Thuringer Dominique, Berthenet Kevin, Cronier Laurent, Solary Eric, Garrido Carmen
INSERM, U866 Faculty of Medecine, 21000 Dijon, France.
University of Bourgogne-Franche-Comté, 21000 Dijon, France.
Oncotarget. 2015 Oct 6;6(30):28800-15. doi: 10.18632/oncotarget.4894.
A gradual loss of functional gap junction between tumor cells has been reported with colorectal cancer (CRC) progression. Here, we explored if colon cancer cells could also affect gap junctions in blood capillary cells. Human microvascular endothelial cells (HMEC) were cultured with two CRC cell lines established from a unique patient. SW480 cells, derived from the primary tumor, migrate much faster across HMEC monolayer than SW620 cells derived from a metastatic site. The motile SW480 cells highly express and release HSP27 that increases gap junction formation with HMEC. Soluble HSP27 phosphorylates the connexin Cx43 on serine residues and induces its interaction with the oncoprotein 14-3-3, which promotes Cx43 delivery at the plasma membrane. The factors secreted by less motile SW620 cells do not affect Cx43 expression but up-regulate the expression of the connexin Cx32 through an activation of the chemokine receptor CXCR2. In turn, SW620 secreted factors induce tubulogenesis and ATP release. Altogether, cell lines derived from CRC primary tumor and metastasis differentially adapt endothelial cell functions by modulating connexin expression through released mediators.
据报道，随着结直肠癌（CRC）的进展，肿瘤细胞之间的功能性间隙连接会逐渐丧失。在此，我们探究了结肠癌细胞是否也会影响毛细血管细胞中的间隙连接。将人微血管内皮细胞（HMEC）与从一名独特患者建立的两种CRC细胞系共同培养。源自原发性肿瘤的SW480细胞穿过HMEC单层的迁移速度比源自转移部位的SW620细胞快得多。具有迁移能力的SW480细胞高度表达并释放热休克蛋白27（HSP27），该蛋白可增加与HMEC的间隙连接形成。可溶性HSP27使连接蛋白Cx43的丝氨酸残基磷酸化，并诱导其与癌蛋白14-3-3相互作用，从而促进Cx43在质膜上的递送。迁移能力较弱的SW620细胞分泌的因子不影响Cx43的表达，但通过激活趋化因子受体CXCR2上调连接蛋白Cx32的表达。反过来，SW620分泌的因子可诱导血管生成和ATP释放。总之，源自CRC原发性肿瘤和转移灶的细胞系通过释放介质调节连接蛋白的表达，从而差异性地调节内皮细胞功能。
