Biology subjects

Kristiansen, G.

Publications and source records attributed to Kristiansen, G..

7 recordsLinked to original sources

bioRxiv2026

XPO1 Inhibition by Selinexor Induces Nuclear p53 and p21 Accumulation, Cell-Cycle Arrest and Apoptosis in Testicular Germ Cell Tumors

Background: Testicular germ cell tumors (TGCTs) are the most common solid malignancies in young men. Despite high cure rates with cisplatin-based chemotherapy, resistance and long-term toxicities remain clinical challenges in TGCTs. Selinexor, an FDA-approved XPO1 inhibitor, has demonstrated anti-tumor activity in other cancers, but its potential in TGCTs remains unknown. Objective: We investigated the antitumor effects of selinexor in TGCT cell lines. Materials and methods: XPO1 RNA expression, protein abundance and localization were evaluated by immunohistochemistry in TGCT tissue microarrays and non-neoplastic testicular tissues, and by meta-analysis of publicly available gene-expression microarray datasets from normal testis, primary TGCT specimens as well as TGCT cell lines. Selinexor effects on cell viability, cell-cycle distribution and apoptosis were evaluated using XTT assay and flow cytometry. p53 and p21 expression and localization were analyzed by Western blotting and Immunofluorescence. Results: XPO1 expression was heterogeneous across normal testis, TGCT tissues and cell lines. Yet, selinexor reduced TGCT cell viability and induced G1 or G2/M cell-cycle arrest, apoptosis, increased total p53 and p21 protein levels, and their nuclear accumulation. Of note, control fibroblast exhibited limited sensitivity to selinexor. Discussion and conclusion: Our findings demonstrate that inhibition of XPO1 with selinexor might be potential therapeutic strategy for TGCTs.

cancer biology↗

bioRxiv2025

ECD, a novel androgen receptor target promotes prostate cancer tumorigenesis by regulating glycolysis

Androgen receptor (AR)-mediated signaling is essential for PC tumorigenesis. In the TCGA database we observed a positive correlation between ECD and AR expression. Consistently, Dihydrotestosterone (DHT) treatment of PC cell lines increased ECD mRNA and protein levels, and AR knockdown (KD) reduced ECD expression. Bioinformatic analysis predicted three consensus androgen response elements in the ECD promoter, and DHT treatment increased AR occupancy at the ECD promoter, and enhanced ECD promoter activity. Enzalutamide treatment decreased ECD levels, and ECD knockout (KO) in PC cells reduced oncogenic traits, suggesting a functional role of ECD to maintain PC oncogenesis. ECD mRNA and protein are overexpressed in PC patient tissues, and its overexpression predicts shorter survival. Overexpression of ECD in PC cell lines enhanced the oncogenic traits in vitro and developed faster and larger highly proliferative xenograft tumors. RNA-seq analysis of mouse tumors revealed an increase in mRNA levels of several glycolytic genes. ECD associates with mRNA of key glycolytic genes and is required for their stability, consistent with our recent demonstration of ECD is an RNA binding protein. Higher glucose uptake and glycolysis was seen upon ECD overexpression in PC cells. Together, we demonstrate the role of a novel AR target gene ECD in PC tumorigenesis.

cancer biology↗

bioRxiv2024

The CCR4/CCL17 axis drives intestinal acute Graft versus Host disease after allogeneic bone marrow transplantation

Acute-Graft-versus-Host disease (aGvHD) is a life-threatening complication after allogeneic stem-cell-transplantation. It is mediated by alloreactive T cells whose trafficking to aGvHD target organs is orchestrated by chemokines. We here asked whether CCL17 and its corresponding receptor CCR4 are involved in aGvHD development and severity. We applied an experimental mouse model of aGvHD in CCR4/CCL17 knockout mice and analyzed gut biopsies of GvHD patients. We show that the absence of CCR4 in transplanted T cells induced significantly less severe aGvHD. This was accompanied by reduced expression of Gata3. Mechanistically, only CD4+, but not CD8+CCR4-/- T cells protected from aGvHD. We next identified dendritic cells in the small intestine to produce CCL17, which selectively recruited CD4+ T cells. IL-4 production by intestinal CD4+ T cells promoted proliferation of CD8+ T cells. In line, we detected an upregulation of CCL17 and Gata3 in human aGvHD samples. Our results indicate that local CCL17 production in aGvHD target organs recruits T cells, reinforcing local tissue damage and immune cell recruitment. We identified the JAK1/2-inhibitor ruxolitinib to dampen CCL17-expression, thereby reducing GvHD severity. We here dissect a to date unknown role of the CCL17-CCR4 axis in aGvHD, which might help to develop novel therapeutic strategies.

immunology↗

bioRxiv2022

Pro-apoptotic and anti-invasive properties underscore the tumor suppressing impact of myoglobin on subset of human breast cancer cells

