Department of Cell Biology, Faculty of Biophysics, Biochemistry and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland, Department of Medical Physics and Biophysics, AGH University of Science and Technology, 30-059 Kraków, Poland, Department of Physical Biochemistry, Faculty of Biophysics, Biochemistry and Biotechnology, Jagiellonian University, ul. Gronostajowa 7, 30-387 Kraków, Poland and Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, 30-663 Kraków, Poland.
Department of Medical Physics and Biophysics, AGH University of Science and Technology, 30-059 Kraków, Poland.
Carcinogenesis. 2014 Sep;35(9):1920-30. doi: 10.1093/carcin/bgu033. Epub 2014 Feb 6.
Suppressive function of connexin(Cx)43 in carcinogenesis was recently contested by reports that showed a multifaceted function of Cx43 in cancer progression. These studies did not attempt to model the dynamics of intratumoral heterogeneity involved in the metastatic cascade. An unorthodox look at the phenotypic heterogeneity of prostate cancer cells in vitro enabled us to identify links between Cx43 functions and Snail-1-regulated functional speciation of invasive cells. Incomplete Snail-1-dependent phenotypic shifts accounted for the formation of phenotypically stable subclones of AT-2 cells. These subclones showed diverse predilection for invasive behavior. High Snail-1 and Cx43 levels accompanied high motility and nanomechanical elasticity of the fibroblastoid AT-2_Fi2 subclone, which determined its considerable invasiveness. Transforming growth factor-β and ectopic Snail-1 overexpression induced invasiveness and Cx43 expression in epithelioid AT-2 subclones and DU-145 cells. Functional links between Snail-1 function and Cx43 expression were confirmed by Cx43 downregulation and phenotypic shifts in AT-2_Fi2, DU-145 and MAT-LyLu cells upon Snail-1 silencing. Corresponding morphological changes and Snail-1 downregulation were seen upon Cx43 silencing in AT-2_Fi2 cells. This indicates that feedback loops between both proteins regulate cell invasive behavior. We demonstrate that Cx43 may differentially predispose prostate cancer cells for invasion in a coupling-dependent and coupling-independent manner. When extrapolated to in vivo conditions, these data show the complexity of Cx43 functions during the metastatic cascade of prostate cancer. They may explain how Cx43 confers a selective advantage during cooperative invasion of clonally evolving, invasive prostate cancer cell subpopulations.
间隙连接蛋白 43（Cx43）在肿瘤发生中的抑制功能最近受到质疑，有报道称 Cx43 在癌症进展中具有多方面的功能。这些研究并未试图模拟肿瘤内异质性的动力学，而肿瘤内异质性涉及转移级联。我们对体外前列腺癌细胞表型异质性进行了非传统的研究，发现 Cx43 功能与 Snail-1 调节的侵袭细胞功能特化之间存在联系。不完全依赖于 Snail-1 的表型转变解释了 AT-2 细胞中形成表型稳定亚克隆的原因。这些亚克隆表现出不同的侵袭行为倾向。高 Snail-1 和 Cx43 水平伴随着成纤维样 AT-2_Fi2 亚克隆的高迁移率和纳米力学弹性，这决定了其较强的侵袭性。转化生长因子-β和外源性 Snail-1 过表达诱导上皮样 AT-2 亚克隆和 DU-145 细胞的侵袭性和 Cx43 表达。通过沉默 Snail-1，下调 AT-2_Fi2、DU-145 和 MAT-LyLu 细胞中的 Cx43 表达和表型转变，证实了 Snail-1 功能与 Cx43 表达之间的功能联系。在 AT-2_Fi2 细胞中沉默 Cx43 时，观察到相应的形态变化和 Snail-1 下调，这表明这两种蛋白质之间存在反馈环，调节细胞侵袭行为。我们证明 Cx43 可能以依赖和不依赖连接的方式使前列腺癌细胞易发生侵袭。将这些数据外推到体内条件下，可以显示 Cx43 在前列腺癌转移级联过程中的功能复杂性。它们可以解释 Cx43 如何在克隆进化、侵袭性前列腺癌细胞亚群的协同侵袭过程中赋予选择性优势。
