Dobrokhotov Oleg, Sunagawa Masaki, Torii Takeru, Mii Shinji, Kawauchi Keiko, Enomoto Atsushi, Sokabe Masahiro, Hirata Hiroaki
Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Front Cell Dev Biol. 2021 Nov 11;9:728383. doi: 10.3389/fcell.2021.728383. eCollection 2021.
Actomyosin contractility regulates various cellular processes including proliferation and differentiation while dysregulation of actomyosin activity contributes to cancer development and progression. Previously, we have reported that actomyosin-generated tension at adherens junctions is required for cell density-dependent inhibition of proliferation of normal skin keratinocytes. However, it remains unclear how actomyosin contractility affects the hyperproliferation ability of cutaneous squamous cell carcinoma (cSCC) cells. In this study, we find that actomyosin activity is impaired in cSCC cells both and . External application of tensile loads to adherens junctions by sustained mechanical stretch attenuates the proliferation of cSCC cells, which depends on intact adherens junctions. Forced activation of actomyosin of cSCC cells also inhibits their proliferation in a cell-cell contact-dependent manner. Furthermore, the cell cycle arrest induced by tensile loading to adherens junctions is accompanied by epidermal differentiation in cSCC cells. Our results show that the degree of malignant properties of cSCC cells can be reduced by applying tensile loads to adherens junctions, which implies that the mechanical status of adherens junctions may serve as a novel therapeutic target for cSCC.
肌动球蛋白收缩性调节包括增殖和分化在内的各种细胞过程，而肌动球蛋白活性失调则会促进癌症的发生和发展。此前，我们报道过，正常皮肤角质形成细胞增殖的细胞密度依赖性抑制需要肌动球蛋白在黏附连接处产生张力。然而，尚不清楚肌动球蛋白收缩性如何影响皮肤鳞状细胞癌（cSCC）细胞的过度增殖能力。在本研究中，我们发现cSCC细胞中的肌动球蛋白活性在体内和体外均受损。通过持续机械拉伸向黏附连接处施加拉伸负荷可减弱cSCC细胞的增殖，这依赖于完整的黏附连接。cSCC细胞的肌动球蛋白的强制激活也以细胞间接触依赖性方式抑制其增殖。此外，向黏附连接处施加拉伸负荷诱导的细胞周期停滞伴随着cSCC细胞的表皮分化。我们的结果表明，通过向黏附连接处施加拉伸负荷可降低cSCC细胞的恶性程度，这意味着黏附连接的机械状态可能成为cSCC的一个新的治疗靶点。
