Department of Medical, Technological and Translational Sciences, University Hospital of Cattinara, Trieste, Italy.
Biochimie. 2010 May;92(5):455-63. doi: 10.1016/j.biochi.2010.01.007. Epub 2010 Feb 6.
For hepatocellular carcinoma (HCC), a leading cause of cancer death world-wide, there is no effective therapy especially for the advanced stage of the disease. Thus, we started the investigations about a novel anti HCC approach based on the depletion of the transcription factor serum response factor (SRF) in HCC cell lines; SRF choice was based on its recently proposed contribution to HCC tissue development and on its important role in cell proliferation. SRF depletion, obtained by a siRNA (siSRF797), was studied in two HCC cell lines, i.e. HepG2 and JHH6 assigned to high and low hepatocytic differentiation grade on the base of the capacity to synthesize albumin. In the HCC cell lines examined, siSRF797 reduced both the mRNA and protein levels of SRF without inducing unspecific interferon response or cytotoxicity. Moreover, SRF depletion induced the reduction of S-phase cells and a decrease in cell number and vitality. Particularly in HepG2, cell growth impairment was paralleled by the decrease of the levels of the transcription factor E2F1 together with some of its regulated genes. In HepG2 but not in JHH6, SRF depletion was associated with apoptosis. Finally, in both HepG2 and JHH6, the combined administration of siSRF797 and bortezomib, a proteasome inhibitor whose therapeutic potential for HCC is considered attractive, further reduced cell viability compared to either siSRF797 or bortezomib treatment alone. In conclusion, SRF depletion affects the expansion of the high and low differentiation grade HCC cells HepG2 and JHH6. These results can pave the way to understand the role of SRF in HCC development and possibly to identify novel anti HCC therapeutic strategies.
对于肝细胞癌（HCC），这是全球癌症死亡的主要原因，目前尚无特别有效的治疗方法，特别是对于疾病的晚期。因此，我们开始研究一种新的抗 HCC 方法，该方法基于 HCC 细胞系中转录因子血清反应因子（SRF）的耗竭；选择 SRF 是基于其最近提出的对 HCC 组织发育的贡献以及其在细胞增殖中的重要作用。通过 siRNA（siSRF797）获得的 SRF 耗竭在两种 HCC 细胞系中进行了研究，即 HepG2 和 JHH6，它们基于合成白蛋白的能力被分配到高和低肝细胞分化等级。在所检查的 HCC 细胞系中，siSRF797 降低了 SRF 的 mRNA 和蛋白水平，而没有诱导非特异性干扰素反应或细胞毒性。此外，SRF 耗竭诱导 S 期细胞减少，细胞数量和活力下降。特别是在 HepG2 中，细胞生长受损与转录因子 E2F1 及其一些调节基因的水平降低同时发生。在 HepG2 中，但不在 JHH6 中，SRF 耗竭与细胞凋亡有关。最后，在 HepG2 和 JHH6 中，siSRF797 和硼替佐米（一种被认为具有吸引力的 HCC 治疗潜力的蛋白酶体抑制剂）的联合给药与单独使用 siSRF797 或硼替佐米治疗相比，进一步降低了细胞活力。总之，SRF 耗竭会影响高分化和低分化等级 HCC 细胞 HepG2 和 JHH6 的扩增。这些结果为理解 SRF 在 HCC 发展中的作用铺平了道路，并可能确定新的抗 HCC 治疗策略。
