Previous studies have found that alpha‐fetoprotein (AFP) can promote the proliferation of hepatoma cells and accelerate the progression of hepatocellular carcinoma (HCC). However, the exact mechanism of action remains unclear. Recent bioinformatics studies have predicted the possible interaction between AFP and retinoic acid receptors (RARs). Thus, the purpose of this study was to investigate the molecular mechanism through which AFP promotes tumour cell proliferation by interfering with the RA‐RAR signal pathway. Our data indicated that AFP could significantly promote the proliferation and weaken ATRA‐induced apoptosis of hepatoma cells. Besides, cytoplasmic AFP interacts with RAR, disrupting its entrance into the nucleus, which in turn affects the expression of the Bcl‐2 gene. In addition, knockdown of AFP in HepG2 cells was synchronously associated with an incremental increase of RAR binding to DNA, as well as down‐regulation of Bcl‐2; the opposite effect was observed in AFP gene‐transfected HLE cells. Moreover, a similar effect of AFP was detected in tumour tissues with high serum AFP, but not in adjacent non‐cancerous liver tissues, or HCC tissues with low serum AFP levels. These results indicate that AFP acts as signalling molecule and prevents RAR from entering into the nucleus by interacting with RAR, thereby promoting the expression of Bcl‐2. Our data reveal a novel mechanism through which AFP regulates Bcl‐2 expression and further suggest that AFP may be used as a novel target for treating HCC.

中文翻译：

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甲胎蛋白通过 RA-RAR 信号通路促进 Bcl-2 基因表达加速肝细胞癌的进展

既往研究发现甲胎蛋白（AFP）可促进肝癌细胞增殖，加速肝细胞癌（HCC）的进展。然而，确切的作用机制仍不清楚。最近的生物信息学研究预测了 AFP 和视黄酸受体 (RAR) 之间可能的相互作用。因此，本研究的目的是研究 AFP 通过干扰 RA-RAR 信号通路促进肿瘤细胞增殖的分子机制。我们的数据表明，AFP可以显着促进肝癌细胞的增殖并减弱ATRA诱导的细胞凋亡。此外，细胞质 AFP 与 RAR 相互作用，破坏其进入细胞核，进而影响Bcl-2的表达。基因。此外，HepG2 细胞中 AFP 的敲低与 RAR 与 DNA 结合的增量增加以及 Bcl-2 的下调同步相关；在转染 AFP 基因的 HLE 细胞中观察到相反的效果。此外，在血清 AFP 水平高的肿瘤组织中检测到 AFP 的类似作用，但在邻近的非癌性肝组织或血清 AFP 水平低的 HCC 组织中未检测到。这些结果表明AFP作为信号分子通过与RAR相互作用阻止RAR进入细胞核，从而促进Bcl-2的表达。我们的数据揭示了 AFP 调节 Bcl-2 表达的新机制，并进一步表明 AFP 可用作治疗 HCC 的新靶点。