Lee Min Kyeong, Park Ji Hyeon, Gi Seol Hwa, Hwang Young Sun
Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Republic of Korea.
Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Republic of Korea
Anticancer Res. 2018 Nov;38(11):6127-6132. doi: 10.21873/anticanres.12964.
BACKGROUND/AIM: Tumor microenvironment plays an important role in tumor growth and metastasis. Cancer cells can promote their growth and malignancy by altering the surrounding stroma. Fascin is an actin-bundling protein that regulates the dynamics of the cytoskeletal structure and plays a significant role in cancer invasion and metastasis. In this study, we observed stromal factors controlling fascin expression in cancer cells and investigated underlying signal transduction pathways.
Fascin depletion was performed with lentiviral short-hairpin RNA (shRNA) against fascin mRNA and a stable cell line (Fascin) was established. Fascin expression and invasion activity induced by IL-1β treatement were observed through Matrigel-Transwell invasion and 3D culture system. Intermediated signaling molecules involved in fascin expression induced by IL-1β were elucidated using western blotting.
Fascin was more highly expressed in human OSCC cells than normal cells. Cancer invasion activity was decreased by fascin depletion using lentiviral shRNA. However, fascin expression was increased by IL-1β treatement, leading to increased extracellular matrix (ECM) degradation and infiltration into 3-dimensional (3-D) collagen matrix. Specific inhibitors of extracellular signal-regulated kinases-1/2 [ERK1/2, (PD98059)], c-Jun N-terminal kinase [JNK, (SP600125)], nuclear factor kappa light chain enhancer of activted B cells [NF-κB, (parthenolide)], and cAMP response element binding protein [CREB, (CREB inhibitor)] suppressed IL-1β -induced fascin expression. IL-1β induced phosphorylation of ERK1/2, JNK, NF-κB and CREB while IL-1 receptor (IL-1R) antagonist abolished their activation.
IL-1β is a critical inducer of fascin expression. ERK1/2, JNK, NF-κB, and CREB signaling pathways are involved in IL-1β-induced fascin expression and these paracrine signaling pathways can induce cancer cell invasion.
背景/目的：肿瘤微环境在肿瘤生长和转移中起重要作用。癌细胞可通过改变周围基质来促进自身生长和恶性程度。丝聚蛋白是一种肌动蛋白成束蛋白，可调节细胞骨架结构的动力学，并在癌症侵袭和转移中起重要作用。在本研究中，我们观察了控制癌细胞中丝聚蛋白表达的基质因子，并研究了潜在的信号转导途径。
用针对丝聚蛋白mRNA的慢病毒短发夹RNA（shRNA）进行丝聚蛋白敲减，并建立稳定细胞系（丝聚蛋白）。通过基质胶-Transwell侵袭和三维培养系统观察白细胞介素-1β（IL-1β）处理诱导的丝聚蛋白表达和侵袭活性。使用蛋白质免疫印迹法阐明参与IL-1β诱导的丝聚蛋白表达的中间信号分子。
丝聚蛋白在人口腔鳞状细胞癌（OSCC）细胞中的表达高于正常细胞。使用慢病毒shRNA敲减丝聚蛋白可降低癌症侵袭活性。然而，IL-1β处理可增加丝聚蛋白表达，导致细胞外基质（ECM）降解增加并浸润到三维（3-D）胶原基质中。细胞外信号调节激酶-1/2 [ERK1/2，（PD98059）]、c-Jun氨基末端激酶[JNK，（SP600125）]、活化B细胞核因子κB轻链增强子[NF-κB，（小白菊内酯）]和cAMP反应元件结合蛋白[CREB，（CREB抑制剂）]的特异性抑制剂可抑制IL-1β诱导的丝聚蛋白表达。IL-1β诱导ERK1/2、JNK、NF-κB和CREB磷酸化，而IL-1受体（IL-1R）拮抗剂可消除它们的激活。
IL-1β是丝聚蛋白表达的关键诱导剂。ERK1/2、JNK、NF-κB和CREB信号通路参与IL-1β诱导的丝聚蛋白表达，这些旁分泌信号通路可诱导癌细胞侵袭。
