Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression
Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression
复制标题
脂肪细胞来源的 IL-6 和瘦素通过上调 Lysyl Hydroxylase-2 表达促进乳腺癌转移。
DOI：
10.1186/s12964-018-0309-z
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发表时间：
2018-12-18
影响因子：
8.4
通讯作者：
Sun, Li
中科院分区：
文献类型：
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作者：
He, Jin-Yong;Wei, Xiao-Hui;Sun, Li
研究背景脂肪细胞是乳腺组织的主要成分，占乳腺间质组织的90%。因此，脂肪细胞和乳腺癌细胞之间的串扰可能在癌症进展中发挥关键作用。脂肪细胞与乳腺癌的相互作用被认为是促进乳腺癌转移的重要因素。然而，这些相互作用背后的具体机制尚不清楚。在本研究中，我们探讨了脂肪细胞介导的乳腺癌转移的机制。方法将乳腺癌细胞与成熟脂肪细胞共培养，进行迁移和3D基质侵袭实验。接下来，利用慢病毒介导的功能丧失实验来探讨赖氨酸羟基酶(PLOD2)在乳腺癌迁移和乳腺癌细胞依赖脂肪细胞迁移中的作用。PLOD2在乳腺癌转移中的作用通过体内原位乳腺脂肪垫异种移植得到进一步证实。临床样本证实PLOD2在肿瘤组织中的表达增加，并与乳腺癌患者的预后不良有关。用细胞因子和药物抑制剂处理细胞，以验证哪些脂肪因子在体外激活了PLOD2的表达，以及哪些信号通路在体外被激活。结果基因表达谱和Western blotting分析表明，与脂肪细胞共同培养的乳腺癌细胞PLOD2表达上调，这一过程伴随着乳腺癌细胞迁移和侵袭的增强。功能丧失研究表明，PLOD2基因敲除抑制了细胞的迁移，扰乱了乳腺癌细胞肌动蛋白应激纤维的形成，并取消了随后与脂肪细胞共同培养所诱导的迁移。此外，在原位乳腺脂肪垫异种移植中进行的实验表明，PLOD2基因敲除可以减少肺和肝脏的转移。此外，PLOD2的高表达与乳腺癌患者的预后不良有关。从机制上讲，脂肪细胞来源的白介素6(IL-6)和瘦素可能促进乳腺癌细胞中PLOD2的上调，并在尾静脉转移试验中促进乳腺癌的转移。进一步研究发现，脂肪细胞来源的IL-6和瘦素通过激活JAK/STAT3和PI3K/AKT信号通路促进PLOD2的表达。结论脂肪细胞来源的IL-6和瘦素通过激活JAK/STAT3和PI3K/AKT信号通路促进PLOD2的表达，从而促进乳腺癌的转移。
BackgroundAdipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.MethodsBreast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.ResultsGene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.ConclusionsOur study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.