SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

Petrović, Isidora; Milivojevic, Milena; Popović, Jelena; Schwirtlich, Marija; Ranković, Branislava; Stevanović, Milena

doi:10.1371/journal.pone.0143591

Cited by 26 publications

(23 citation statements)

References 70 publications

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“…SOX17 has been reported to be down‐regulated in CRC and HCC and to suppress tumor progression by antagonizing the Wnt/β‐catenin pathway . SOX18, however, functions as an oncogene by promoting cell proliferation and by facilitating tumor metastasis in breast cancer and cervical carcinoma . Although a previous study has reported that SOX18 promotes cell proliferation and inhibits apoptosis in HCC, the mechanism underlying the oncogenic function remains largely unknown.…”

mentioning

confidence: 99%

Fibroblast Growth Factor 19–Mediated Up‐regulation of SYR‐Related High‐Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms‐Related Tyrosine Kinase 4

Chen

Dang

et al. 2020

Hepatology

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BaCKgRoUND aND aIMS:The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY-related high-mobility group box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report on a role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. appRoaCH aND ReSUltS: The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher tumor-node-metastasis (TNM) stage, and poor prognosis. Overexpression of SOX18 promoted HCC metastasis by up-regulating metastasis-related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms-related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18-mediated HCC invasion and metastasis, whereas the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, up-regulated SOX18 expression. A mechanistic investigation indicated that the up-regulation of SOX18 that was mediated by the FGF19-FGFR4 pathway relied on the phosphorylated (p)-fibroblast growth factor receptor substrate 2/p-glycogen synthase kinase 3 beta/β-catenin pathway. SOX18 knockdown significantly reduced FGF19enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced SOX18-mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4, and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. CoNClUSIoNS:We defined a FGF19-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.

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confidence: 99%

Fibroblast Growth Factor 19–Mediated Up‐regulation of SYR‐Related High‐Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms‐Related Tyrosine Kinase 4

Chen

Dang

et al. 2020

Hepatology

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“…Consistent with an oncogenic role, some studies found that transduction of CC cell lines with SOX2 , SOX4 , and SOX18 promoted cell proliferation, metastasis, and invasion 52,66-68 . Specifically, endogenous overexpression of SOX2 or SOX4 in CC cell lines drove the cell cycle from G0/G1 to S stage by promoting expression of cell cycle promoters, such as cyclinE2, minichromosome maintenance protein 10 (MCM10), and weel protein kinase 52,66 .…”

Section: Sox Genes In Gcsmentioning

confidence: 75%

“…However, the action of SOX2 at the cellular level did not necessarily reflect the same behavior in clinical samples because of the absence of the body’s internal environment. SOX18 promoted the development of CC without clear mechanisms, so further studies are needed to clarify the mechanisms responsible for the oncogenic role of SOX18 68 . …”

Section: Sox Genes In Gcsmentioning

confidence: 99%

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

et al. 2019

Cancer Biol Med

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Sex-determining region Y box-containing genes are transcription factors with roles in multiple biological processes, including cell differentiation, proliferation, and apoptosis. Sex-determining region Y box-containing genes have also been shown to act as regulators and biomarkers in the progression of many different cancers, including gynecological cancers such as ovarian, cervical, and endometrial cancer. In this review, we summarize the contrasting regulatory roles of Sex-determining region Y box-containing genes in different gynecological cancers, as promotors with high expression levels or as suppressors with low expression levels. Expression levels of Sex-determining region Y box-containing genes were also identified as biomarkers of clinical features, including International Federation of Gynecology and Obstetrics stage, histopathologic grade together with disease-free survival, and treatment efficacy in patients with gynecological cancers. An understanding of the mechanisms whereby Sex-determining region Y box-containing genes regulate the progression of gynecological cancers will aid in the development of novel diagnostic and therapeutic strategies, while analysis of Sex-determining region Y box-containing expression levels will help to predict the prognosis of patients with gynecological cancers.

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“…It was proved that the inhibitors GL1 and GL2, involved in the regulation of the aforementioned pathway, are also responsible for the reduction of the expression level of the SOX18 gene. Moreover, the in vitro tests on the human cervix cancer cell lines HeLa, SiHa and CaSki showed that a SOX18 overexpression did not increase the proliferative potential, but significantly increased the invasiveness and migration of the cells of this cancer (41). This could suggest a contribution of the SOX18 protein to the promotion of tumor progression in cervix cancers.…”

Section: Ovarian and Cervical Cancermentioning

confidence: 96%

“…Due to the fact that SOX18 is expressed not only by vascular endothelial cells but also by tumor cells themselves, Petrovic et al decided to investigate the role of this transcription factor in cervix cancers (41). So far, the involvement of the SOX18 protein has been confirmed in the Hedgehog pathway in non-cancerous human cells, primarily during embryonic development.…”

Section: Ovarian and Cervical Cancermentioning

confidence: 99%

Role of the SOX18 protein in neoplastic processes (Review)

2018

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Abstract. There is a high demand for anticancer drugs due to the fact that the chemotherapeutics currently used have numerous side effects, which lowers the patient's quality of life. However, the latest antibody therapies are extremely expensive, hence the requirement to identify novel, equally effective but low-toxic treatments that have limited side effects. As a result of this, a number of research centres around the world are attempting to identify novel molecular markers that could be effective targets for anticancer therapy in the future. The SOX18 protein has been suggested to be a significant diagnostic and prognostic marker in various types of cancer. SRY-related HMG-box 18 (SOX18) is an important transcription factor involved in the development of cardiovascular and lymphatic vessels during embryonic development. In addition, it is involved in the progression of atherosclerosis and wound-healing processes. It has been observed that its level is higher in a number of cancer types, including melanoma, pancreas, stomach, liver, breast, lung, ovarian and cervical cancer. Furthermore, an association between a high expression of SOX18 in gastric cancer stromal cells and a poor prognosis has been demonstrated. The literature indicates how complex the pathogenesis of cancer is. Knowing the molecular basis of the pathogenesis of the tumor will allow for the effective use of targeted therapy, which may result in a higher success in treating patients. It is therefore important to identify novel and effective therapies as well as new proteins that could be potential markers. The SOX18 family, represented by the SOX18 protein, seems to be in this respect a promising element in modern anticancer therapy.

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SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines

Cited by 26 publications

References 70 publications

Fibroblast Growth Factor 19–Mediated Up‐regulation of SYR‐Related High‐Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms‐Related Tyrosine Kinase 4

Fibroblast Growth Factor 19–Mediated Up‐regulation of SYR‐Related High‐Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms‐Related Tyrosine Kinase 4

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

Role of the SOX18 protein in neoplastic processes (Review)

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