Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Cancer Lett. 2024 Aug 28;598:217107. doi: 10.1016/j.canlet.2024.217107. Epub 2024 Jul 9.
Glioblastoma (GBM) presents a daunting challenge due to its resistance to temozolomide (TMZ), a hurdle exacerbated by the proneural-to-mesenchymal transition (PMT) from a proneural (PN) to a mesenchymal (MES) phenotype. TAGLN2 is prominently expressed in GBM, particularly in the MES subtype compared to low-grade glioma (LGG) and the PN subtype. Our research reveals TAGLN2's involvement in PMT and TMZ resistance through a series of in vitro and in vivo experiments. TAGLN2 knockdown can restrain proliferation and invasion, trigger DNA damage and apoptosis, and heighten TMZ sensitivity in GBM cells. Conversely, elevating TAGLN2 levels amplifies resistance to TMZ in cellular and intracranial xenograft mouse models. We demonstrate the interaction relationship between TAGLN2 and ERK1/2 through co-immunoprecipitation (Co-IP) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) spectrometry analysis. Knockdown of TAGLN2 results in a decrease in the expression of p-ERK1/2, whereas overexpression of TAGLN2 leads to an increase in p-ERK1/2 expression within the nucleus. Subsequently, the regulatory role of TAGLN2 in the expression and control of MGMT has been demonstrated. Finally, the regulation of TAGLN2 by NF-κB has been validated through chromatin immunoprecipitation and ChIP-PCR assays. In conclusion, our results confirm that TAGLN2 exerts its biological functions by interacting with the ERK/MGMT axis and being regulated by NF-κB, thereby facilitating the acquisition of promoting PMT and increased resistance to TMZ therapy in glioblastoma. These results provide valuable insights for the advancement of targeted therapeutic approaches to overcome TMZ resistance in clinical treatments.
胶质母细胞瘤（GBM）由于对替莫唑胺（TMZ）的耐药性而带来严峻挑战，而由神经前体细胞（PN）向间质表型（MES）的神经前体细胞-间质转化（PMT）进一步加剧了这一困境。TAGLN2 在 GBM 中表达明显，与低级别胶质瘤（LGG）和 PN 亚型相比，其在 MES 亚型中表达更高。我们的研究通过一系列的体外和体内实验揭示了 TAGLN2 通过参与 PMT 和 TMZ 耐药。TAGLN2 敲低可以抑制增殖和侵袭，引发 DNA 损伤和凋亡，并提高 GBM 细胞对 TMZ 的敏感性。相反，提高 TAGLN2 水平会增强细胞和颅内异种移植小鼠模型对 TMZ 的耐药性。我们通过共免疫沉淀（Co-IP）和液相色谱-串联质谱（LC-MS/MS）分析证实了 TAGLN2 与 ERK1/2 之间的相互作用关系。TAGLN2 敲低导致 p-ERK1/2 的表达减少，而 TAGLN2 的过表达导致核内 p-ERK1/2 的表达增加。随后，证明了 TAGLN2 对 MGMT 的表达和调控的调节作用。最后，通过染色质免疫沉淀和 ChIP-PCR 实验验证了 NF-κB 对 TAGLN2 的调节作用。总之，我们的研究结果证实了 TAGLN2 通过与 ERK/MGMT 轴相互作用，并受 NF-κB 调节，从而发挥其生物学功能，促进 PMT 的发生和 TMZ 治疗耐药性的增加。这些结果为临床治疗中克服 TMZ 耐药性的靶向治疗方法的发展提供了有价值的见解。
