Dong Yuan-Lin, Kabir Syeda M, Lee Eun-Sook, Son Deok-Soo
Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, United States of America.
Department of Physiology, Meharry Medical College, Nashville, Tennessee, United States of America.
PLoS One. 2013 Dec 20;8(12):e83789. doi: 10.1371/journal.pone.0083789. eCollection 2013.
Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-κB (NF-κB) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of IκB. CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation. CXCR2 positive cells also activated more EGFR, which led to higher Akt activation. Enhanced NF-κB activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of IκB. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-κB inhibitor, Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-κB inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-κB site. Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-κB activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.
卵巢癌是一种与炎症相关的恶性肿瘤，死亡率很高。表达CXCR2的卵巢癌具有侵袭性，预后较差。因此，我们通过比较CXCR2阳性和阴性卵巢癌细胞系，研究了CXCR2驱动癌症进展的分子机制。与用空载体转染的对照细胞相比，稳定转染CXCR2的SKOV-3细胞生长速度更快。特别是，在卵巢癌中大量表达的肿瘤坏死因子（TNF）通过减少CXCR2转染细胞中的G0-G1期来增强细胞增殖。TNF在CXCR2转染细胞中比对照细胞更能增加核因子-κB（NF-κB）活性，并且对IκB的激活作用更强。CXCR2转染细胞表达更高水平的促炎配体CXCL1/2，并增强了更多的增殖、迁移、侵袭和集落形成。CXCR2阳性细胞还激活了更多的表皮生长因子受体（EGFR），从而导致更高的蛋白激酶B（Akt）激活。CXCR2阳性细胞中增强的NF-κB活性被磷脂酰肌醇-3激酶（PI3K）/Akt抑制剂降低，而不是被细胞外信号调节激酶（Erk）抑制剂降低。添加到CXCR2阳性细胞中的CXCL1导致IκB的激活增加。CXCL1还导致CXCR2转染细胞中侵袭细胞的数量显著增加，这被NF-κB抑制剂Bay 11-7082阻断。此外，CXCR2阳性细胞中增强的细胞增殖对CXCL1抗体或NF-κB抑制剂更敏感。最后，亲代细胞的CXCR2转染通过一个NF-κB位点增加了CXCL1启动子活性。因此，通过EGFR反式激活的Akt增强NF-κB激活来增加促炎趋化因子CXCL1/2，有助于CXCR2驱动的卵巢癌进展。
