Ingemar Ernberg Group

Project Leaders in the Ingemar Ernberg Group

LiFu Hu Project

Elisabeth Norin Project

Roland Möllby Project

Research Summary

In Ingemar Ernbergs and LiFu Hu's groups we focus on experimental systems and clinical collaborations to understand better the connection between infections and cancer in man. Anneka Ehrnst's group study HIV, in particular mother-child transmission.

Epstein-Barr virus (EBV) infection in man is the model" that we are using to elucidate the complex sequence of events leading to tumor development. This is the most common virus in man and at the same time associated with a dozen tumors in man. With this natural infection we study viral and cellular genes involved in tumorigenicity and cell-cell interactions. LiFu Hu's group focuses on the EBV-associated Nasopharyngeal Carcinoma (NPC).

A subgroup works with bioinformatics and computational tools in cancer and infections, designated the Biocomplexity group, collaborating with the Royal School of Technology (KTH).

We are also developing tools to allow comparisons of the normal flora of the gut.


Epstein-Barr Virus

Natural infections are involved in the pathogenesis of 15-20% of all cancer in humans. In particular persistent viral infections and some bacterial infections are linked to cancer risks: hepatitis B virus, human hepatit C virus, human T-cell lymphoma virus, papilloma virus, Epstein-Barr virus (EBV), HHV-8 and H.pylori. Understanding the biology of the interaction between the host and the invading microorganism is crucial for future design of epidemiologic surveys, for identification of risk-groups, prevention, diagnosis and treatment. On the other hand natural infections as a cause of cancer opens unique possibilities to reduce the human cancer burden, by using several of these measures. Characteristic of all the cancer-associated infections known until now is that they may cause chronic or latent persistence of the virus, or bacteria in or at cells of the target tissues. This is either the result of natural strategy or of biological accidents. The subsequent cancer risk depends on direct effects of microbial genes on cellular control systems, and/or on tissue damage and inflammatory type of responses.

All tumor-associated viruses have evolved strategies for survival and spread as part of their physiologic infection, which affects cell cycle and apoptosis control. By inducing transient proliferation in their target organ/cells they prepare for lytic replication by engaging more cells, as an amplification mechanism. Virus infections per se induce apoptosis, which may be regarded as a defense mechanism by the host/host cell. Progression from cells at risk to overt tumor only takes place if late replicative events are truncated or blocked (e.g. by integration, accidental infection of wrong cell type), if the infection cannot be handled by the immune system and/or if the infection raises an inappropriate host reaction.

Epstein-Barr virus (EBV) infection in man, illustrates these points, due to extensive though incomplete knowledge on several of these issues. EBV is the most common virus in the human population (>90% of adults carry the virus). It normally gives rise to an inconspicuous or benign infection, paradoxically, however, under rare circumstances it induces tumors and in vitro it is very efficient in transforming its natural host cell, the B-lymphocyte.

We are studying the following aspects:

  • The switch between viral programs controlling B-cell activation and proliferation or resting cell states (latency programs)
  • Immune escape and latency in patients at risk detected as virus load and infected cells in different latency programs
  • The Biocomplexity group is developing tools and using them to analyze and model from high through put data, such as transcriptomes, microRNAs arrays, statistical mechanics. One project addresses the issue of cells as 'dynamic attractors'

Latent EBV Infection

Latent EBV infection controlling B-cell switches

EBV cooperates with the host B-cell in controlling its fate, either proliferation or G0-rest. This switch is likely to be a cornerstone in that the virus is a risk factor for human B-cell lymphomas.

The minimal requirement for this switch are two viral promoters, the virus household protein EBNA 1 and cellulat transcription factors. We have identified cellular transcription factors of the oct-family and its co-regulators that cooperate with the virus in executing this switch with dramatic downstream consequences for the host cell. A mechanical statistical model for the switch was elaborated with professor Erik Aurell and graduate student Mia Werner, KTH and the model is presently being validated using shRNA knock down and transfection upregulation of the key regulatory proteins.

Viral Latency in Risk Patients

Viral latency in patients at risk detected as virus load and infected cells in different latency programs

The impact of variation of virus infected cells in blood and solid lymphoid organs is studied. We compare healthy EBV-carriers with groups with high risk of lymphoma, HIV-carriers and bone marrow transplant patients. Also, the form of latent infection in vivo is studied in order to find out if this affects lymphoma risk.

