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瘦素通过Src家族激酶介导的、不依赖于janus激酶2的途径诱导雌激素受体阴性乳腺癌中鞘氨醇激酶1的上调。

Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway.

作者信息

Alshaker Heba, Krell Jonathan, Frampton Adam E, Waxman Jonathan, Blyuss Oleg, Zaikin Alexey, Winkler Mathias, Stebbing Justin, Yagüe Ernesto, Pchejetski Dmitri

出版信息

Breast Cancer Res. 2014 Oct 25;16(5):426. doi: 10.1186/s13058-014-0426-6.

Abstract

INTRODUCTION

Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated.

METHODS

Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays.

RESULTS

Our findings show for the first time that human primary breast tumours and associated lymph node metastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77, respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA).

CONCLUSIONS

Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer.

摘要

引言

肥胖是已知的乳腺癌风险因素。鞘氨醇激酶1(SK1)是一种致癌脂质激酶,在乳腺肿瘤中过度表达且与预后不良相关,然而,其在肥胖驱动的乳腺癌中的作用从未得到阐明。

方法

使用定量实时聚合酶链反应(qRT-PCR)分析人原发性和继发性乳腺癌组织中SK1和瘦素受体的表达。使用蛋白质免疫印迹、qRT-PCR和放射性标记分析在人雌激素受体(ER)阳性和阴性乳腺癌细胞中瘦素诱导的信号传导。

结果

我们的研究结果首次表明,人原发性乳腺肿瘤及相关淋巴结转移灶中SK1和瘦素受体表达之间存在强相关性(Pearson相关系数分别为R = 0.78和R = 0.77,P <0.001)。这两个基因在ER阴性患者的转移灶中升高,且在体重指数(BMI)较高的患者中显著增加。瘦素诱导ER阴性乳腺癌细胞系MDAMB - 231和BT - 549中SK1的表达和激活,但在ER阳性细胞系中则不然。药理学抑制和基因敲低表明,瘦素诱导的SK1活性和表达是由细胞外信号调节激酶1/2(ERK1/2)和Src家族激酶(SFK)途径的激活介导的,而非由瘦素受体(LEPR)下游的主要途径——janus激酶2(JAK2)和信号转导及转录激活因子3(STAT3)介导。含Src同源2结构域的磷酸酶2(SHP2)似乎是SK1激活的关键,并且可能作为SFK和LEPR之间的衔接蛋白发挥作用。重要的是,瘦素诱导的乳腺癌细胞增殖被SK1特异性小干扰RNA(siRNA)消除。

结论

总体而言,我们的研究结果证明了一种新的SFK/ERK1/2介导的途径,该途径将瘦素信号传导与乳腺肿瘤中致癌酶SK1的表达联系起来,并提示该途径在ER阴性乳腺癌中的潜在重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/43b8/4303110/7819a9b46693/13058_2014_426_Fig1_HTML.jpg

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