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Sako N, Dessirier V, Bagot M, et al.HACE1, a Potential Tumor Suppressor Gene on 6q21, Is Not Involved in Extranodal Natural Killer/T-Cell Lymphoma Pathophysiology. Am J Pathol. 2014,184(11):2899-2907. Abstract Extranodal natural killer-T-cell lymphoma (NKTCL) of nasal type is a malignant disorder of cytotoxic lymphocytes of natural killer or more rarely T cells, associated with clonal Epstein-Barr virus infection. NKTCL is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of NKTCL is little understood, some insight has been gained in the recent years, especially from genome-wide studies, which revealed a deletion on chromosome 6q21 in more than 50% of patients. Of interest, this deleted region contains four candidate tumor suppressor genes whose decreased expression has been confirmed at the mRNA level: PRDM1, ATG5, AIM1, and HACE1. Mutations and methylation in PRDM1, ATG5, and AIM1 have been reported in NKTCL cell lines. We investigated the involvement of HACE1 in NKTCL pathophysiology. Even though the hypermethylation of CpG-177 island located directly upstream of HACE1 locus led to down-regulation of HACE1 mRNA, the protein product was expressed at nearly normal levels and was functional in the NKTCL cell lines regardless of 6q21 deletion (and indeed no double deletion of 6q21 and no nonfunctional mutations have been reported). Furthermore, contrary to previous report, overexpression of HACE1 by transduction of recombinant protein did not affect proliferation or survival of NKTCL cell lines. We therefore conclude that HACE1 is not directly involved in NKTCL pathophysiology. 结外鼻型NK/T细胞淋巴瘤（NKTCL）是由自然杀伤细胞或较少见的T细胞中细胞毒性淋巴细胞增生紊乱引起的一种恶性肿瘤，与EB病毒感染有关。NKTCL是一种预后非常差的侵袭性淋巴瘤。尽管有关NKTCL的致病过程知之甚少，然而最近几年从全基因组的研究中，发现多于50%的患者存在染色体6q21的缺失。有趣的是，这些缺失区域包括四种候选肿瘤抑制基因：PRDM1、ATG5、AIM1和HACE1，且已证明它们在mRNA水平的表达减少。NKTCL细胞系中存在PRDM1、ATG5和AIM1的突变和甲基化。作者研究了NKTCL致病过程中HACE1的所扮演的角色。尽管位于HACE1上游区域CpG-177的甲基化能够导致HACE1在mRNA水平的下调，但其在蛋白水平的表达几乎处于正常水平，并且在NKTCL细胞系中不管是否存在6q21缺失，HACE1蛋白是有功能的（确实没有双重6q21缺失和无功能突变的报道）。此外，和以前的报道相反，通过重组蛋白的转导导致HACE1的过表达，并不影响NKTCL细胞系的增殖和生存，因此作者推断HACE1并不直接参与NKTCL的致病过程。

 

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