The purpose is to understand the basis for increased risk of lymphomatous malignancies in HIV-carriers. Four studies have been completed and are under publication: 1) EBV genome load in blood B-lymphocyte populations increase after HIV-infection, but decrease upon development of AIDS. The individual span of virus load is conspicuously wide ranging. 2) Immunostimulatory treatment such as vaccine adjuvant (alun) contributes to considerable increase of EB virus load in HIV-carriers, further enhanced by history of symtoms upon primary HIV-infection. 3) Primary HIV-infection without adjuvant treatment as above results in no significant increase compared to a group of long term survivors (> 10 years). HIV-RNA levels and EBV-DNA levels in B-cells correlate before treatment with HAART, while the decrease of HIV-RNA after HAART treatment does not correlate to a decrease of EBV genomes after short term observation. 4) Long term follow up of EBV-DNA load for more than three years of HIV-carriers reveals a correlation between high genome levels and various complications.

This project is performed by post doc Jie-Zhi Zou and graduate students Qin Li and Anna Friis in collaboration with clinicians at Huddinge Hospital (Åsa Jernberg-Gustavsson, Jacek Winiarski, Börje Åkerlund and Katarina Gyllensten).

Signal transduction, migration and invasion
Subversion of signal transduction: control of latency

NPC is one of the most common malignancies in certain geographical regions as in Greenland (31 cases /105 inhabitants / year) and Southern China ( 42 cases /105 inhabitants /year) with the highest incidence in the world , although it is rare in other countries (0.6 cases /105 /year in Sweden). Such a pronounced, uneven distribution and the high rate of familial clustering of this cancer strongly suggest that environmental risk factors, including the EBV infection, cooperate with the genetically susceptible background in the high risk populations

In this project we study the impact of EB-viral genes that are expressed in NPC, particularly latent membrane protein 1 (LMP 1) and latent membrane protein 2 (LMP 2). Their effects on signal transduction and cell cycle are studied in in vitro model epithelial systems.

The LMP2A messages are constantly detected in NPC tumor biopsies and, along with EBNA1, is the only protein-coding EBV-specific message detected in individuals harboring EBV latent infection, suggesting that LMP2A plays an important role in vivo for control of latency and EBV-related diseases in humans.

It is quite established a role of LMP2A as a modulator of cell signaling. LMP2A does it by snapping away tyrosine kinases Syk and Lyn from B-cell receptor (BCR) in B cells, and Zap70 and Lck from TCR in T cells. We have shown, in close collaboration with Tony Pawsons group in Toronto, that LMP2A binds and initiates proteasomal degradation of these kinases, which lead to impaired BCR and TCR signaling. The more LMP2A is expressed, such as during the initial step of EBV infection of naïve B cells, the more it interferes with BCR signaling while at the lower expression level, such as in the resting, memory type B cells, LMP2A may even mimic the cellular receptor function by sending tonic, survival signals. LMP2A does it by activating the major pro-survival kinase, Akt. The differential effects of LMP2A are tuned to the viral strategy of latency and sporadic reactivation, as for other herpesviruses.

It is much less known about LMP2A-mediated interference with cell signaling in epithelial cells apart that LMP2A interacts with Syk in epithelial cells as well. We have found a novel interacting partner for LMP2A in epithelial cells, a scaffolding protein Shb. Moreover, we have demonstrated that the LMP2A-Shb complex is functional in epithelial cells, it corroborates Syk-mediated activation of Akt pathway. We focus on impact the LMP2A-rewired signaling may have on function of epithelial cell surface receptors, integrins. We work on another aspect of LMP2A expression in epithelial cells, its impact on endo- and exo-somal traffic of cell surface receptors, such as EGFR, CXCR4, GPCR and pattern recognition receptors of TLR family (TLR 3/7/9).

This work is done by Ingemar Ernberg, Liudmilla Matskova, research associate and graduate student Xiaoying Zhou in collaboration with Tony Pawsons group in Toronto. The LMP1 work was performed by XiangNing Zhang, former graduate student of the group in collaboration with LiFu Hu's group.

Hodgkin's Lymphoma

The role of EBV latency in Hodgkins lymphoma

In collaboration with the Hematology Unit at the Dept of Medicine, Karolinska University Hospital, we are studying the impact of EBV in subtypes of Hogkins lymphoma. The trascriptomes of the Nodular Sclerosis (NS) and Mixed Cellularity (MC) are correlated to presence of EBV in the tumors. Experimental validation of genes of interest are performed in in vitro cell lines, including a 3-dimensional cell culture system.

This project is perfomed in collaboration with Magnus Björkholm, Anja Porwit-MacDonald and Jan Sjöberg at the Dept of Medicine. Former graduate student Anna Birgersdotter presented a thesis on this.

