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  • 1. Edfeldt, Katarina
    Small Intestinal Neuroendocrine Tumours: Genetic and Epigenetic Studies and Novel Serum Biomarkers2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Small intestinal neuroendocrine tumours (SI-NETs) are rare, hormone producing and proliferate slowly. Patients usually display metastases at time of diagnosis, the tumours are difficult to cure, and the disease course is unpredictable.

    The gene expression pattern was investigated in paper I, with emphasis on aggressive disease and tumour progression. Expression microarrays were performed on 42 tumours. Unsupervised hierarchal clustering revealed three clusters that were correlated to clinical features, and expression changes from primary tumour to metastasis. Eight novel genes, ACTG2, GREM2, REG3A, TUSC2, RUNX1, TGFBR2, TPH1 and CDH6 may be of importance for tumour progression.

    In paper II, expression of ACTG2 was detected in a fraction of SI-NETs, but not in normal enterochromaffin cells. Inhibition of histone methyltransferase and transfection of miR-145 induced expression and no effect was seen after DNA methylation or selective EZH2 inhibition in vitro. miR-145 expression was reduced in metastases compared to primary tumours. Overexpression of ACTG2 inhibited cell growth, and inducing ACTG2 may have therapeutic effects.

    TCEB3C (Elongin A3) is located on chromosome 18 and is imprinted in some tissues. In paper III a reduced protein expression was detected. The gene was epigenetically repressed by both DNA and histone methylation in a tumour tissue specific context. The expression was also induced in primary cell cultures after DNA demethylation and pyrosequencing revealed promoter region hypermethylation. Overexpression of TCEB3C inhibited cell growth by 50%, suggesting TCEB3C to be a tumour suppressor gene.

    In paper IV, 69 biomarkers were analysed in blood serum using multiplex proximity ligation assay. Nineteen markers displayed different levels between patients and controls. In an extended cohort, ELISA analysis showed elevated serum levels of Mindin, DcR3 and TFF3 in patients and protein expression in tumour cells. High levels of DcR3 and TFF3 were associated with poor survival, and DcR3 may be a marker for liver metastases. Mindin, DcR3, and TFF3 are potential novel diagnostic biomarkers for SI-NETs.

  • 2.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Ahmad, Tanveer
    Uppsala universitet, Institutionen för kirurgiska vetenskaper.
    Åkerström, Göran
    Uppsala universitet, Endokrinkirurgi.
    Janson, Eva T
    Uppsala universitet, Onkologisk endokrinologi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    TCEB3C a putative tumor suppressor gene of small intestine neuroendocrine tumors2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 2, p. 275-284Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs), formerly midgut carcinoids, are rare and slow-growing neoplasms. Frequent loss of one copy of chromosome 18 in primary tumors and metastases has been observed. The aim of the study was to investigate a possible role of TCEB3C (Elongin A3), currently the only imprinted gene on chromosome 18, as a tumor suppressor gene in SI-NETs, and whether its expression is epigenetically regulated. Primary tumors, metastases, the human SI-NET cell line CNDT2.5, and two other cell lines were included. Immunohistochemistry, gene copy number determination by PCR, colony formation assay, Western blotting, real-time quantitative RT-PCR, RNA interference, and quantitative CpG methylation analysis by pyrosequencing were performed. The large majority of tumors (33/43) showed very low to undetectable Elongin A3 expression and as expected 89% (40/45) displayed one TCEB3C gene copy. The DNA hypomethylating agent 5-aza-2'-deoxycytidine induced TCEB3C expression in CNDT2.5 cells, in primary SI-NET cells prepared directly after surgery, but not in two other cell lines. Also siRNA to DNMT1 and treatment with the general histone methyltransferase inhibitor 3-deazaneplanocin A induced TCEB3C expression in a cell type-specific way. CpG methylation at the TCEB3C promoter was observed in all analyzed tissues and thus not related to expression. Overexpression of TCEB3C resulted in a 50% decrease of clonogenic survival of CNDT2.5 cells, but not of control cells. The results support a putative role of TCEB3C as a tumor suppressor gene in SI-NETs. Epigenetic repression of TCEB3C seems to be tumor cell type-specific and involves both DNA and histone methylation.

