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Gu, X., Wang, L., Boldrup, L., Coates, P. J., Fåhraeus, R., Sgaramella, N., . . . Nylander, K. (2019). AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck. Cancers, 11(3), Article ID 347.
Open this publication in new window or tab >>AP001056.1, A Prognosis-Related Enhancer RNA in Squamous Cell Carcinoma of the Head and Neck
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 3, article id 347Article in journal (Refereed) Published
Abstract [en]

A growing number of long non-coding RNAs (lncRNAs) have been linked to squamous cell carcinoma of the head and neck (SCCHN). A subclass of lncRNAs, termed enhancer RNAs (eRNAs), are derived from enhancer regions and could contribute to enhancer function. In this study, we developed an integrated data analysis approach to identify key eRNAs in SCCHN. Tissue-specific enhancer-derived RNAs and their regulated genes previously predicted using the computational pipeline PreSTIGE, were considered as putative eRNA-target pairs. The interactive web servers, TANRIC (the Atlas of Noncoding RNAs in Cancer) and cBioPortal, were used to explore the RNA levels and clinical data from the Cancer Genome Atlas (TCGA) project. Requiring that key eRNAs should show significant associations with overall survival (Kaplan-Meier log-rank test, p < 0.05) and the predicted target (correlation coefficient r > 0.4, p < 0.001), we identified five key eRNA candidates. The most significant survival-associated eRNA was AP001056.1 with ICOSLG encoding an immune checkpoint protein as its regulated target. Another 1640 genes also showed significant correlation with AP001056.1 (r > 0.4, p < 0.001), with the "immune system process" being the most significantly enriched biological process (adjusted p < 0.001). Our results suggest that AP001056.1 is a key immune-related eRNA in SCCHN with a positive impact on clinical outcome.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
AP001056.1, lncRNA, enhancer, SCCHN, ICOSLG, tumor immunity
National Category
Cell and Molecular Biology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-159881 (URN)10.3390/cancers11030347 (DOI)000468550200077 ()30862109 (PubMedID)
Funder
Swedish Cancer Society, 18 05 42Swedish Cancer Society, 18 02 96Västerbotten County Council
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Gu, X., Coates, P. J., Boldrup, L., Wang, L., Krejci, A., Hupp, T., . . . Nylander, K. (2019). Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue. Journal of Oral Pathology & Medicine, 48(1), 24-30
Open this publication in new window or tab >>Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue
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2019 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 48, no 1, p. 24-30Article in journal (Refereed) Published
Abstract [en]

Background The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment. Materials and methods To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (<= 40 years) and five elderly patients (>= 50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes. Results In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044). Conclusions Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
age, copy number variation, prognosis, squamous cell carcinoma of the oral tongue, whole-exome sequencing
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155648 (URN)10.1111/jop.12792 (DOI)000454799800005 ()30357923 (PubMedID)
Funder
Swedish Cancer Society, 17 0663Västerbotten County Council
Available from: 2019-01-25 Created: 2019-01-25 Last updated: 2019-01-25Bibliographically approved
Holm, A., Schindele, A., Allard, A., Eriksson, I., Sandström, K., Laurell, G., . . . Olofsson, K. (2019). Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease. Laryngoscope Investigative Otolaryngology, 4(3), 285-291
Open this publication in new window or tab >>Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease
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2019 (English)In: Laryngoscope Investigative Otolaryngology, E-ISSN 2378-8038, Vol. 4, no 3, p. 285-291Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.

Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.

Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).

Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.

Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.

