Biotech Research and Innovation Centre, BRIC, University of Copenhagen, Copenhagen, Denmark.
Beatson Institute, Glasgow, UK.
Oncogene. 2018 Feb 15;37(7):847-860. doi: 10.1038/onc.2017.333. Epub 2017 Oct 23.
Cellular movement is controlled by small GTPases, such as RhoA. Although migration is crucial for cancer cell invasion, the specific role of RhoA in tumor formation is unclear. Inducing skin tumors in mice with a keratinocyte-restricted loss of RhoA, we observed increased tumor frequency, growth and invasion. In vitro invasion assays revealed that in the absence of RhoA cell invasiveness is increased in a Rho-associated protein kinase (ROCK) activation and cell contraction-dependent manner. Surprisingly, loss of RhoA causes increased Rho signaling via overcompensation by RhoB because of reduced lysosomal degradation of RhoB in Gamma-aminobutyric acid receptor-associated protein (GABARAP)+ autophagosomes and endosomes. In the absence of RhoA, RhoB relocalized to the plasma membrane and functionally replaced RhoA with respect to invasion, clonogenic growth and survival. Our data demonstrate for the first time that RhoA is a tumor suppressor in 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol 13-acetate skin carcinogenesis and identify Rho signaling dependent on RhoA and RhoB as a potent driver of tumor progression.
细胞运动受小 GTPases 控制，如 RhoA。虽然迁移对于癌细胞的侵袭至关重要，但 RhoA 在肿瘤形成中的具体作用尚不清楚。通过角质形成细胞特异性缺失 RhoA 诱导小鼠皮肤肿瘤，我们观察到肿瘤发生频率、生长和侵袭增加。体外侵袭实验表明，在缺乏 RhoA 的情况下，细胞侵袭性增加，这是一种 Rho 相关蛋白激酶（ROCK）激活和细胞收缩依赖性的方式。令人惊讶的是，由于 Gamma-氨基丁酸受体相关蛋白 (GABARAP) + 自噬体和内体中 RhoB 的溶酶体降解减少，RhoA 的缺失导致 Rho 信号增加，这是由于 RhoB 的过度补偿。在缺乏 RhoA 的情况下，RhoB 重新定位于质膜，并在侵袭、集落形成生长和存活方面替代 RhoA。我们的数据首次表明，RhoA 是 7,12-二甲基苯并[a]蒽/12-O-十四烷酰佛波醇 13-乙酸酯皮肤致癌作用中的肿瘤抑制因子，并确定了依赖于 RhoA 和 RhoB 的 Rho 信号作为肿瘤进展的强大驱动因素。