  • 3.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Ahmad, Tanvver
    Åkerstrom, Göran
    Uppsala universitet, Endokrinkirurgi.
    Janson, Eva Tiensuu
    Uppsala universitet, Onkologisk endokrinologi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Stalberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    TCEB3C (Elongin A3) on chromosome 18 presents a putative tumor suppressor gene of small intestine neuroendocrine tumors.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 4.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Endokrinkirurgi.
    Åkerström, Göran
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Different gene expression profiles in metastasizing midgut carcinoid tumors2011In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 18, no 4, p. 479-489Article in journal (Refereed)
    Abstract [en]

    The genetic events leading the progression of midgut carcinoid tumors are largely unknown. The disease course varies from patient to patient, and there is a lack of reliable prognostic markers. In order to identify genes involved in tumor progression, gene expression profiling was performed on tumor specimens. Samples comprised 18 primary tumors, 17 lymph node (LN) metastases, and seven liver metastases from a total of 19 patients. Patients were grouped according to clinical data and histopathology into indolent or progressive course. RNA was subjected to a spotted oligo microarray and B-statistics were performed. Differentially expressed genes were verified using quantitative real-time PCR. Self-organizing maps demonstrated three clusters: 11 primary tumors separated in one cluster, five LN metastases in another cluster, whereas all seven liver metastases, seven primary, and 12 LN metastases formed a third cluster. There was no correlation between indolent and progressive behavior. The primary tumors with Ki67>5%, with low frequency of the carcinoid syndrome, and a tendency toward shorter survival grouped together. Primary tumors differed in expression profile from their associated LN metastases; thus, there is evidence for genetic changes from primary tumors to metastases. ACTG2, GREM2, REG3A, TUSC2, RUNX1, TPH1, TGFBR2, and CDH6 were differentially expressed between clusters and subgroups of tumors. The expression profile that assembles tumors as being genetically similar on the RNA expression level may not be concordant with the clinical disease course. This study reveals differences in gene expression profiles and novel genes that may be of importance in midgut carcinoid tumor progression.

  • 5.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Bäcklin, Christofer
    Uppsala universitet, Cancerfarmakologi och beräkningsmedicin.
    Tiensuu Janson, Eva
    Uppsala universitet, Onkologisk endokrinologi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Novel Serum Biomarkers in Small Intestinal Neuroendocrine TumorsManuscript (preprint) (Other academic)
  • 6.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Stalberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    ACTG2 Inhibits Growth and Is Epigenetically Repressed in Small Intestinal Neuroendocrine Tumors2014In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 99, no 3-4, p. 227-227Article in journal (Other academic)
  • 7.
    Edfeldt, Katarina
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    A Plausible Role for Actin Gamma Smooth Muscle 2 (ACTG2) in Small Intestinal Neuroendocrine Tumorgenesis2016In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 16, article id 19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from the enterochromaffin cells in the ileum and jejunum. The knowledge about genetic and epigenetic abnormalities is limited. Low mRNA expression levels of actin gamma smooth muscle 2 (ACTG2) have been demonstrated in metastases relative to primary SI-NETs. ACTG2 and microRNA-145 (miR-145) are aberrantly expressed in other cancers and ACTG2 can be induced by miR-145. The aim of this study was to investigate the role of ACTG2 in small intestinal neuroendocrine tumorigenesis.

    METHODS: Protein expression was analyzed in SI-NETs (n = 24) and in enterochromaffin cells by immunohistochemistry. The cell line CNDT2.5 was treated with the histone methyltransferase inhibitor 3-deazaneplanocin A (DZNep), the selective EZH2 inhibitor EPZ-6438, or 5-aza-2'-deoxycytidine, a DNA hypomethylating agent. Cells were transfected with ACTG2 expression plasmid or miR-145. Western blotting analysis, quantitative RT-PCR, colony formation- and viability assays were performed. miR-145 expression levels were measured in tumors.

    RESULTS: Eight primary tumors and two lymph node metastases displayed variable levels of positive staining. Fourteen SI-NETs and normal enterochromaffin cells stained negatively. Overexpression of ACTG2 significantly inhibited CNDT2.5 cell growth. Treatment with DZNep or transfection with miR-145 induced ACTG2 expression (>10-fold), but no effects were detected after treatment with EPZ-6438 or 5-aza-2'-deoxycytidine. DZNep also induced miR-145 expression. SI-NETs expressed relatively low levels of miR-145, with reduced expression in metastases compared to primary tumors.

    CONCLUSIONS: ACTG2 is expressed in a fraction of SI-NETs, can inhibit cell growth in vitro, and is positively regulated by miR-145. Theoretical therapeutic strategies based on these results are discussed.