Level of Evidence: Cross‐sectional study

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
Human papillomavirus, Epstein-Barr virus, non-malignant tonsillar disease, EBER-ISH, PapilloCheck, immunohistochemistry
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
urn:nbn:se:umu:diva-158485 (URN)10.1002/lio2.260 (DOI)000471907200002 ()
Funder
Västerbotten County Council
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-07-11Bibliographically approved
Sgaramella, N., Wilms, T., Boldrup, L., Loljung, L., Gu, X., Coates, P. J., . . . Nylander, K. (2018). Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue. Oncology Letters, 16(5), 6603-6607
Open this publication in new window or tab >>Ethnicity based variation in expression of E-cadherin in patients with squamous cell carcinoma of the oral tongue
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2018 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 16, no 5, p. 6603-6607Article in journal (Refereed) Published
Abstract [en]

The oral tongue is the most common site for tumours within the oral cavity. Despite intense research, there has been no improvement in the survival rate for patients with oral tongue squamous cell carcinoma (OTSCC) during the last decades. Differences between oral cancer patients based on ethno-geographical distribution have been reported. The present study used immunohistochemistry to evaluate commonly used markers of cancer cell phenotypes, E-cadherin, -catenin and cytokeratins 5 and 19, in 120 patients with OTSCC. To evaluate the impact of ethnicity, patients from Sweden and Italy were included. A higher proportion of Swedish patients exhibited high expression of E-cadherin in their tumours (P=0.039), and high levels of E-cadherin in Swedish OTSCC patients that had succumbed to their disease were associated with poor prognosis. These data demonstrated differences in the pathological characteristics of OTSCC between two different European populations. The findings emphasise the need to take ethnicity/geographical location of patients into account when comparing results from different studies of OTSCC.

Place, publisher, year, edition, pages
Spandidos Publications, 2018
Keywords
E-cadherin, beta catenin, squamous cell carcinoma, oral tongue, ethnicity
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-153550 (URN)10.3892/ol.2018.9452 (DOI)000448433500141 ()30405799 (PubMedID)
Funder
Swedish Cancer Society, 17 06 63Västerbotten County Council, MEYS-NPSI-LO1413
Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-05-10Bibliographically approved
Holm, A., Hellman, U., Laurent, C., Laurell, G., Nylander, K. & Olofsson, K. (2018). Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis. Acta Oto-Laryngologica, 138(11), 1020-1027
Open this publication in new window or tab >>Hyaluronan in vocal folds and false vocal folds in patients with recurrent respiratory papillomatosis
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2018 (English)In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 138, no 11, p. 1020-1027Article in journal (Refereed) Published
Abstract [en]

Background: Hyaluronan (HA) is a glycosaminoglycan with viscoelastic properties necessary for vocal fold (VF) vibration and voice production. Changes in HAs molecular mass, possibly related to human papilloma virus, could affect formation/persistence of recurrent respiratory papillomatosis (RRP).

Aims/Objective: Describing mass and localization of HA and localization of HA receptor CD44 in VF and false vocal folds (FVF) in RRP.

Materials and Methods: Biopsies from VF and FVF from 24 RRP patients. Twelve were studied with histo-/immunohistochemistry for HA and CD44 in epithelium, stroma and RRP lesions. Twelve samples were analyzed for HA molecular mass distribution with gas-phase-electrophoretic-molecular-mobility-analyzer (GEMMA).

Results: Three of 23 stains (VF and FVF combined) showed faint HA staining in the epithelium; there was more extensive staining in the stroma. CD44 was present throughout all areas in FVF and VF, it did not concur with HA. GEMMA analysis revealed very high mass HA (vHMHA) with more varying amounts in VF.

Conclusions/Significance: HA was mainly distributed in the stroma. CD44 not binding to HA might explain the non-inflammatory response described in RRP. Possibly crosslinked vHMHA was seen in VF and FVF, with more variable amounts in VF samples. Counteracting HA crosslinking could become a treatment option in RRP.

