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Bivik, Cecilia
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Publications (10 of 19) Show all publications
Ekman, A.-K., Vegfors, J., Bivik, C. & Enerbäck, C. (2017). Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.. Acta Dermato-Venereologica, 97(4), 441-448
Open this publication in new window or tab >>Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.
2017 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, no 4, p. 441-448Article in journal (Refereed) Published
Abstract [en]

Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.

Place, publisher, year, edition, pages
Society for the Publication of Acta Dermato - Venereologica, 2017
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-133860 (URN)10.2340/00015555-2596 (DOI)000401127000005 ()27958610 (PubMedID)
Note

Funding agencies: Ingrid Asp Foundation; Welander Foundation; Swedish psoriasis association; Medical Research Council

Available from: 2017-01-12 Created: 2017-01-12 Last updated: 2018-05-02Bibliographically approved
Bivik Eding, C., Domer, J., Wäster, P., Jerhammar, F., Rosdahl, I. & Öllinger, K. (2015). Melanoma Growth and Progression After Ultraviolet A Irradiation: Impact of Lysosomal Exocytosis and Cathepsin Proteases. Acta Dermato-Venereologica, 95(7), 792-797
Open this publication in new window or tab >>Melanoma Growth and Progression After Ultraviolet A Irradiation: Impact of Lysosomal Exocytosis and Cathepsin Proteases
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2015 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, no 7, p. 792-797Article in journal (Refereed) Published
Abstract [en]

Ultraviolet (UV) irradiation is a risk factor for development of malignant melanoma. UVA-induced lysosomal exocytosis and subsequent cell growth enhancement was studied in malignant melanoma cell lines and human skin melanocytes. UVA irradiation caused plasma membrane damage that was rapidly repaired by calcium-dependent lysosomal exocytosis. Lysosomal content was released into the culture medium directly after irradiation and such conditioned media stimulated the growth of non-irradiated cell cultures. By comparing melanocytes and melanoma cells, it was found that only the melanoma cells spontaneously secreted cathepsins into the surrounding medium. Melanoma cells from a primary tumour showed pronounced invasion ability, which was prevented by addition of inhibitors of cathepsins B, D and L. Proliferation was reduced by cathepsin L inhibition in all melanoma cell lines, but did not affect melanocyte growth. In conclusion, UVA-induced release of cathepsins outside cells may be an important factor that promotes melanoma growth and progression.

Place, publisher, year, edition, pages
ACTA DERMATO-VENEREOLOGICA, 2015
Keywords
lysosome; cathepsin; UVA; exocytosis; melanocyte; melanoma
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-122545 (URN)10.2340/00015555-2064 (DOI)000362925500005 ()25669167 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Ostgotaregionens Cancer Foundation; Stiftelsen Olle Engkvist Byggmastare; Swedish Cancer Society; Welander-Finsen Foundation

Available from: 2015-11-06 Created: 2015-11-06 Last updated: 2017-12-01
Bostner, J., Karlsson, E., Bivik Eding, C., Perez-Tenorio, G., Franzén, H., Konstantinell, A., . . . Stål, O. (2015). S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts. Endocrine-Related Cancer, 22(3), 331-343
Open this publication in new window or tab >>S6 kinase signaling: tamoxifen response and prognostic indication in two breast cancer cohorts
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2015 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 22, no 3, p. 331-343Article in journal (Refereed) Published
Abstract [en]

Detection of signals in the mammalian target of rapamycin (mTOR) and the estrogen receptor (ER) pathways may be a future clinical tool for the prediction of adjuvant treatment response in primary breast cancer. Using immunohistological staining, we investigated the value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen benefit in two independent clinical trials comparing adjuvant tamoxifen with no tamoxifen or 5 years versus 2 years of tamoxifen treatment. In addition, the prognostic value of the S6Ks was evaluated. We found that S6K1 correlated with proliferation, HER2 status, and cytoplasmic AKT activity, whereas high protein expression levels of S6K2 and phosphorylated (p) S6K were more common in ER-positive, and low-proliferative tumors with pAKT-s473 localized to the nucelus. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen effect (hazard ratio (HR): 1.07, 95% CI: 0.53-2.81, P=0.84), compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation (HR: 0.42, 95% CI: 0.29-0.62, Pless than0.00001). Also S6K1 and S6K2 activation, indicated by pS6K-t389 expression, was associated with low benefit from tamoxifen (HR: 0.97, 95% CI: 0.50-1.87, P=0.92). In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis in a multivariate analysis, P=0.00041 (cytoplasm), P=0.016 (nucleus). In conclusion, the mTOR-activated kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity and intracellular localization may provide biomarkers for breast cancer treatment, allowing the identification of a group of patients less likely to benefit from tamoxifen and thus in need of an alternative or additional targeted treatment.

