Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway
Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1→HIF-1α pathway
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DOI：
10.1007/s00277-010-1070-6
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发表时间：
2011-03-01
影响因子：
3.5
通讯作者：
Rontogianni, Dimitra
中科院分区：
文献类型：
--
作者：
Argyriou, Pinelopi;Papageorgiou, Sotirios G.;Rontogianni, Dimitra
磷酸肌醇 3 激酶/Akt (PI3K/Akt) 和哺乳动物雷帕霉素靶点 (mTOR) 信号传导的异常激活与套细胞淋巴瘤 (MCL) 的发病机制有关。我们之前在 MCL 患者亚群中发现了 PI3K/Akt 通路的致癌激活。在本研究中，我们研究了同一系列 MCL 患者中 (Ser2448)pmTOR [指示 mTOR 复合物 1 (mTORC1) 激活状态]以及缺氧诱导因子 1 α (HIF-1 α)、缺氧诱导因子 2 α (HIF-2 α)、p53 和 p21 的下游免疫组织化学表达。此外，还检查了这些蛋白质与激活的 Akt ((Ser473)pAkt) 和已确定的组织学预后因素的相关性。包括 35 个组织样本（28 个经典类型和 7 个胚变体）。 61.7% 的肿瘤细胞表达 (Ser2448)pmTOR，73.5% 表达 HIF-1 α，23.5% 表达 HIF-2 α，18.2% 表达 p53，而所有检查样本中 p21 均为阴性。此外，72% 表达 HIF-1 α 的患者也表达 (Ser2448)pmTOR (p = 0.041)。 HIF-1 α 表达还与 Ki-67 升高（p = 0.031）和疾病变体（p = 0.017）相关（千分之 30%）。总之，我们首次报告了 MCL 患者中 HIF-α，尤其是 HIF-1 α 的常见表达。此外，还表明 mTORC1 -> HIF-1 α 轴的整体激活以及 (Ser2448)pmTOR 在 MCL 患者的 HIF-1 α 调节中的潜在作用。最后，HIF-1 α 似乎与更具侵袭性的疾病有关。 mTORC1 和 HIF-1 α 在 MCL 中均具有致病作用，这可能会导致更有效的靶向治疗。
Aberrant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling is implicated in the pathogenesis of mantle cell lymphoma (MCL). We previously showed oncogenic activation of PI3K/Akt pathway in a subset of MCL patients. In this study, we investigated downstream the immunohistochemical expression of (Ser2448)pmTOR [indicative of mTOR complex 1 (mTORC1) activation status] as well as of hypoxia-inducible factor 1 alpha (HIF-1 alpha), hypoxia-inducible factor 2 alpha (HIF-2 alpha), p53, and p21 in the same series of MCL patients. Additionally, correlation of these proteins with activated Akt ((Ser473)pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed (Ser2448)pmTOR in 61.7%, HIF-1 alpha in 73.5%, HIF-2 alpha in 23.5%, and p53 in 18.2% of patients, while p21 was negative in all examined samples. In addition, 72% of patients who expressed HIF-1 alpha had also (Ser2448)pmTOR expression (p = 0.041). HIF-1 alpha expression was also correlated to an elevated (a parts per thousand yen30%) Ki-67 (p = 0.031) and blastoid variant of disease (p = 0.017). In conclusion, we report for the first time common expression of HIF-alphas, especially HIF-1 alpha, in MCL patients. Furthermore, an overall activation of mTORC1 -> HIF-1 alpha axis and a potential role of (Ser2448)pmTOR in the regulation of HIF-1 alpha in MCL patients are suggested. Finally, HIF-1 alpha appears to be associated with more aggressive disease. A pathogenetic role for both mTORC1 and HIF-1 alpha in MCL is implied, which will possibly lead to more efficient target therapies.