Abstract [zh]

背景:透明质酸(HA)是一种糖胺聚糖, 具有声带(VF)振动和发声所必需的粘弹性。HA 分子量的变化可能与人乳头瘤病毒相关, 还可能影响复发性呼吸道乳头状瘤病(RRP)的形成或持续。

目的:描述HA的量和定位, HA受体CD44在VF中的定位和假性声带(FVF)在RRP中的定位。

材料和方法:24名RRP患者的VF和FVF的活组织检查。用组织/免疫组织化学方法研究12个样品的上皮、基质和RRP病变中的HA和CD44。用气-相-电泳 - 分子-迁移率-分析仪(GEMMA)分析另12个样品的HA分子量分布。

结果:23个染色中的3个(VF和FVF组合)在上皮细胞中显示出微弱的HA染色;基质中有更强的染色。 CD44存在于FVF和VF的所有区域, 它与HA不同时存在。 GEMMA分析显示非常高量的HA(vHMHA), 它在VF中的量多变。

结论/意义:HA主要分布在基质中。 CD44不与HA接合可能解释所描述的RRP中的非炎症反应。在VF和FVF中观察到可能交合的vHMHA, 而在VF样品中具有更多的变量。抗HA交合可能成为RRP的治疗选择。

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
Vocal folds, hyaluronan, CD44, human papilloma virus, recurrent respiratory papillomatosis
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156749 (URN)10.1080/00016489.2018.1500712 (DOI)000459000600012 ()30776265 (PubMedID)2-s2.0-85061778147 (Scopus ID)
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-04-29Bibliographically approved
Sgaramella, N., Gu, X., Boldrup, L., Coates, P. J., Fåhraeus, R., Califano, L., . . . Nylander, K. (2018). Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue. Current Topics in Medicinal Chemistry, 18(3), 214-218
Open this publication in new window or tab >>Searching for new targets and treatments in the battle against squamous cell carcinoma of the head and neck, with specific focus on tumours of the tongue
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2018 (English)In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 18, no 3, p. 214-218Article, review/survey (Refereed) Published
Abstract [en]

Squamous cell carcinoma of the head and neck, SCCHN, is a heterogeneous group of tumours not only concerning the site of origin but also regarding aetiology. The 5-year survival for the whole group of SCCHN tumours has not significantly improved over the last 20-25 years. Apart from tumour spread to lymph nodes, N status, gains and losses of specific chromosomes are the only factors shown to be independent prognostic markers for these tumours. Worldwide, an increasing number of people ≤ 40 years are seen being affected by tongue SCC, the most common tumour within the SCCHN group. Even without any clinical signs of metastasis, up to 30% of all tongue SCC have histologically detectable spread to lymph nodes. In this mini review, field cancerization, tumour microenvironment, the so called EMT (epithelial mesenchymal transition) process and the role of viruses in development of SCCHN are discussed as well as potential new therapeutic targets. For the group of tongue SCC, with the increasing incidence seen in young patients and particularly women, new data with impact on prognosis and treatment are urgently needed. But as long as data from the analyses of several sub sites are presented as valid for the whole group of tumours, this vital point is missed.

Place, publisher, year, edition, pages
Bentham Science Publishers, 2018
Keywords
squamous cell carcinoma, tongue, prognosis, therapy, miRNA, HPV, EBV, p63
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-148841 (URN)10.2174/1568026618666180116121624 (DOI)000432250800006 ()29345578 (PubMedID)
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-05-10Bibliographically approved
Danielsson, K., Ebrahimi, M., Nylander, E., Wahlin, Y. B. & Nylander, K. (2017). Alterations in factors involved in differentiation and barrier function in the epithelium in oral and genital lichen planus. Acta Dermato-Venereologica, 97(2), 214-218
Open this publication in new window or tab >>Alterations in factors involved in differentiation and barrier function in the epithelium in oral and genital lichen planus
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2017 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 97, no 2, p. 214-218Article in journal, Editorial material (Refereed) Published
Abstract [en]

Lichen planus is a chronic recurrent inflammatory disease affecting both skin and mucosa, mainly in oral and/or genital regions. Keratinocytes go through a well-regulated process of proliferation and differentiation, alterations in which may result in defects in the protective epithelial barrier. Long-term barrier impairment might lead to chronic inflammation. In order to broaden our understanding of the differentiation process in mucosal lichen planus, we mapped the expression of 4 factors known to be involved in differentiation. Biopsies were collected from oral and genital lichen planus lesions and normal controls. Altered expression of all 4 factors in epithelium from lichen planus lesions was found, clearly indicating disturbed epithelial differentiation in lichen planus lesions.

