uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
He, Liqun
Publications (10 of 16) Show all publications
Hu, X., Matsumoto, K., Jung, R. S., Weston, T. A., Heizer, P. J., He, C., . . . Jian, H. (2019). GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients. eLIFE, 8, Article ID e47178.
Open this publication in new window or tab >>GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients
Show others...
2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e47178Article in journal (Refereed) Published
Abstract [en]

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-390688 (URN)10.7554/eLife.47178 (DOI)000473014000001 ()31169500 (PubMedID)
Funder
Australian Research Council
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Kundu, S., Ali, M. A., Handin, N., Padhan, N., Larsson, J., Karoutsou, M., . . . Sjöblom, T. (2018). Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells. Genome Medicine, 10, Article ID 2.
Open this publication in new window or tab >>Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells
Show others...
2018 (English)In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 10, article id 2Article in journal (Refereed) Published
Abstract [en]

Background:

The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in similar to 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway.

Methods:

To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted.

Results:

Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells.

Conclusions:

This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

Keywords
Forward genetics, piggyBac transposon, Colorectal cancer, Ras pathway
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-341500 (URN)10.1186/s13073-017-0511-4 (DOI)000419613600002 ()29301589 (PubMedID)
Available from: 2018-02-14 Created: 2018-02-14 Last updated: 2018-02-14Bibliographically approved
Mäe, M. A., Li, T., Bertuzzi, G., Raschperger, E., Vanlandewijck, M., He, L., . . . Genove, G. (2018). Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier. Scientific Reports, 8, Article ID 17462.
Open this publication in new window or tab >>Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier
Show others...
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 17462Article in journal (Refereed) Published
Abstract [en]

Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer's disease. The exact pathophysiology of these conditions is poorly understood. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage. The majority of these reports, however, are based on methods including in vitro BBB modeling or streptozotocininduced diabetes in rodents, opening questions regarding the translation of the in vitro findings to the in vivo situation, and possible direct effects of streptozotocin on the brain vasculature. Here we used a genetic mouse model of hyperglycemia (Ins2(AKITA)) to address whether prolonged systemic hyperglycemia induces BBB dysfunction and leakage. We applied a variety of methodologies to carefully evaluate BBB function and cellular integrity in vivo, including the quantification and visualization of specific tracers and evaluation of transcriptional and morphological changes in the BBB and its supporting cellular components. These experiments did neither reveal altered BBB permeability nor morphological changes of the brain vasculature in hyperglycemic mice. We conclude that prolonged hyperglycemia does not lead to BBB dysfunction, and thus the cognitive impairment observed in diabetes may have other causes.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-372388 (URN)10.1038/s41598-018-35576-0 (DOI)000451619100004 ()30498224 (PubMedID)
Funder
Swedish Research Council, 2015-00550EU, European Research Council, AdG294556Knut and Alice Wallenberg Foundation, 2015.0030Swedish Cancer Society, CAN-2016-0777Swedish Cancer Society, 150735
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved
Egaña, I., Kaito, H., Nitzsche, A., Becker, L., Ballester-Lopez, C., Niaudet, C., . . . Hellström, M. (2017). Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema. Scientific Reports, 7(15453)
Open this publication in new window or tab >>Female mice lacking Pald1 exhibit endothelial cell apoptosis and emphysema
Show others...
2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 15453Article in journal (Refereed) Published
Abstract [en]

Paladin (Pald1, mKIAA1274 or x99384) was identified in screens for vascular-specific genes and is a putative phosphatase. Paladin has also been proposed to be involved in various biological processes such as insulin signaling, innate immunity and neural crest migration. To determine the role of paladin we have now characterized the Pald1 knock-out mouse in a broad array of behavioral, physiological and biochemical tests. Here, we show that female, but not male, Pald1 heterozygous and homozygous knock-out mice display an emphysema-like histology with increased alveolar air spaces and impaired lung function with an obstructive phenotype. In contrast to many other tissues where Pald1 is restricted to the vascular compartment, Pald1 is expressed in both the epithelial and mesenchymal compartments of the postnatal lung. However, in Pald1 knock-out females, there is a specific increase in apoptosis and proliferation of endothelial cells, but not in non-endothelial cells. This results in a transient reduction of endothelial cells in the maturing lung. Our data suggests that Pald1 is required during lung vascular development and for normal function of the developing and adult lung in a sex-specific manner. To our knowledge, this is the first report of a sex-specific effect on endothelial cell apoptosis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-281704 (URN)10.1038/s41598-017-14894-9 (DOI)000415023200014 ()29133847 (PubMedID)
Funder
Swedish Cancer SocietyÅke Wiberg Foundation
Note

List of authors in thesis manuscript: Egaña I, Nitzsche A, Kaito H, Becker L, Garrett L, Niaudet C, Liu W, Vanlandewijck M, Larsson J, Hrabe de Angelis M, Fuchs H, Gailus-Durner V, Vernaleken A, Klopstock T, Hölter S M, Wurst W, Rask-Andersen H, German Mouse Clinic Consortium, Yildirim A Ö, Hellström M

Available from: 2016-04-18 Created: 2016-03-29 Last updated: 2018-02-22Bibliographically approved
Larsson, C., Ali, M. A., Djureinovic, T., Lindroth, A. M., He, L. & Sjöblom, T. (2017). Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition. BMC Cancer, 17, Article ID 487.
Open this publication in new window or tab >>Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition
Show others...
2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 487Article in journal (Refereed) Published
Abstract [en]

Background: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells.

