resistance. To examine evidence of rapid evolutionary change, and to understand the genetic basis of herbivory and insecticide resistance, we tested for structural and functional genomic changes relative to other arthropod species using genome sequencing, transcriptomics, and community annotation. Two factors that might facilitate rapid evolutionary change include transposable elements, which comprise at least 17% of the genome and are rapidly evolving compared to other Coleoptera, and high levels of nucleotide diversity in rapidly growing pest populations. Adaptations to plant feeding are evident in gene expansions and differential expression of digestive enzymes in gut tissues, as well as expansions of gustatory receptors for bitter tasting. Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles. Finally, duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA. The L. decemlineata genome provides opportunities to investigate a broad range of phenotypes and to develop sustainable methods to control this widely successful pest.

Published
2018

14. ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.

Author

Bakr, Ali, Corte, Giuditta Della, Veselinov, Olivera, Kelekçi, Simge, Chen, Mei-Ju May, Lin, Yu-Yu, Sigismondo, Gianluca, Iacovone, Marika, Cross, Alice, Syed, Rabail, Jeong, Yunhee, Sollier, Etienne, Liu, Chun- Shan, Lutsik, Pavlo, Krijgsveld, Jeroen, Weichenhan, Dieter, Plass, Christoph, Popanda, Odilia, and Schmezer, Peter

Published
2024
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29. Bleb-related infection after primary trabeculectomy: medical chart reviews from 1993 to 2021

Author

Yang, Hsin-Yu, Chi, Sheng-Chu, Ko, Yu-Chieh, Chen, Mei-Ju, Kuang, Tung-Mei, Chang, Yu-Fan, and Liu, Catherine Jui-Ling

Abstract

BackgroundTo investigate the incidence of and risk factors for bleb-related infection (BRI) in patients who underwent mitomycin C-augmented primary trabeculectomy.MethodsWe reviewed the medical charts of consecutive patients who had received primary trabeculectomy in Taipei Veterans General Hospital. We recorded the demographic and clinical characteristics of patients before, during and after surgery. Furthermore, we recorded the time interval between surgery and infection onset, clinical manifestations and visual outcomes of patients with BRI. The cumulative incidence of BRI was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to explore factors associated with BRI.ResultsIn total, 1663 eyes were postoperatively followed up for 94.57±65.23 months. The cumulative incidence of BRI was 1.86 per 1000 person-years during the 28-year follow-up period: 24 (1.44%) patients developed BRI and 6 (0.36%) patients additionally developed endophthalmitis. A multivariate analysis revealed a significant association of BRI with wound manipulation, high myopia and hyperlipidaemia. Patients younger than 60 years were more likely to receive wound manipulation than their elderly counterparts (<0.001). One year after BRI, the best corrected visual acuity of the eyes with blebitis did not change significantly, whereas that of the eyes with endophthalmitis worsened significantly.ConclusionRisk factors for BRI after trabeculectomy include wound manipulation, high myopia and hyperlipidaemia. Considering myopia is highly prevalent throughout the world and is a risk factor for glaucoma, the lifelong risk of BRI after trabeculectomy in eyes with high myopia warrants the attention of ophthalmologists.

Published
2024
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39. A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Author

Yao, Fan, Deng, Yalan, Zhao, Yang, Mei, Ying, Zhang, Yilei, Liu, Xiaoguang, Martinez, Consuelo, Su, Xiaohua, Rosato, Roberto R, Teng, Hongqi, Hang, Qinglei, Yap, Shannon, Chen, Dahu, Wang, Yumeng, Chen, Mei-Ju May, Zhang, Mutian, Liang, Han, Xie, Dong, Chen, Xin, Zhu, Hao, Chang, Jenny C, You, M James, Sun, Yutong, Gan, Boyi, and Ma, Li

Subjects
Male, Liver Cancer, Leukemia Inhibitory Factor Receptor alpha Subunit, Carcinogenesis, Down-Regulation, Inbred C57BL, Piperazines, Antibodies, Cell Line, Mice, Non-Receptor Type 6, Rare Diseases, Lipocalin-2, Animals, Humans, Ferroptosis, 2.1 Biological and endogenous factors, Aetiology, Neutralizing, Cancer, Neoplastic, Tumor, Liver Disease, Carcinoma, Liver Neoplasms, NF-kappa B, Hepatocellular, Sorafenib, Xenograft Model Antitumor Assays, Up-Regulation, HEK293 Cells, Good Health and Well Being, Gene Expression Regulation, 5.1 Pharmaceuticals, Protein Tyrosine Phosphatase, Development of treatments and therapeutic interventions, Digestive Diseases, Signal Transduction, Biotechnology
Abstract

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Published
2021

41. Genome-Wide Polygenic Risk Score for Predicting High Risk Glaucoma Individuals of Han Chinese Ancestry

Author

Hsiao, Yu-Jer, primary, Chuang, Hao-Kai, additional, Chi, Sheng-Chu, additional, Wang, Yung-Yu, additional, Chiang, Pin-Hsuan, additional, Teng, Pai-Chi, additional, Kuang, Tung-Mei, additional, Yarmishyn, Aliaksandr A., additional, Lin, Tai-Chi, additional, Hwang, De-Kuang, additional, Chen, Shih-Jen, additional, Chiou, Shih-Hwa, additional, Chen, Mei-Ju, additional, Hsieh, Ai-Ru, additional, and Hsu, Chih-Chien, additional

Published
2021
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50. The sequential data of transcription expression of heart in aldosterone-infusion mice

Author

Chi-Sheng Hung, Chia-Hung Chou, Chang, Yu-Chuan, Ping-Han Hsieh, Chen, Mei-Ju May, Chien-Yu Chen, and Yen-Hung Lin

Subjects
Aldosterone-infusion Mice, Gene Expression, RNA-Seq
Abstract

Transcript expression in the myocardium of aldosterone-infused mice and control mice weekly over 16 weeks at different time periods. In order to characterize the sequential effect of aldosterone in the heart, we conducted RNA-sequencing to monitor the transcript expression in the myocardium of aldosterone-infused mice and control mice weekly over 16 weeks at different time periods. We implanted 21-day continuous aldosterone release pellets subcutaneously in Institute of Cancer Research (ICR) male mice to establish the aldosterone infusion model. We obtained hearts at baseline and at 1, 4, 10 and 16 weeks after aldosterone release pellet implantation. To infer the transcript expression,we used Kallisto (ver. 0.43.1) with parameters (index: -k 31, quant: -b 1000 --bias --rf-stranded) to quantify the abundance of transcripts in each dataset.

Published
2020
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