The Normal Flora of the Gut

We develop techniques to compare the normal flora of the gut between healthy persons and those suffering from bowel problems (with E Zabarovsky, T Midvedt and R Möllby, MTC, and O Ljungqvist, Ersta hospital).

The main concept is to select representative short sequences from the gut microbiome in an unbiased manner. These are analyzed by sequencing and with arrays. Differences in microbiome composition are identified by cross-clonal hybridization between patient samples and controls. This is most likely the only way to make such comparisons until many full microbiomes have been fully sequenced.


Development of a population-based cancer case-control study in southern china.
Ye W, Chang E, Liu Z, Liu Q, Cai Y, Zhang Z, et al
Oncotarget 2017 Oct;8(50):87073-87085

Ancient permafrost staphylococci carry antibiotic resistance genes.
Kashuba E, Dmitriev A, Kamal S, Melefors O, Griva G, Römling U, et al
Microb. Ecol. Health Dis. 2017 ;28(1):1345574

Degradation of cofilin is regulated by Cbl, AIP4 and Syk resulting in increased migration of LMP2A positive nasopharyngeal carcinoma cells.
Gainullin M, Zhukov I, Zhou X, Mo Y, Astakhova L, Ernberg I, et al
Sci Rep 2017 Aug;7(1):9012

Epstein-Barr virus (EBV) provides survival factors to EBVdiffuse large B-cell lymphoma (DLBCL) lines and modulates cytokine induced specific chemotaxis in EBV DLBCL.
Wu L, Ehlin-Henriksson B, Zhou X, Zhu H, Ernberg I, Kis L, et al
Immunology 2017 Dec;152(4):562-573

Epstein-Barr virus-encoded LMP2A stimulates migration of nasopharyngeal carcinoma cells via the EGFR/Ca/calpain/ITGβ4 axis.
Liang J, Zheng S, Xiao X, Wei J, Zhang Z, Ernberg I, et al
Biol Open 2017 Jun;6(6):914-922

Quantification of familial risk of nasopharyngeal carcinoma in a high-incidence area.
Liu Z, Chang E, Liu Q, Cai Y, Zhang Z, Chen G, et al
Cancer 2017 Jul;123(14):2716-2725

George Klein (1925-2016).
Ernberg I, Kärre K, Wigzell H
Nature 2017 02;542(7641):296

Tumor suppressor BLU promotes TRAIL-induced apoptosis by downregulating NF-κB signaling in nasopharyngeal carcinoma.
Zhou J, Huang Z, Wang Z, Liu S, Grandien A, Ernberg I, et al
Oncotarget 2017 Jul;8(27):43853-43865

Fulminant anaplastic large cell lymphoma (ALCL) concomitant with primary cytomegalovirus (CMV) infection, and human herpes virus 8 (HHV-8) infection together with Epstein-Barr-virus (EBV) reactivation in a patient with asymptomatic HIV-infection.
Grützmeier S, Porwit A, Schmitt C, Sandström E, Åkerlund B, Ernberg I
Infect. Agents Cancer 2016 ;11():46

Short Chain Fatty Acids (SCFA) Reprogram Gene Expression in Human Malignant Epithelial and Lymphoid Cells.
Astakhova L, Ngara M, Babich O, Prosekov A, Asyakina L, Dyshlyuk L, et al
PLoS ONE 2016 ;11(7):e0154102

Oral Hygiene and Risk of Nasopharyngeal Carcinoma-A Population-Based Case-Control Study in China.
Liu Z, Chang E, Liu Q, Cai Y, Zhang Z, Chen G, et al
Cancer Epidemiol. Biomarkers Prev. 2016 08;25(8):1201-7

A new prognostic histopathologic classification of nasopharyngeal carcinoma.
Wang H, Chang Y, To K, Hwang J, Mai H, Feng Y, et al
Chin J Cancer 2016 May;35():41

Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning.
Li Q, Rane L, Poiret T, Zou J, Magalhaes I, Ahmed R, et al
Oncotarget 2016 May;7(21):30230-40

Dynamics inside the cancer cell attractor reveal cell heterogeneity, limits of stability, and escape.
Li Q, Wennborg A, Aurell E, Dekel E, Zou J, Xu Y, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 Mar;113(10):2672-7

From the first curative targeted cancer treatment to the implementation of the most extensive healthcare reform.
Ernberg I
J. Intern. Med. 2015 Dec;278(6):643-4

Epigenetic downregulation of the ISG15-conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma.
Zhou X, Wei J, Chen F, Xiao X, Huang T, He Q, et al
Oncotarget 2015 Dec;6(38):41077-91

