Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK-Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

中文翻译：

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甲胎蛋白/内质网应激信号可减轻肝癌细胞的损伤。

甲胎蛋白 (AFP) 和内质网 (ER) 应激在肝细胞癌中发挥多种作用。在这里，我们分析了人肝癌细胞中 AFP 和 ER 应激之间的串扰。我们用毒胡萝卜素（TG，一种 ER 应激诱导剂）诱导人肝癌细胞系（HepG2 和 SK-Hep1 细胞）的 ER 应激，并用 4-苯基丁酸（4-PBA，一种 ER 应激抑制剂）减轻 ER 应激。AFP 表达被 AFP 短发夹 RNA 击倒并被 pCI-AFP 载体拯救。检测了 AFP 表达和 ER 应激，并分析了它们在细胞凋亡、坏死性凋亡和增殖中的作用。TG显着诱导内质网应激、细胞凋亡、坏死性凋亡和细胞内AFP蛋白水平，并降低HepG2和SK-Hep1细胞的增殖和AFP mRNA表达以及上清液AFP蛋白水平。4-PBA 预处理部分逆转了 HepG2 细胞中的这些变化。与 AFP 过表达相比，AFP 的敲低显着加剧了 TG 诱导的 ER 应激、细胞凋亡和坏死性凋亡，并降低了增殖和激活转录因子 6 α 的表达。综上所述，ER应激导致AFP蛋白的积累，这可能与AFP分泌减少有关。累积的 AFP 可减轻细胞凋亡和坏死性凋亡，并通过减少 ER 应激来恢复肝癌细胞的增殖。这可能与 AFP 分泌减少有关。累积的 AFP 可减轻细胞凋亡和坏死性凋亡，并通过减少 ER 应激来恢复肝癌细胞的增殖。这可能与 AFP 分泌减少有关。累积的 AFP 可减轻细胞凋亡和坏死性凋亡，并通过减少 ER 应激来恢复肝癌细胞的增殖。