Zhang Zhuo, Li Jingxia, Willis Daneah, Tu Huailu, Costa Max
Division of Environmental Medicine, Dept of Medicine, Grossman School of Medicine, New York University, 341 E. 25(th) Street, New York, NY 10010, United States of America.
Division of Environmental Medicine, Dept of Medicine, Grossman School of Medicine, New York University, 341 E. 25(th) Street, New York, NY 10010, United States of America.
Toxicol Appl Pharmacol. 2025 Sep;502:117452. doi: 10.1016/j.taap.2025.117452. Epub 2025 Jun 24.
Numerous studies have shown that exposure to cadmium [Cd(II)] contributes to the development of cancers in the lung and other organs. Cd(II) compounds are classified as confirmed human carcinogens; however, the mechanisms underlying Cd(II)-induced carcinogenesis remain poorly understood. Small nucleolar RNA host gene 1 (SNHG1), a long non-coding RNA (lncRNA), has been identified as an oncogene. In this study, we investigated the role of SNHG1 in the invasion and migration of Cd(II)-transformed cells. Our findings revealed that SNHG1 expression was significantly elevated in Cd(II)-transformed cells compared to their passage-matched normal BEAS-2B counterparts. Silencing SNHG1 reduced the invasive and migratory capacities of Cd(II)-transformed cells and inhibited malignant transformation induced by long-term Cd exposure. Notably, ectopic expression of SNHG1 alone in BEAS-2B cells was sufficient to drive malignant transformation and enhance invasion and migration, underscoring its oncogenic potential. SRY-box 2 (Sox2), a transcription factor implicated in cancer cell proliferation, invasion, and migration, was found to be upregulated in Cd(II)-transformed cells, while SNHG1 knockdown led to decreased Sox2 protein levels. Similarly, ras-related C3 botulinum toxin substrate 1 (Rac1), a key regulator of cytoskeletal dynamics linked to tumor growth, invasion, and metastasis, was also elevated in Cd(II)-transformed cells. Knockdown of SNHG1 reduced Rac1 protein levels, and Rac1 knockout significantly suppressed invasion and migration. Additionally, we observed increased expression of Slug, a key transcription factor invovlved in epithelial-mesenchymal transition (EMT), and decreased expression of its downstream target E-cadherin in Cd(II)-transformed cells. Collectively, these results demonstrate that elevated SNHG1 promotes the expression of Sox2, Rac1, and Slug, thereby driving the invasive and migratory behavior of Cd(II)-transformed cells.
大量研究表明，接触镉[Cd(II)]会促使肺部和其他器官发生癌症。Cd(II)化合物被归类为已确认的人类致癌物；然而，Cd(II)诱导致癌作用的潜在机制仍知之甚少。小核仁RNA宿主基因1（SNHG1）是一种长链非编码RNA（lncRNA），已被确定为一种癌基因。在本研究中，我们调查了SNHG1在Cd(II)转化细胞的侵袭和迁移中的作用。我们的研究结果显示，与传代匹配的正常BEAS-2B细胞相比，SNHG1在Cd(II)转化细胞中的表达显著升高。沉默SNHG1可降低Cd(II)转化细胞的侵袭和迁移能力，并抑制长期镉暴露诱导的恶性转化。值得注意的是，仅在BEAS-2B细胞中异位表达SNHG1就足以驱动恶性转化并增强侵袭和迁移，突出了其致癌潜力。SRY盒2（Sox2）是一种与癌细胞增殖、侵袭和迁移有关的转录因子，在Cd(II)转化细胞中被发现上调，而SNHG1敲低导致Sox2蛋白水平降低。同样，Ras相关的C3肉毒杆菌毒素底物1（Rac1）是一种与肿瘤生长、侵袭和转移相关的细胞骨架动力学关键调节因子，在Cd(II)转化细胞中也升高。敲低SNHG1可降低Rac1蛋白水平，而敲除Rac1可显著抑制侵袭和迁移。此外，我们观察到在Cd(II)转化细胞中，参与上皮-间质转化（EMT）的关键转录因子Slug的表达增加，其下游靶点E-钙黏蛋白的表达减少。总的来说，这些结果表明，SNHG1升高促进了Sox2、Rac1和Slug的表达，从而驱动了Cd(II)转化细胞的侵袭和迁移行为。