  • 8.
    Hultin, Hella
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Edfeldt, Katarina
    Uppsala universitet, Endokrinkirurgi.
    Sundbom, Magnus
    Uppsala universitet, Gastrointestinalkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Left-Shifted Relation between Calcium and Parathyroid Hormone in Obesity2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 8, p. 3973-3981Article in journal (Refereed)
    Abstract [en]

    Background: A condition resembling secondary hyperparathyroidism (HPT), including raised levels of PTH and normal levels of serum calcium, has been reported in obesity. A plausible reason may be vitamin D deficiency, but conflicting data have been reported. Objective: Our objective was to investigate calcium homeostasis in obese individuals with emphasis on the function of the parathyroid glands. Design and Intervention: Morbidly obese patients (mean body mass index = 46.6 +/- 6) were examined for their status of calcium homeostasis. A subset was thoroughly investigated with calcium-citrate (CiCa) clamping. Patients: Of 108 morbidly obese patients, 11 underwent CiCa clamping as well as 21 healthy volunteers of normal weight and 15 with primary HPT (pHPT). Large patient cohorts of normal individuals and pHPT patients were also used as comparisons. Outcome Measures and Results: All obese individuals had normal serum calcium and creatinine levels. Mean levels of 25-OH-vitamin D-3 in serum were low, 53 nmol/liter (reference range 75-250 nmol/liter). Mean intact plasma PTH was 5.1 pmol/liter (reference range 1.1-6.9 pmol/liter). There was a significant positive correlation between PTH and duration of obesity. CiCa clamping in obese subjects revealed a remarkably high sensitivity for calcium and a left-shifted relation between plasma calcium and PTH (set point) compared with the normal population. CiCa clamping in pHPT patients demonstrated a right-shifted PTH-Ca curve. Conclusion: Although vitamin D levels in the obese individuals were low, few displayed overt signs of secondary HPT. The CiCa clamping implied a disturbance in the calcium homeostasis comparable to early renal insufficiency, with a left-shifted Ca-PTH curve and a lower set point compared with the normal population.

  • 9.
    Lejonklou, Margareta Halin
    et al.
    Uppsala universitet, Institutionen för medicinska vetenskaper.
    Edfeldt, Katarina
    Uppsala universitet, Endokrinkirurgi.
    Johansson, Térèse A.
    Uppsala universitet, Institutionen för medicinska vetenskaper.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Skogseid, Britt
    Uppsala universitet, Institutionen för medicinska vetenskaper.
    Neurogenin 3 and neurogenic differentiation 1 are retained in the cytoplasm of multiple endocrine neoplasia type 1 islet and pancreatic endocrine tumor cells2009In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 38, no 3, p. 259-266Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    To investigate if transcription factors involved in pancreatic differentiation and regeneration are present in pancreatic endocrine tumors and if they are differentially expressed in normal pancreas compared with multiple endocrine neoplasia type 1 (MEN1) nontumorous pancreas.

    METHODS:

    The expression of neurogenin 3 (NEUROG3), neurogenic differentiation 1 (NEUROD1), POU class 3 homeobox 4 (POU3F4), pancreatic duodenal homeobox factor 1 (PDX1), ribosomal protein L10 (RPL10), delta-like 1 homolog (Drosophila; DLK1), and menin was analyzed by immunohistochemistry in normal pancreas and pancreatic endocrine tumors from 6 patients with MEN1 and 16 patients with sporadic tumors, as well as pancreatic specimens from Men1 heterozygous and wild type mice. Quantitative polymerase chain reaction was performed in a subset of human tumors.

    RESULTS:

    Tumors and MEN1 nontumorous endocrine cells showed a prominent cytoplasmatic NEUROG3 and NEUROD1 expression. These factors were significantly more expressed in the cytoplasm of Men1 heterozygous mouse islet cells compared with wild type islets; the latter showed an exclusively nuclear reactivity. The degree of Pou3f4, Rpl10, and Dlk1 immunoreactivities differed significantly between islets of heterozygous and wild type mice. The expressions of RPL10 and NEUROD1 were prominent in the MEN1 human and heterozygous mouse exocrine pancreas. Insulinomas had significantly higher PDX1 and DLK1 messenger RNA levels compared with other tumor types.

    CONCLUSIONS:

    Transcription factors involved in pancreatic development show altered expression and subcellular localization in MEN1 nontumorous pancreas and pancreatic endocrine tumors.

  • 10.
    Norlén, Olov
    et al.
    Uppsala universitet, Endokrinkirurgi.
    Edfeldt, Katarina
    Uppsala universitet, Endokrinkirurgi.
    Åkerström, Göran
    Uppsala universitet, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Endokrinkirurgi.
    Hellman, Per
    Uppsala universitet, Endokrinkirurgi.
    Björklund, Peyman
    Uppsala universitet, Endokrinkirurgi.
    Stålberg, Peter
    Uppsala universitet, Endokrinkirurgi.
    Peritoneal carcinomatosis from small intestinal neuroendocrine tumors: Clinical course and genetic profiling2014In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 156, no 6, p. 1512-1522Article in journal (Refereed)
    Abstract [en]

    Background. One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. Methods. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Results. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy number variation data from single-nucleotide polymorphism array of the primary tumors (P = .042). Conclusion. SI-NET patients with PC have poor survival, which diminishes with increasing PC load after surgery. Clustering based on copy number variation and loss of heterozygosity data suggests different genotypes in primary tumors comparing patients with and without PC.

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