The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia-associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia-inducible factor-1α activating its downstream genes, which are responsible for E2F7-dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti-mTOR–based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

中文翻译：

---

E2F7促进肝移植后肝细胞癌中雷帕霉素抑制剂耐药的哺乳动物靶点

哺乳动物雷帕霉素靶标 (mTOR) 通路经常失调，在癌症进展中起着关键作用。mTOR抑制剂已广泛应用于多种癌症，强烈推荐用于肝移植（LT）后肝细胞癌（HCC）患者。然而，由于耐药性导致对 mTOR 抑制剂的不良反应仍然是一个挑战。缺氧相关的耐药性限制了靶向药物的治疗效果。本研究建立了HCC临床样本和细胞系对mTOR抑制剂西罗莫司耐药的模型，并筛选出E2F7作为缺氧诱导和促进西罗莫司耐药的候选基因。E2F7 通过直接结合 TSC1 基因的启动子来抑制 mTOR 复合物 1，并稳定缺氧诱导因子 1α 激活其下游基因，负责 E2F7 依赖性 mTOR 抑制剂耐药性。在临床上，低 E2F7 表达可能是推荐 HCC 患者在 LT 后进行基于抗 mTOR 治疗的有效生物标志物。靶向 E2F7 在体内与西罗莫司协同抑制 HCC 生长。E2F7 是逆转 mTOR 抑制抗性的有前途的目标。总的来说，我们的研究指出了 E2F7 在促进 HCC 中 mTOR 抑制剂耐药性方面的作用，并强调了其在 LT 后 HCC 患者中的潜在临床意义。