Centre de Lutte Contre le Cancer Eugène Marquis, Inserm, University of Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), 35042 Rennes, France.
Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11796, Egypt.
Cells. 2021 Aug 26;10(9):2207. doi: 10.3390/cells10092207.
Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGFβ activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGFβ. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., , ). We also report that the promoter of was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGFβ pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.
转化生长因子β（TGFβ）在肝癌发生中起着关键作用。然而，其作用很复杂，因为 TGFβ 表现出肿瘤抑制或致癌特性，这取决于肿瘤的阶段。在早期，TGFβ 表现出细胞静止的特征，但在后期，它促进细胞生长和转移，作为上皮间质转化（EMT）的有效诱导剂。在这里，我们评估了 DNA 甲基化作为 TGFβ 在肝细胞癌（HCC）中向肿瘤进展的活性转变的可能分子机制。我们报告说，地西他滨，一种已在临床上用于治疗多种癌症的去甲基化剂，极大地削弱了 SNU449 HCC 细胞对 TGFβ 的转录反应。重要的是，地西他滨被证明可以诱导 EMT 相关转录因子的表达（例如， ）。我们还报告说，在预后不良的人 HCC 中， 的启动子呈低甲基化状态，即与高等级、高 AFP 水平、转移和复发相关。总的来说，这些数据强调了 TGFβ 通路的几个效应物在人 HCC 中的表观遗传控制，可能涉及到 EMT 和肿瘤进展的活性转变。因此，我们得出结论，表皮药物在治疗 HCC 时应仔细评估，因为它们可能会激活促进肿瘤的途径。
