Role of the SOX18 protein in neoplastic processes (Review)

Olbromski, Mateusz; Podhorska‐Okołów, Marzenna; Dzięgiel, Piotr

doi:10.3892/ol.2018.8819

Cited by 10 publications

(13 citation statements)

References 55 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although SOX18 is involved in a variety of patho-physiological processes (Olbromski et al, 2018), HLTRS is a rare and severe vascular disorder. In order to further investigate propranolol in this disease scenario, we used a mouse model of HLTRS, SOX18 Ragged Opossum ( RaOp ) (Pennisi et al, 2000; Slee, 1957).…”

Section: Resultsmentioning

confidence: 99%

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

Overman

Fontaine

Wylie-Sears

et al. 2019

eLife

View full text Add to dashboard Cite

Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in SOX18. Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

Overman

Fontaine

Wylie-Sears

et al. 2019

eLife

View full text Add to dashboard Cite

show abstract

“…Taking into account that expression of SOX18 transcription factor is increased in numerous cancer types, for example, gastric stromal tumors, pancreatic, liver, ovary, and breast cancer, 7‐10 it seems that this transcription factor may play a fundamental role in the processes of cancer promotion and progression.…”

Section: Discussionmentioning

confidence: 99%

“…SOX18 belongs to group F and is involved in maturation and differentiation of endothelial cells prenatally and in angiogenesis 5 and lymphangiogenesis postnatally 6 . Recent studies detected upregulation of SOX18 in various kinds of human neoplasm and suggested that it may have an oncogenic role in tumor promotion and progression 7‐10 . However, its contribution in NMSCs is not yet elucidated.…”

Section: Introductionmentioning

confidence: 99%

Significance of SOX18 expression in nonmelanoma skin cancers for prediction of high‐risk patients: a preliminary study

et al. 2020

View full text Add to dashboard Cite

Background SOX18 is an integral transcription factor that is involved in endothelial cells differentiation during both angiogenesis and lymphangiogenesis. Therefore, it has been implicated in tumor progression and metastasis. Objective To study SOX18 expression in nonmelanoma skin cancers (NMSCs) in comparison to seborrheic keratosis (SK) and normal control skin, and to assess its probable role in tumor evolution and progression. Patients and Methods This study was conducted on 60 specimens of NMSCs: 30 basal cell carcinomas (BCC) and 30 squamous cell carcinomas (SCC), 30 specimens of SK, and 30 normal skin specimens. All were examined for immunohistochemical expression of SOX18 antibody. Additionally, morphometric assessment of vessel density (blood & lymphatic) in each specimen was estimated. Results Significant SOX18 overexpression was observed in all studied cutaneous tumors in comparison to control skin. The highest score of SOX18 expression was detected in SCC, then BCC, and the least expression was reported in SK with significant difference between them. Furthermore, significant upregulation of SOX18 expression was observed in high‐risk types of both BCC and SCC compared to low‐risk types. Stromal vessel density showed significant differences between the studied tumors with the highest mean value in SCC, followed by BCC and then SK. Positive correlation between SOX18 expression in the studied tumors and their vessel density was detected. Conclusions SOX18 may have a potential role in the evolution as well as progression of NMSCs, possibly through induction of both angiogenesis and lymphangiogenesis. Furthermore, it could be beneficial for prediction of NMSC patients with poor prognosis.

show abstract

“…This is the first time that SOX18 is associated to a key function in viral life cycle. It has so far been linked to the transcriptional regulation of ECs and to the progression of solid cancers 34, 35 . SOX18 forms a dimer 20, 21 , able to bind to the viral and cellular genomes.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Gramolelli

Elbasani

Nurminen

et al. 2019

Preprint

View full text Add to dashboard Cite

27Kaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection 28 and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency 29 in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with 30 high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, 31 SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique 32 KSHV infection program. We found that these factors were co-expressed in KS tumours with the 33 viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent 34 mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition 35 significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator 36 of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces 37 KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in 38 the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate 39 the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and 40 introduce SOX18 inhibition as a potential, novel therapeutic modality for KS. 41 42 43 KEYWORDS 44 Kaposi sarcoma, KSHV, herpesvirus, K8.1, transcription factors, PROX1, SOX18, lymphatic 45 endothelial cells, viral genome replication, viral reactivation. 46 47 3 MAIN 48Kaposi sarcoma (KS) is an angiogenic endothelial tumour caused by KS herpesvirus (KSHV). KS is 49 the most common cancer among AIDS patients and a frequent malignancy in Sub-Saharan Africa 1 . 50 KS presents with skin lesions that progress from patch to plaque and ultimately to nodular tumours; 51 in advanced disease visceral involvement is also seen 2,3 . The histopathological hallmark of KS is the 52 presence of KSHV-positive spindle cells (SC), the tumour cells of KS 2,3 . The cell of origin of SC has 53 been debated for two decades 3 . The prevailing hypothesis suggests lymphatic endothelial origin, 54 although blood endothelial cells or mesenchymal cells are also candidates 1,4 . In vitro, latency is the 55 default replication program in KSHV-infected cells with undetectable levels of lytic genes expressed. 56 However, KSHV infection of lymphatic, but not blood, endothelial cells (LEC and BEC) leads to a 57 unique infection program characterized by high KSHV genome copies, spontaneous lytic gene 58 expression and release of infectious virus 5-8 . 59 60 During embryonic development, LEC precursors originate from COUPTF2/SOX18 double-positive 61 BECs that physically separate from the cardinal vein to establish a primary lymphatic vascular plexus. 62 In this process, COUPTF2 and SOX18 drive the expression of PROX1 thereby orchestrating LEC 63 differentiation 9,10 . Here, we explored the role of these transcription factors (TF), instrumental for 64 establishment...

show abstract

Role of the SOX18 protein in neoplastic processes (Review)

Cited by 10 publications

References 55 publications

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

R-propranolol is a small molecule inhibitor of the SOX18 transcription factor in a rare vascular syndrome and hemangioma

Significance of SOX18 expression in nonmelanoma skin cancers for prediction of high‐risk patients: a preliminary study

Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production

Contact Info

Product

Resources

About