Place, publisher, year, edition, pages
BioScientifica, 2015
Keywords
pS6K; S6K1; S6K2; mTOR; AKT; estrogen receptor; endocrine treatment
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120883 (URN)10.1530/ERC-14-0513 (DOI)000359003500016 ()25972244 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; Ostergotland County Council; Lions Research Fund

Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2017-12-04
Ekman, A.-K., Verma, D., Fredrikson, M., Bivik, C. & Enerbäck, C. (2014). Genetic variations of NLRP1: susceptibility in psoriasis. British Journal of Dermatology, 171(6), 1517-1520
Open this publication in new window or tab >>Genetic variations of NLRP1: susceptibility in psoriasis
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2014 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 171, no 6, p. 1517-1520Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: NACHT, LRR and PYD domain-containing protein (NLRP)1 is part of the inflammasome multiprotein complex involved in the production of interleukin (IL)-1β and IL-18, two cytokines strongly implicated in psoriasis pathogenesis. Genetic variations in NLRP1 are associated with a predisposition for chronic inflammatory conditions.

OBJECTIVES: The aim of the study was to investigate the role of genetic variation in the NLRP1 inflammasome in psoriasis susceptibility.

MATERIAL AND METHODS: Four haplotype-tagging single-nucleotide polymorphisms (SNPs) (rs6502867, rs8079034, rs878329 and rs12150220) were investigated by TaqMan allelic discrimination in a patient sample comprising 1847 individuals from 478 families and 802 healthy controls.

RESULTS: Using the transmission disequilibrium test, a significant increase in the transmission of the NLRP1 rs8079034C and rs878329C alleles to patients with psoriasis was demonstrated (P = 0·006 and P = 0·033, respectively). Furthermore, homozygosity for the rs878329C allele correlated with a younger age of onset. We also observed an increase in the expression of NLRP1 mRNA in the peripheral blood cells of patients with psoriasis. This was accompanied by a higher level of circulating IL-18 and appeared to be associated with the rs878329C allele.

CONCLUSIONS: Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-112730 (URN)10.1111/bjd.13178 (DOI)000347236100197 ()24909542 (PubMedID)
Note

The study was funded by the Ingrid Asp foundation, the Welander Foundation and the Swedish Psoriasis Association.

Available from: 2014-12-10 Created: 2014-12-10 Last updated: 2018-01-11Bibliographically approved
Thunell, L., Bivik, C., Wäster, P., Fredrikson, M., Stjernstrom, A., Synnerstad, I., . . . Enerbäck, C. (2014). MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma. Melanoma research, 24(3), 190-197
Open this publication in new window or tab >>MDM2 SNP309 promoter polymorphism confers risk for hereditary melanoma
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2014 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 24, no 3, p. 190-197Article in journal (Refereed) Published
Abstract [en]

The p53 pathway regulates stress response, and variations in p53, MDM2, and MDM4 may predispose an individual to tumor development. The aim of this study was to study the impact of genetic variation on sporadic and hereditary melanoma. We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls. Genotyping was performed by PCR-restriction fragment length polymorphism, pyrosequencing, and allelic discrimination. We found an increased risk for hereditary melanoma in MDM2 GG homozygotes, which was more pronounced among women (P=0.035). In the event of pairwise combinations of the single nucleotide polymorphisms, a risk elevation was shown for MDM2 GG homozygotes/p53 wild-type Arg in hereditary melanoma (P=0.01). Individuals with sporadic melanomas of the superficial spreading type, including melanoma in situ, showed a slightly higher frequency of the MDM2 GG genotype compared with those with nodular melanomas (P=0.04). The dysplastic nevus phenotype, present in the majority of our hereditary melanoma cases and also in some sporadic cases, further enhanced the effect of the MDM2 GG genotype on melanoma risk (P=0.005). In conclusion, the results show an association between MDM2 SNP309 and an increased risk for hereditary melanoma, especially among women. Analysis of sporadic melanoma also shows an association between MDM2 and the superficial spreading melanoma subtype, as well as an association with the presence of dysplastic nevi in sporadic melanoma.

