Feedback regulation plays a pivotal role in determining the intensity and duration of TGF-β signaling and subsequently affecting the pathophysiological roles of TGF-β, including those in liver malignancy. KLF2, a member of the Krüppel-like factor (KLF) family transcription factors, has been implicated in impeding hepatocellular carcinoma (HCC) development. However, the underlying molecular mechanisms are not fully understood. In the present study, we found that TGF-β stimulates the expression of KLF2 gene in several HCC cell lines. KLF2 protein is able to inhibit TGF-β/Smad signaling in HCC cells as assessed by luciferase reporter assay. Further studies indicated that KLF2 inhibits the transcriptional activity of Smad2/3 and Smad4 and ameliorates TGF-β-induced target gene expression, therefore creating a novel negative feedback loop in TGF-β signaling. Functionally, stably expression of KLF2 in HCCLM3 cells attenuated TGF-β-induced cancer cell motility in wound-healing and transwell assays by interfering with TGF-β-mediated upregulation of MMP2. Together, our results revealed that KLF2 protein has a tumor-suppressive function in HCC through a negative feedback loop over TGF-β signaling.

中文翻译：

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KLF2抑制肝细胞癌中TGF-β介导的癌细胞运动。

反馈调节在确定TGF-β信号传导的强度和持续时间以及随后影响TGF-β的病理生理作用（包括肝恶性肿瘤的病理生理作用）中起着关键作用。KLF2是Krüppel样因子（KLF）家族转录因子的成员，已被认为阻碍肝细胞癌（HCC）的发展。但是，潜在的分子机制尚未完全了解。在本研究中，我们发现TGF-β刺激KLF2的表达几个HCC细胞系中的基因 如荧光素酶报告基因分析所评估，KLF2蛋白能够抑制HCC细胞中的TGF-β/ Smad信号传导。进一步的研究表明，KLF2抑制Smad2 / 3和Smad4的转录活性，并改善TGF-β诱导的靶基因表达，从而在TGF-β信号传导中产生新的负反馈环。通过干扰TGF-β介导的MMP2上调，HCCLM3细胞中KLF2的功能稳定表达在伤口愈合和Transwell分析中减弱了TGF-β诱导的癌细胞运动性。总之，我们的结果表明，KLF2蛋白通过TGF-β信号的负反馈回路在肝癌中具有肿瘤抑制功能。