The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia
The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia
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DOI：
10.1016/j.cub.2021.04.078
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发表时间：
2021-07-26
期刊：
影响因子：
9.2
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Kozawa, Kei;Sekai, Miho;Fujita, Yasuyuki
在癌症发展的早期阶段，致癌突变通常导致多层上皮结构。然而，潜在的分子机制仍然是谜。通过进行一系列针对质膜蛋白的筛选，我们发现胶原XVII（COL 17 A1）和CD 44在RasV 12-、Src-或ErbB 2-转化的上皮细胞中积累。此外，COL 17 A1和CD 44的表达也受细胞密度和顶细胞挤出的调节。我们进一步证明，COL 17 A1和CD 44的表达在体外和体内的多层转化上皮细胞的上层显著上调。积累的COL 17 A1和CD 44抑制线粒体膜电位和活性氧（ROS）的产生。降低的细胞内ROS水平然后促进对细胞挤压时亚铁凋亡介导的细胞死亡的抗性，从而积极调节多层结构的形成。为了进一步了解COL 17 A1的功能作用，我们进行了全面的代谢组学分析，并比较了RasV 12和COL 17 A1敲除RasV 12细胞之间的细胞内代谢产物。这些数据表明，COL 17 A1通过琥珀酸调节从GABA分流到线粒体复合物I的代谢途径，从而抑制ROS的产生。此外，我们证明，CD 44调节COL 17 A1在多层结构中的膜积累。这些结果表明，CD 44和COL 17 A1是多层上皮内转化细胞克隆扩增的关键调节因子，因此是癌前病变的早期诊断和预防性治疗的潜在靶点。
At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.