Place, publisher, year, edition, pages
Lippincott, Williams andamp; Wilkins, 2014
Keywords
superficial spreading melanoma; MDM2; hereditary melanoma; MDM4; p53; dysplastic nevi
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-107446 (URN)10.1097/CMR.0000000000000063 (DOI)000335683500002 ()
Available from: 2014-06-12 Created: 2014-06-12 Last updated: 2017-12-05
Vegfors, J., Bivik, C., Ekman, A.-K. & Enerbäck, C. (2014). Psoriasin (S100A7) contributes to stress-induced angiogenesis in psoriasis by the regulation of angiogenic factors in keratinocytes and promotion of angiogenic properties of dermal endothelial cells.
Open this publication in new window or tab >>Psoriasin (S100A7) contributes to stress-induced angiogenesis in psoriasis by the regulation of angiogenic factors in keratinocytes and promotion of angiogenic properties of dermal endothelial cells
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The S100 protein psoriasin, S100A7, is highly expressed in psoriasis. Vascular modifications occur early in the development of psoriasis and angiogenesis is one of the key features in the pathogenesis of the disease. This study aims to define the angiogenic properties of psoriasin in keratinocytes and to investigate the effects on dermal endothelial cells, thereby promoting angiogenesis in psoriasis. We showed that psoriasin expression, demonstrated by qPCR, is induced by hydrogen peroxide (H2O2) in keratinocytes and by cellular stress, such as hypoxia and cobalt chloride (CoCl2). Down-regulation of psoriasin, by siRNA, decreased the H2O2-induced expression of VEGF, heparin-binding EGF-like growth factor (HB-EGF) and matrix metalloproteinase (MMP)-1, and counteracted the reduction of the anti-angiogenic factor thrombospondin (THBS)-1. Extracellularly psoriasin was found to induce cell proliferation, migration and tube formation to a similar degree as VEGF and to induce the pro-angiogenic factors VEGF and IL-8 in dermal endothelial cells. Furthermore, we demonstrated that psoriasin-induced migration was mediated by the phosphoinositide-3-kinase (PI3K) and nuclear factor-kappa beta (NF-κB) signaling pathways. In conclusion, psoriasin is induced by cellular stress conditions and amplifies H2O2-induced expression of angiogenic factors relevant for psoriasis in keratinocytes. Moreover, psoriasin contributes to key features of the angiogenic process by inducing proliferation, migration and tube formation and increasing pro-angiogenic factors in dermal endothelial cell. Altogether, our data suggest that psoriasin is promoted by oxidative stress and mediate angiogenesis in psoriasis.

National Category
Rheumatology and Autoimmunity Health Sciences
Identifiers
urn:nbn:se:liu:diva-110028 (URN)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2015-04-09Bibliographically approved
Vegfors, J., Ekman, A.-K., Bivik, C. & Enerbäck, C. (2014). Psoriasin (S100A7) is regulated by protein kinase C (PKC) and contributes to keratinocyte differentiation by regulating the expression of epidermal differentiation markers.
Open this publication in new window or tab >>Psoriasin (S100A7) is regulated by protein kinase C (PKC) and contributes to keratinocyte differentiation by regulating the expression of epidermal differentiation markers
2014 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Psoriasis is a chronic inflammatory skin disease that is characterized by hyperproliferation and a disturbed maturation of the epidermal cells. The differentiation process of keratinocytes in active psoriatic lesions differs from that of normal epidermis, denoted by an altered expression of differentiation markers. Psoriasin, a protein which is highly expressed in psoriasis, is located within the epidermal differentiation complex (EDC), a gene cluster that contains several genes that are important in the terminal differentiation of the human epidermis. The potential role of psoriasin in keratinocyte differentiation remain however unclear. The aim of this present study was to investigate the possible involvement of psoriasin in keratinocyte differentiation. We demonstrated, by immunohistochemical staining, a gradient of psoriasin expression in the psoriatic epidermis, from an undefined or weak expression in the basal layer to an intense expression in the suprabasal differentiated layers. The expression of psoriasin was up-regulated in cultured keratinocytes in response to stimuli known to induce differentiation, such as an elevation of extracellular calcium or  12-Otetradecanoylphorbol-13-acetate (TPA). Down-regulation of psoriasin expression, by siRNA, resulted in decreased expression of the differentiation markers involucrin, desmoglein 1, transglutaminase 1 and CD24. Inhibition of protein kinase C (PKC) counteracted the calciuminduced expression of psoriasin and involucrin. In summary, our data demonstrate that psoriasin is regulated by the PKC signaling pathway and contributes to keratinocyte differentiation by the regulation of differentiation markers.

