Sphk1 promotes breast epithelial cell proliferation via NF-κB-p65-mediated cyclin D1 expression

Li, Shifei; Zhou, Yan; Zheng, Xiaodong; Wu, Xiujuan; Liang, Yueyang; Wang, Shushu; Zhang, Yi

doi:10.18632/oncotarget.13013

Cited by 24 publications

(19 citation statements)

References 24 publications

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“…Abnormal expression of SPHK1 has been strongly associated with the development and progression of various cancers (9,14). Several studies of breast cancer and other cancer types have also shown that SPHK1 plays a role in cancer cell proliferation (34)(35)(36). In contrast, our data showed that SPHK1 cannot drive TNBC cell proliferation in vitro nor tumor growth in vivo in multiple TNBC models and in both gain-and loss-of-function studies.…”

Section: Discussioncontrasting

confidence: 64%

“…Previous studies have shown that the SPHK1/S1P signaling can induce activation or inhibition of various transcription factors, including NFkB, E2F, c-Myc, and Sp1, and consequently impact on cell proliferation, apoptosis, and/or inflammation (36,47,48). SPHK1 was reported to induce NFkB activation via intracellular S1P that serves as a cofactor of TRAF2 to activate IKKa/b, then IKKa/b phosphorylates IkBa, resulting in its degradation to allow NFkB activation upon TNFa stimulation (31).…”

Section: Discussionmentioning

confidence: 99%

“…Using online software (PROMO), we identified that the À333bp to À93 bp region of FSCN1 promoter harbors binding sites of various transcription factors, one of which was NFkB (Fig. 5E), that can be activated by SPHK1 (30). Indeed, NFkB pathway was activated more in SPHK1-overexpressing 231SPHK1 tumor lysates and 435.shScr cells growing in 3D culture compared with respective controls ( Supplementary Fig.…”

Section: Sphk1 Upregulates Fscn1 Transcription Via Activation Of Nfkbmentioning

confidence: 97%

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Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer

Acharya

Yao

et al. 2019

Cancer Research

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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. To identify TNBC therapeutic targets, we performed integrative bioinformatics analysis of multiple breast cancer patient-derived gene expression datasets and focused on kinases with FDA-approved or inpipeline inhibitors. Sphingosine kinase 1 (SPHK1) was identified as a top candidate. SPHK1 overexpression or downregulation in human TNBC cell lines increased or decreased spontaneous metastasis to lungs in nude mice, respectively. SPHK1 promoted metastasis by transcriptionally upregulating the expression of the metastasispromoting gene FSCN1 via NFkB activation. Activation of the SPHK1/NFkB/FSCN1 signaling pathway was associated with distance metastasis and poor clinical outcome in patients with TNBC. Targeting SPHK1 and NFkB using clinically applicable inhibitors (safingol and bortezomib, respectively) significantly inhibited aggressive mammary tumor growth and spontaneous lung metastasis in orthotopic syngeneic TNBC mouse models. These findings highlight SPHK1 and its downstream target, NFkB, as promising therapeutic targets in TNBC. Significance: SPHK1 is overexpressed in TNBC and promotes metastasis, targeting SPHK1 or its downstream target NFkB with clinically available inhibitors could be effective for inhibiting TNBC metastasis.

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Section: Discussioncontrasting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Sphk1 Upregulates Fscn1 Transcription Via Activation Of Nfkbmentioning

confidence: 97%

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Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer

Acharya

Yao

et al. 2019

Cancer Research

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“…Huang and Natarajan (14) reported that NIH 3T3 fibroblasts with overexpression of SPHK1 acquired transformed phenotypes and that tumorigenesis was promoted, which implied that SPHK1 has a marked oncogenic activity. Numerous studies have also demonstrated that the expression of SPHK1 was elevated in multiple human tumor types, and was extensively involved in head and neck squamous cell carcinoma (14), glioma (15), salivary gland carcinoma (16), prostate cancer (17), non-Hodgkin lymphomas (18), gastric cancer and papillary TC (14)(15)(16)(17)(18)(19). Furthermore, upregulation of SPHK1 in certain cancer types is closely associated with a worse clinical prognosis (20).…”