Expression of myoglobin (MB), well known as the oxygen storage and transport protein of myocytes, is a novel hallmark of the luminal subtype in breast cancer patients and correlates with better prognosis. The mechanisms by which MB impacts mammary tumorigenesis are hitherto unclear. We aimed to unravel this role, by using CRISPR/Cas9 technology to generate MB-deficient clones of MCF7 and SKBR3 breast cancer cell lines and subsequently characterize them by transcriptomics plus molecular and functional analyses. As main findings, loss of MB, at normoxia, upregulated the expression of cell cyclins and increased cell survival while it prevented apoptosis in MCF7 cells. Also, MB-deficient cells were less sensitive to doxorubicin but not ionizing radiation. Under hypoxia, loss of MB enhanced partial epithelial to mesenchymal transition, thus augmenting the migratory and invasive cell behavior. Notably, in human invasive mammary ductal carcinoma tissues, MB and apoptotic marker levels were positively correlated. In addition, MB protein expression in invasive ductal carcinomas was associated with a positive prognostic value, independent of the known tumor suppressor p53. In conclusion, we provide multiple lines of evidence that endogenous MB in cancer cells by itself exerts novel tumor-suppressive roles through which it can reduce cancer malignancy.

cancer biology↗

bioRxiv2021

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

Progressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study. This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

molecular biology↗

bioRxiv2019

Unique and redundant roles of SOX2 and SOX17 in regulating the germ cell tumour fate

Embryonal carcinomas (ECs) and seminomas are testicular germ cell tumours. ECs display expression of SOX2, while seminomas display expression of SOX17. In somatic differentiation, SOX17 drives endodermal cell fate. However, seminomas lack expression of endoderm markers, but show features of pluripotency. Here, we use ChIP-sequencing to report and compare the binding pattern of SOX17 in seminoma-like TCam-2 cells to SOX2 in EC-like 2102EP cells and SOX17 in somatic cells. In seminoma-like cells, SOX17 was detected at canonical (SOX2/OCT4), compressed (SOX17/OCT4) and other SOX family member motifs. SOX17 directly regulates TFAP2C, PRDM1 and PRDM14, thereby maintaining latent pluripotency and supressing somatic differentiation. In contrast, in somatic cells canonical motifs are not bound by SOX17. In sum only 11% of SOX17 binding sites overlap in seminoma-like and somatic cells. This illustrates that binding site choice is highly dynamic and cell type specific. Deletion of SOX17 in seminoma-like cells resulted in loss of pluripotency, marked by a reduction of OCT4 protein level and loss of alkaline phosphatase activity. Further, we found that in EC-like cells SOX2 regulates pluripotency-associated genes, predominantly by partnering with OCT4. In conclusion, SOX17 (in seminomas) functionally replaces SOX2 (in ECs) to maintain expression of the pluripotency cluster.

cancer biology↗

bioRxiv2019

Biomarker-based outcome prediction in prostate adenocarcinoma depends on the TMPRSS2-ERG status

BackgroundProstate adenocarcinoma (PCa) with/without the TMPRSS2-ERG (T2E)-fusion represent distinct molecular subtypes. ObjectiveTo investigate gene-signatures associated with metastasis in T2E-positive and -negative PCa, and to identify and validate subtype-specific prognostic biomarkers. Design, setting and participantsGene expression and clinicopathological data of two discovery PCa cohorts (total n=783) were separately analyzed regarding the T2E-status. Selected subtype-specific biomarkers were validated in two additional cohorts (total n=405). Outcome measurements and statistical analysisFrom both discovery cohorts, we generated two gene lists ranked by their differential intratumoral expression in patients with/without metastases stratified by T2E-status, which were subjected to gene set enrichment and leading-edge analyses. The resulting top 20 gene-signatures of both gene lists associated with metastasis were analyzed for overlaps between T2E-positive and -negative cases. Genes shared by several functional gene-signatures were tested for their association with event-free survival using the Kaplan-Meier method in a validation cohort. Immunohistochemistry was performed in another validation cohort. Results and limitationsMetastatic T2E-positive and -negative PCa are characterized by different gene-signatures. Five genes (ASPN, BGN, COL1A1, RRM2 and TYMS) were identified whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. This was validated in an independent cohort for all genes and additionally for RRM2 by immunohistochemistry in a separate validation cohort. No prognostic biomarkers were identified exclusively for T2E-positive tumors. ConclusionsOur study demonstrates that the prognostic value of biomarkers critically depends on the molecular subtype, i.e. the T2E-status, which should be considered when screening for and applying novel prognostic biomarkers for outcome prediction in PCa. Patient summaryOutcome prediction for PCa is complex. The results of this study highlight that the validity of prognostic biomarkers depends on the molecular subtype, specifically the presence/absence of T2E. The reported new subtype-specific biomarkers exemplify that biomarker-based outcome prediction in PCa should consider the T2E-status.

cancer biology↗