Keywords
lichen planus, differentiation, epithelial barrier
National Category
Dentistry Dermatology and Venereal Diseases
Research subject
Medical Cell Biology; Pathology
Identifiers
urn:nbn:se:umu:diva-125780 (URN)10.2340/00015555-2533 (DOI)000393895500009 ()27599552 (PubMedID)
Available from: 2016-09-16 Created: 2016-09-16 Last updated: 2019-05-10Bibliographically approved
Boldrup, L., Troiano, G., Gu, X., Coates, P., Fåhraeus, R., Wilms, T., . . . Nylander, K. (2017). Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue. OncoTarget, 8(61), 103437-103448
Open this publication in new window or tab >>Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103437-103448Article in journal (Refereed) Published
Abstract [en]

Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up-regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
miRNA, circulating markers, NT-3, miR-150, squamous cell carcinoma of the tongue
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144977 (URN)10.18632/oncotarget.21402 (DOI)000419562500057 ()29262574 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2018-06-09Bibliographically approved
Troiano, G., Caponio, V. C., Boldrup, L., Gu, X., Lo Muzio, L., Sgaramella, N., . . . Nylander, K. (2017). Expression of the long non-coding RNA HOTAIR as a prognostic factor in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. OncoTarget, 8(42), 73029-73036
Open this publication in new window or tab >>Expression of the long non-coding RNA HOTAIR as a prognostic factor in squamous cell carcinoma of the head and neck: a systematic review and meta-analysis
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 42, p. 73029-73036Article, review/survey (Refereed) Published
Abstract [en]

Introduction: Long noncoding RNAs (lncRNAs) are often dysregulated in cancer tissue and seem to play an important role in neoplastic processes. Recent studies have shown that the HOX transcript antisense intergenic RNA (HOTAIR) may play a role as a marker of prognosis in squamous cell carcinoma of the head and neck (SCCHN). The aim of this study was to perform a meta-analysis of studies focused on the prognostic role of HOTAIR in SCCHN.

Results: At the end of the selection process, four studies were considered eligible for inclusion in the meta-analysis, comprising a total of 271 patients. Meta-analysis revealed that high expression of HOTAIR was associated with poor overall survival (HR, 1.90; 95% CI: [1.42, 2.53]; p < 0,0001), advanced tumor stage (OR, 3.44; 95% CI: [1.84, 6.43]; p < 0,001) and lymph-node metastasis (OR, 3.31; 95% CI: [1.24, 8.79]; p = 0,02).

Materials and Methods: The literature search was performed in the following databases: PUBMED, SCOPUS, EMBASE and Web of Science, in order to find studies that met the inclusion criteria.

Conclusions: Findings from this systematic review and meta-analysis revealed that HOTAIR represents a potential biomarker of prognosis in patients with squamous cell carcinoma of the head and neck.

Place, publisher, year, edition, pages
Impact Journals LLC, 2017
Keywords
lncRNA, lncRNAs, non-coding RNA, HOTAIR, biomarker
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-140648 (URN)10.18632/oncotarget.20373 (DOI)000411509400134 ()
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2019-05-10Bibliographically approved
Boldrup, L., Gu, X., Coates, P. J., Norberg-Spaak, L., Fåhraeus, R., Laurell, G., . . . Nylander, K. (2017). Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma. OncoTarget, 8(12), 19389-19402
Open this publication in new window or tab >>Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 12, p. 19389-19402Article in journal (Refereed) Published
Abstract [en]

Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.

Keywords
tongue cancer, RNA expression, field cancerization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-133220 (URN)10.18632/oncotarget.14288 (DOI)000396879200062 ()
Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2018-06-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4831-4100

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