Section: Introductionmentioning

confidence: 99%

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

Zhao

et al. 2018

Exp Ther Med

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Thyroid carcinoma is characterized by an aggressive behavior, lack of effective targeted therapies and a high rate of relapse. Sphingosine kinase 1 (SPHK1) has been reported to be a critical regulatory factor in the progression of thyroid carcinoma, but the correlation between SPHK1 and clinical prognosis of patients with thyroid carcinoma has remained to be fully elucidated. The present study aimed to systematically assess the roles of SPHK1 in thyroid carcinoma metastasis and further investigate the possible underlying mechanisms. First, the expression of SPHK1 was detected in tissue samples from 53 thyroid carcinoma patients and in thyroid carcinoma cell lines by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the level of phospho-(p)-SPHK1 was immunohistochemically detected in human thyroid carcinoma tissue samples. The activity of SPHK1 was measured with a commercial SPHK1 Activity Assay kit. A sphingosine-1-phosphate (S1P) competitive ELISA kit was used to determine the extracellular S1P levels. The metastatic potential was assessed by a Transwell assay. In addition, the association between SPHK1 and clinicopathological features of the patients was analyzed. The results indicated that the expression of SPHK1 in thyroid carcinoma samples was significantly higher than in paired adjacent normal thyroid tissues. High levels of SPHK1 were positively correlated with poor overall survival and progression-free survival. Downregulation of SPHK1 by lentiviral vector expressing SPHK1 small interfering (si)RNA evidently repressed Notch signaling and reduced the migration and invasion of thyroid carcinoma cells and in a NOD/SCID mouse model. Furthermore, inhibition of SPHK1 by siRNA or treatment with SPHK1 inhibitor 5C sensitized thyroid carcinoma to cisplatin and doxorubicin. In addition, it was demonstrated that silencing of SPHK1 effectively inhibits processes associated with thyroid carcinoma metastasis through the Notch signaling pathway, and SPHK1 may therefore represent a potential therapeutic target in thyroid carcinoma. In conclusion, the present study indicated that high levels of p-SPHK1 were positively correlated with high levels of S1P which in turn promoted thyroid carcinoma metastasis via the S1P/S1P receptor 3/Notch signaling pathway, suggesting possible prognostic markers and therapeutic targets.

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“…Meanwhile, as a transmembrane signaling peptide, FGFR4 could activate the downstream nuclear factor-κB (NF-κB) signaling pathway [19] and promote the distant metastasis of tumour. NF-κB could upregulate CyclinD1, so as to accelerate the proliferation and growth of cancer cells [20,21]. In addition, after FGFR4 was phosphorylated, it could promote the production of MMP-7, mitogen-activated protein kinase, and accelerate the generation of angiogenesis, so as to hasten the nutrient supplement for cell proliferation [22].…”

Section: Discussionmentioning

confidence: 99%

Study on the Association between the Fibroblast Growth Factor Receptor 4 Expression and High-Risk Human Papillomavirus Infection in Cervical Cancer and Precancerous Lesions

Guo

Zhao

Zhang

et al. 2018

Gynecol Obstet Invest

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Aims: To discuss the correlation between the expression of fibroblast growth factor receptor 4 (FGFR4) and human papillomavirus (HPV) infection in cervical cancer and precancerous lesions. Methods: One hundred and sixty four cases of cervical lesions tissue samples were collected (60 cases of cervical cancer, 38 cases of cervical intraepithelial neoplasia [CIN] stage I, 32 cases of CIN II, 34 cases of CIN III). HPV infection status and expression strength of FGFR4 of all samples were detected and compared among different groups. The correlation between the HPV infection and the expression strength of FGFR4 was analyzed. Results: There were differences of the HPV infection status and type distribution and FGFR4 expression strength among the 4 groups; The infection rate of high-risk HPV in cervical cancer group was higher than that of the 3 CIN groups. The FGFR4 positive expression rate of the cervical cancer group was also obviously higher than that of the 3 CIN groups; HPV infection was correlated with the FGFR4 expression strength and the FGFR4 expression was stronger when infected with high-risk type HPV. Conclusion: The expression of FGFR4 in the cervical cancer and CIN tissues was correlated with the HPV infection and the FGFR4 may be involved in the development of the HPV-infected cervical lesions.

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Sphk1 promotes breast epithelial cell proliferation via NF-κB-p65-mediated cyclin D1 expression

Cited by 24 publications

References 24 publications

Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer

Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway

Study on the Association between the Fibroblast Growth Factor Receptor 4 Expression and High-Risk Human Papillomavirus Infection in Cervical Cancer and Precancerous Lesions

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