Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-β and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.

中文翻译：

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新型K6-K14角蛋白融合增强口腔鳞状细胞癌的癌干性和侵略性。

角蛋白中间丝（IF）是细胞结构的一个组成部分，可为克服环境压力提供必要的机械支持。最近的发现揭示了它参与机械转导和相关的干细胞重编程，暗示了其在癌症发展中的可能作用。在这里，我们将t（12; 17）（q13.13; q21.2）染色体重排报告为OSCC中最常见的融合事件，从而导致多种角蛋白间融合。交界处部位图谱验证了9个符合框架的K6-K14变体，其中三个与淋巴结浸润，晚期肿瘤分期（T3 / T4）和较短的无病生存时间相关。当在OSCC细胞中表达时，这些融合变体通过直接相互作用或聚集体形成干扰野生型K14组织，导致核周结构丧失和核变形。蛋白质阵列分析显示K6-K14变体7（K6-K14 / V7）上调TGF-β和G-CSF信号传导的能力，这有助于细胞干性，药物耐受性和细胞侵袭性。值得注意的是，表达K6-K14 / V7的细胞在体外易于适应软3-D培养条件，并在体内形成较大，分化程度较低的肿瘤。除了抗机械应力活性外，我们的数据还揭示了OSCC开发过程中由基因融合引起的新型角蛋白细丝的致癌功能。