National Category
Rheumatology and Autoimmunity Health Sciences
Identifiers
urn:nbn:se:liu:diva-110030 (URN)
Available from: 2014-09-01 Created: 2014-09-01 Last updated: 2015-04-09Bibliographically approved
Sigurdardottir, G., Ekman, A.-K., Ståhle, M., Bivik, C. & Enerbäck, C. (2014). Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.. The Journal of American Academy of Dermatology, 70(6), 1067-1075
Open this publication in new window or tab >>Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.
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2014 (English)In: The Journal of American Academy of Dermatology, ISSN 0190-9622, E-ISSN 1097-6787, Vol. 70, no 6, p. 1067-1075Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Psoriasis is associated with a systemic inflammation and an increased frequency of the metabolic syndrome, both of which are believed to link psoriasis to an increased risk of cardiovascular disease.

OBJECTIVE: The study aimed to investigate the systemic expression of markers of cardiovascular risk and determine their response to ultraviolet B therapy and treatment with the tumor necrosis factor-alfa inhibitor, etanercept.

METHODS: Six markers of cardiovascular risk were measured in 28 patients with psoriasis and 28 control subjects.

RESULTS: Five of the 6 investigated markers were elevated in patients with psoriasis. Four of these correlated to the body mass index and waist-hip ratio, suggesting a link to the metabolic syndrome. Total plasminogen activator inhibitor-1 remained elevated independently of these factors. The levels of the investigated risk markers decreased considerably after tumor necrosis factor-alfa inhibitor treatment but remained unaffected by ultraviolet therapy.

LIMITATIONS: A relatively limited study population and nonrandomization are limitations.

CONCLUSION: These findings suggest that the choice of treatment in psoriasis may influence the cardiovascular risk in patients with psoriasis and the metabolic syndrome.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-107732 (URN)10.1016/j.jaad.2013.12.044 (DOI)000336030400026 ()24656729 (PubMedID)
Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2018-10-12
Bivik, C., Verma, D., Winge, M. C., Lieden, A., Bradley, M., Rosdahl, I. & Söderkvist, P. (2013). Letter: Genetic Variation in the Inflammasome and Atopic Dermatitis Susceptibility [Letter to the editor]. Journal of Investigative Dermatology, 133(10), 2486-2489
Open this publication in new window or tab >>Letter: Genetic Variation in the Inflammasome and Atopic Dermatitis Susceptibility
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2013 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, no 10, p. 2486-2489Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Hybrid Model Option A, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-99395 (URN)10.1038/jid.2013.168 (DOI)000324899100028 ()
Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-12-06
Bostner, J., Karlsson, E., Bivik, C., Perez-Tenorio, G., Franzén, H., Konstantinell, A., . . . Stål, O. (2013). S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts.
Open this publication in new window or tab >>S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts
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2013 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. A simultaneous knockdown of the S6Ks in ER-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6K1+S6K2 dependent, suggesting separate roles in proliferation and in tamoxifen response. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.

In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity andintracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely tobenefit from tamoxifen and thus in need of an alternative or additional treatment.

Keywords
pS6K, S6K1, S6K2, mTOR, Akt, estrogen receptor, endocrine treatment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100902 (URN)
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-11-14Bibliographically approved
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