Department of Hepatobiliary, Fuling Central Hospital of Chongqing City, Chongqing, China.
Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
Cell Oncol (Dordr). 2021 Aug;44(4):821-834. doi: 10.1007/s13402-021-00605-0. Epub 2021 May 11.
Lenvatinib is a long-awaited alternative to Sorafenib for first-line targeted therapy of patients with advanced hepatocellular carcinoma (HCC). However, resistance to Lenvatinib results in tumor progression and has become a major obstacle to improving the prognosis of HCC patients. Exploring the mechanisms underlying Lenvatinib resistance is considered essential for the treatment of advanced HCC.
Lenvatinib resistant HCC (LR-HCC) cells were generated and potential long non-coding RNAs (Lnc-RNAs) upregulated in LR-HCC cells were identified by RNA sequencing. The effects of upregulated Lnc-RNAs were evaluated in vitro in cell models and in vivo in experimental animals using quantitative cell viability and apoptosis assays.
We found that Lnc-RNA MT1JP (MT1JP) was upregulated in LR-HCC cells and inhibited the apoptosis signaling pathway. In addition, we found that sponging of microRNA-24-3p by MT1JP released Bcl-2 like 2 (BCL2L2), an anti-apoptotic protein, thereby forming a positive-feedback loop. The role of this feedback loop was validated using rescue assays. Additionally, we found that upregulation of MT1JP and BCL2L2 impaired the sensitivity of HCC cells to Lenvatinib both vitro and vivo.
Our results suggest a novel molecular feedback loop between MT1JP and apoptosis signaling in Lenvatinib sensitive HCC cells.
仑伐替尼是索拉非尼治疗晚期肝细胞癌（HCC）一线靶向治疗的期待已久的替代药物。然而，仑伐替尼耐药导致肿瘤进展，已成为改善 HCC 患者预后的主要障碍。探索仑伐替尼耐药的机制被认为是治疗晚期 HCC 的关键。
通过 RNA 测序生成仑伐替尼耐药 HCC（LR-HCC）细胞，并鉴定出 LR-HCC 细胞中上调的潜在长链非编码 RNA（Lnc-RNAs）。通过定量细胞活力和凋亡测定，在细胞模型和实验动物中评估上调的 Lnc-RNAs 的作用。
我们发现 Lnc-RNA MT1JP（MT1JP）在 LR-HCC 细胞中上调，并抑制凋亡信号通路。此外，我们发现 MT1JP 通过海绵吸附 microRNA-24-3p 释放抗凋亡蛋白 Bcl-2 样 2（BCL2L2），从而形成正反馈环。通过挽救实验验证了该反馈环的作用。此外，我们发现 MT1JP 和 BCL2L2 的上调均损害了 HCC 细胞对仑伐替尼的体外和体内敏感性。
我们的结果表明，在仑伐替尼敏感 HCC 细胞中，MT1JP 和凋亡信号之间存在一种新的分子反馈环。