Proteoglycan expression correlates with the phenotype of malignant and non-malignant EBV-positive B-cell lines.
Tsidulko A, Matskova L, Astakhova L, Ernberg I, Grigorieva E
Oncotarget 2015 Dec;6(41):43529-39

Integrin α9 gene promoter is hypermethylated and downregulated in nasopharyngeal carcinoma.
Nawaz I, Hu L, Du Z, Moumad K, Ignatyev I, Pavlova T, et al
Oncotarget 2015 Oct;6(31):31493-507

Detection of nasopharyngeal carcinoma in Morocco (North Africa) using a multiplex methylation-specific PCR biomarker assay.
Nawaz I, Moumad K, Martorelli D, Ennaji M, Zhou X, Zhang Z, et al
Clin Epigenetics 2015 ;7():89

SYK interaction with ITGβ4 suppressed by Epstein-Barr virus LMP2A modulates migration and invasion of nasopharyngeal carcinoma cells.
Zhou X, Matskova L, Rathje L, Xiao X, Gish G, Werner M, et al
Oncogene 2015 Aug;34(34):4491-9

TCR+CD4-CD8- T cells in antigen-specific MHC class I-restricted T-cell responses after allogeneic hematopoietic stem cell transplantation.
Ahmed R, Poiret T, Ambati A, Rane L, Remberger M, Omazic B, et al
J. Immunother. 2014 Oct;37(8):416-25

Development of a multiplex methylation specific PCR suitable for (early) detection of non-small cell lung cancer.
Nawaz I, Qiu X, Wu H, Li Y, Fan Y, Hu L, et al
Epigenetics 2014 Aug;9(8):1138-48

Development of a multiplex methylation specific PCR suitable for (early) detection of non-small cell lung cancer.
Nawaz I, Qiu X, Wu H, Li Y, Fan Y, Hu L, et al
Epigenetics 2014 Aug;9(8):1138-48

Transcriptional Activity of Heparan Sulfate Biosynthetic Machinery is Specifically Impaired in Benign Prostate Hyperplasia and Prostate Cancer.
Suhovskih A, Tsidulko A, Kutsenko O, Kovner A, Aidagulova S, Ernberg I, et al
Front Oncol 2014 ;4():79

Epstein Barr virus DNA analysis in blood predicts disease progression in a rare case of plasmablastic lymphoma with effusion.
Friis A, Akerlund B, Christensson B, Gyllensten K, Aleman A, Zou J, et al
Infect. Agents Cancer 2013 Jul;8(1):28

Increase of faecal tryptic activity relates to changes in the intestinal microbiome: analysis of Crohn's disease with a multidisciplinary platform.
Midtvedt T, Zabarovsky E, Norin E, Bark J, Gizatullin R, Kashuba V, et al
PLoS ONE 2013 ;8(6):e66074

An update on viral association of human cancers.
Zhang X, Zhang Z, Zheng B, He Z, Winberg G, Ernberg I
Arch. Virol. 2013 Jul;158(7):1433-43

EBV counteracts IL-21-induced apoptosis in an EBV-positive diffuse large B-cell lymphoma cell line.
Wu L, Ehlin-Henriksson B, Zhu H, Ernberg I, Klein G
Int. J. Cancer 2013 Aug;133(3):766-70

Development of a non-invasive method, multiplex methylation specific PCR (MMSP), for early diagnosis of nasopharyngeal carcinoma.
Zhang Z, Sun D, Hutajulu S, Nawaz I, Nguyen Van D, Huang G, et al
PLoS ONE 2012 ;7(11):e45908

Epstein-Barr virus genome load is increased by therapeutic vaccination in HIV-l carriers, and further enhanced in patients with a history of symptomatic primary infection.
Friis A, Akerlund B, Gyllensten K, Aleman A, Bratt G, Sandström E, et al
Vaccine 2012 Sep;30(42):6093-8

The TCF4/β-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer.
Mostovich L, Prudnikova T, Kondratov A, Gubanova N, Kharchenko O, Kutsenko O, et al
Epigenetics 2012 Aug;7(8):930-9

Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays.
Dmitriev A, Kashuba V, Haraldson K, Senchenko V, Pavlova T, Kudryavtseva A, et al
Epigenetics 2012 May;7(5):502-13

Clinical significance of elevated spleen tyrosine kinase expression in nasopharyngeal carcinoma.
Du Z, Kou C, Wang H, Huang M, Liao D, Hu C, et al
Head Neck 2012 Oct;34(10):1456-64

Host-Epstein-Barr virus relationship affected by immunostimulation in HIV-infected patients representing distinct progressor profile groups.
Friis A, Åkerlund B, Gyllensten K, Aleman A, Ernberg I
Scand. J. Infect. Dis. 2012 May;44(5):388-92

