Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5
Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5
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DOI：
10.1371/journal.pone.0228015
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发表时间：
2020-01-30
期刊：
影响因子：
3.7
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
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作者：
Ando, Yohei;Ohuchida, Kenoki;Nakamura, Masafumi
背景坏死是一种伴随细胞内物质释放的程序性细胞死亡，据报道与多种疾病有关。在这里，我们调查的意义necroptosis在pancreatic cancer.MethodsWe采用免疫组化和蛋白质印迹分析，以评估表达的关键介质necroptosis受体相互作用丝氨酸/苏氨酸蛋白激酶3（RIP 3）和混合谱系激酶域样（MLKL）-在人类胰腺癌。我们还在Transwell迁移和Matrigel侵袭测定中测试了来自坏死性凋亡细胞的条件培养基（CM）对胰腺癌细胞的影响。结果RIP 3和MLKL在人胰腺癌组织中的表达高于正常胰腺组织。MLKL表达在肿瘤浸润前沿特别强烈。坏死性凋亡细胞来源的CM促进癌细胞的迁移和侵袭，而凋亡细胞来源的CM则无此作用。C-X-C基序趋化因子5（CXCL 5）在来自坏死性凋亡细胞的CM中与来自对照或凋亡细胞的CM相比上调。此外，胰腺癌细胞中CXCL 5受体C-X-C基序趋化因子受体2（CXCR 2）的表达上调。抑制CXCR 2抑制癌细胞的迁移和侵袭行为增强necroptosis.ConclusionThese研究结果表明，necroptosis在胰腺癌的侵袭前线可以促进癌细胞的迁移和侵袭通过CXCL 5-CXCR 2轴。
BackgroundNecroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer.MethodsWe used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells.ResultsRIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis.ConclusionThese findings indicate that necroptosis at the pancreatic cancer invasion front can promote cancer cell migration and invasion via the CXCL5-CXCR2 axis.