Methods: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.

Results: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.

Conclusions: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Cancer, DIP2C, Gene knockout, rAAV-mediated gene targeting, Tumour cell biology, DNA methylation, Epithelial-mesenchymal transition (EMT)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-331232 (URN)10.1186/s12885-017-3472-5 (DOI)000405865300001 ()28716088 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154, 2007/775, 2012/834, 2012/1235Swedish Foundation for Strategic Research , F06-0050, RBa08-0114Swedish Society for Medical Research (SSMF)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved
Guzman, A., Lange, S., Silva, M. E., Gonzalez, G. A., Tempfer, H., van Wijngaarden, P., . . . Rivera, F. J. (2017). Pericytes promote the generation of oligodendrocytes during remyelination. Paper presented at 13th European Meeting on Glial Cells in Health and Disease, JUL 08-11, 2017, Edinburgh, SCOTLAND. Glia, 65(S1), E541-E542
Open this publication in new window or tab >>Pericytes promote the generation of oligodendrocytes during remyelination
Show others...
2017 (English)In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 65, no S1, p. E541-E542Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology Neurology
Identifiers
urn:nbn:se:uu:diva-333840 (URN)10.1002/glia.23157 (DOI)000403071700836 ()
Conference
13th European Meeting on Glial Cells in Health and Disease, JUL 08-11, 2017, Edinburgh, SCOTLAND
Funder
EU, FP7, Seventh Framework Programme, HEALTH-F2-2011-278850, HEALTH-F2-2011-279288, FP7-REGPOT-316120EU, European Research Council, AdG 294556 BBBARRIERSwedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2018-05-18Bibliographically approved
Falkevall, A., Mehlem, A., Palombo, I., Sahlgren, B. H., Ebarasi, L., He, L., . . . Eriksson, U. (2017). Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease. Cell Metabolism, 25(3), 713-726
Open this publication in new window or tab >>Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease
Show others...
2017 (English)In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 25, no 3, p. 713-726Article in journal (Refereed) Published
Abstract [en]

Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-318926 (URN)10.1016/j.cmet.2017.01.004 (DOI)000396355700026 ()28190774 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20110451, 20120077Swedish Research Council, 2011-03861Swedish Cancer Society, CAN 2011/792, CAN 2014/630
Available from: 2017-04-05 Created: 2017-04-05 Last updated: 2017-11-29Bibliographically approved
Pandzic, T., Rendo, V., Lim, J., Larsson, C., Larsson, J., Stoimenov, I., . . . Sjöblom, T. (2017). Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth. OncoTarget, 8(58), 98646-98659
Open this publication in new window or tab >>Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth
Show others...
2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed) Published
Abstract [en]

The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345974 (URN)10.18632/oncotarget.21713 (DOI)000419392300074 ()
Funder
Swedish Foundation for Strategic Research , F06-0050 RBa08-0114Swedish Cancer Society, 2006/2154 2007/775 2012/834
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-09-20Bibliographically approved
Andrae, J., Gouveia, L., Gallini, R., He, L., Fredriksson, L., Nilsson, I., . . . Betsholtz, C. (2016). A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex. BIOLOGY OPEN, 5(4), 461-474
Open this publication in new window or tab >>A role for PDGF-C/PDGFR alpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex
Show others...
2016 (English)In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 5, no 4, p. 461-474Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFR alpha. Analysis of Pdgfc null mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFR alpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants for Pdgfc(-/-) and Pdgfra(GFP/+). These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data on Pdgfa, Pdgfc and Pdgfra in the cerebral cortex and microarray data on cerebral meninges.

Keywords
PDGF-C, Meninges, Basement membrane, Cerebrum, PDGFR alpha
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-297369 (URN)10.1242/bio.017368 (DOI)000374955200011 ()26988758 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationEU, European Research CouncilÅke Wiberg Foundation, 362565719Åke Wiberg Foundation, 946216308Lars Hierta Memorial FoundationMagnus Bergvall Foundation, 2014-00174The Karolinska Institutet's Research FoundationVINNOVA
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2018-05-18Bibliographically approved
Tobin, N. P., Wennmalm, K., Lindstrom, L. S., Foukakis, T., He, L., Genove, G., . . . Bergh, J. (2016). An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors. Clinical Cancer Research, 22(10), 2417-2426
Open this publication in new window or tab >>An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors
Show others...
2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 10, p. 2417-2426Article in journal (Refereed) Published
Abstract [en]

Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-297782 (URN)10.1158/1078-0432.CCR-15-1691 (DOI)000375839200014 ()26769751 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council, 524-2014-4483Swedish Research Council, 521-2014-2057Forte, Swedish Research Council for Health, Working Life and Welfare, 2014-1962Knut and Alice Wallenberg FoundationAstraZeneca
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2017-11-28Bibliographically approved
Organisations

Search in DiVA

Show all publications