Department of Environmental Hygiene, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, PR China.
Biobank of Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen 518035, PR China.
Ecotoxicol Environ Saf. 2021 Apr 15;213:112031. doi: 10.1016/j.ecoenv.2021.112031. Epub 2021 Feb 9.
Nickel is a component of biomedical alloys that is released during corrosion or friction and causes cytotoxicity, mutation, differentiation or even carcinogenesis in tissues. However, the mechanisms underlying the potential hazards of Nickel-containing alloys implanted in the human body by surgery remain uncertain.
To study the effect of Ni(II) (NiCl6HO) on cancer cells.
A549 and RKO cells were treated with various concentrations of Ni(II) to determine the effect of Ni(II) on cellular viability using a CCK8 assay. Flow cytometry was performed to analyze the effect of Ni(II) on apoptosis and the cell cycle. Sphere-forming assays were conducted to examine the stemness properties of A549 and RKO cells. Western blotting was to evaluate the expression levels of SOX2, IDH1, HIF-1ɑ and β-catenin. The expression of isocitrate dehydrogenase (IDH1) in rectum adenocarcinoma (READ) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Kaplan-Meier analysis was used to calculate the correlation between survival and IDH1 expression.
Long-term exposure (120 days) to 100 µM Ni(II) significantly repressed cell proliferation, decreased colony formation and arrested the cell cycle at the G/G phase. In addition, the stem-like traits of A549 and RKO cells were significantly augmented. Ni(II) also significantly decreased the protein expression of IDH1 and the synthesis rate of NAPDH, which competitively inhibited α-ketoglutarate (α-KG) generation. The downregulation of IDH1 not only promoted β-catenin accumulation in the cell nucleus in a HIF-1ɑ signaling-dependent manner but also induced the expression of the transcription factor SOX2 to maintain the stemness properties of cancer cells. Moreover, IDH1 expression negatively correlated with the clinicopathologic characteristics of READ.
These findings demonstrate that chronic and continuous release of Ni(II) to the microenvironment suppresses IDH1 expression and augments the stemness properties of cancer cells via the activation HIF-1ɑ/β-catenin/SOX2 pathway to enhance local tumor recurrence in patients with implanted Nickel-containing alloys at surgical sites.
镍是生物医学合金的组成部分，在腐蚀或摩擦过程中会释放出来，导致细胞毒性、突变、分化甚至致癌。然而，手术植入人体内的含镍合金潜在危害的机制仍不确定。
研究 Ni(II)（NiCl6HO）对癌细胞的影响。
用不同浓度的 Ni(II)处理 A549 和 RKO 细胞，用 CCK8 法测定 Ni(II)对细胞活力的影响。用流式细胞术分析 Ni(II)对细胞凋亡和细胞周期的影响。球形成实验检测 A549 和 RKO 细胞的干性特征。Western blot 法评价 SOX2、IDH1、HIF-1ɑ 和β-catenin 的表达水平。采用基因表达谱分析交互分析（GEPIA）分析直肠腺癌（READ）中异柠檬酸脱氢酶 1（IDH1）的表达。Kaplan-Meier 分析用于计算生存与 IDH1 表达的相关性。
长期（120 天）暴露于 100μM Ni(II) 显著抑制细胞增殖，降低集落形成，并使细胞周期停滞在 G0/G1 期。此外，A549 和 RKO 细胞的干性特征明显增强。Ni(II)还显著降低了 IDH1 的蛋白表达和 NAPDH 的合成率，从而竞争性抑制了α-酮戊二酸（α-KG）的生成。IDH1 的下调不仅以 HIF-1ɑ 信号依赖的方式促进β-catenin 在细胞核中的积累，还诱导转录因子 SOX2 的表达，维持癌细胞的干性特征。此外，IDH1 的表达与 READ 的临床病理特征呈负相关。
这些发现表明，慢性和持续向微环境中释放 Ni(II)通过激活 HIF-1ɑ/β-catenin/SOX2 通路抑制 IDH1 的表达，增强癌症干细胞的干性特征，从而增强植入手术部位含镍合金患者局部肿瘤的复发。