Eight-signature classifier for prediction of nasopharyngeal [corrected] carcinoma survival.
Wang H, Sun B, Zhu Z, Chang E, To K, Hwang J, et al
J. Clin. Oncol. 2011 Dec;29(34):4516-25

CDH4 as a novel putative tumor suppressor gene epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma.
Du C, Huang T, Sun D, Mo Y, Feng H, Zhou X, et al
Cancer Lett. 2011 Oct;309(1):54-61

A single nucleotide polymorphism in the matrix metalloproteinase 2 promoter is closely associated with high risk of nasopharyngeal carcinoma in Cantonese from southern China.
Shao J, Cao Y, Miao X, Huang M, Deng L, Hao J, et al
Chin J Cancer 2011 Sep;30(9):620-6

Systems medicine and integrated care to combat chronic noncommunicable diseases.
Bousquet J, Anto J, Sterk P, Adcock I, Chung K, Roca J, et al
Genome Med 2011 Jul;3(7):43

Upregulation of MiR-155 in nasopharyngeal carcinoma is partly driven by LMP1 and LMP2A and downregulates a negative prognostic marker JMJD1A.
Du Z, Hu L, Wang H, Yan L, Zeng Y, Shao J, et al
PLoS ONE 2011 Apr;6(4):e19137

CDH4 as a novel putative tumor suppressor gene epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma.
Du C, Huang T, Sun D, Mo Y, Feng H, Zhou X, et al
Cancer Lett. 2011 Oct;309(1):54-61

[Probiotics--friends or enemies of the intestine?].
Benno P, Ernberg I, Midtvedt T, Norin E, Zachrisson K
Lakartidningen ;107(13-14):907-9

[Intestinal flora--the biggest organ of the body. Unstable ecosystem which can easily topple].
Benno P, Blomquist L, Ernberg I, Midtvedt T, Möllby R, Norin E
Lakartidningen ;107(13-14):900-3

Inhibition spectrum studies of microthecin and other anhydrofructose derivatives using selected strains of Gram-positive and -negative bacteria, yeasts and moulds, and investigation of the cytotoxicity of microthecin to malignant blood cell lines.
Fiskesund R, Thomas L, Schobert M, Ernberg I, Lundt I, Yu S
J. Appl. Microbiol. 2009 Feb;106(2):624-33

High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer.
Kashuba V, Pavlova T, Grigorieva E, Kutsenko A, Yenamandra S, Li J, et al
PLoS ONE 2009 May;4(5):e5231

A review of human carcinogens--Part B: biological agents.
Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al
Lancet Oncol. 2009 Apr;10(4):321-2

Infectious agents and lymphoma development: molecular and clinical aspects.
Ferreri A, Ernberg I, Copie-Bergman C
J. Intern. Med. 2009 Apr;265(4):421-38

Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma.
Birgersdotter A, Baumforth K, Porwit A, Sjöberg J, Wei W, Björkholm M, et al
Br. J. Cancer 2009 Oct;101(8):1393-401

Cancer attractors: a systems view of tumors from a gene network dynamics and developmental perspective.
Huang S, Ernberg I, Kauffman S
Semin. Cell Dev. Biol. 2009 Sep;20(7):869-76

Connective tissue growth factor is expressed in malignant cells of Hodgkin lymphoma but not in other mature B-cell lymphomas.
Birgersdotter A, Baumforth K, Wei W, Murray P, Sjöberg J, Björkholm M, et al
Am. J. Clin. Pathol. 2010 Feb;133(2):271-80

Ernberg, I. Et al.
Vad är liv? I människan, i kosmos, i cellen
Karolinska Universitet

y Press, Stockholm, 2010.

Earlier Publications

Publications 2007-2008

Publications 1997-2000

Group Members

Professor, senior

Ingemar Ernberg

Organizational unit: Ingemar Ernberg group

Andrey AlexeyenkoBioinformatician
Peter BennoAssociated
Gunnar BjursellAssociated
Benedek BozokyGraduate Student
Ingemar ErnbergProfessor, senior
Elvira GrigorievaAssociated
Li-Fu HuSenior researcher
Bo LIAssociated
Liudmila MatskovaResearch engineer
Tore MidtvedtAssociated
Roland MöllbyAssociated
Elisabeth Lissa NorinAssociated
Iurii PetrovPhD student, Graduate Student
Li-Sophie RathjeAssociated
Anders WennborgAssociated
Shixing ZhengGraduate Student
Jie-Zhi ZouSenior lab manager

Tumour Biology