PO.ET06.06 · 实验与分子治疗
HMGB1表达与结直肠癌的不良肿瘤特征和预后不良相关
HMGB1 expression is linked to unfavorable tumor features and poor prognosis in colorectal cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
高迁移率族蛋白B1（HMGB1）是一种染色质相关蛋白，在DNA损伤修复和基因组稳定性中起关键作用，参与DNA复制、转录和染色质重塑。HMGB1从细胞核向细胞质的转位可能赋予其在自噬、凋亡和线粒体功能之间相互作用方面的额外功能。通过调节多条信号通路，HMGB1参与癌细胞的关键特征，包括炎症、血管生成、增殖、迁移和侵袭，以及肿瘤能量代谢。HMGB1表达的增加和减少均被发现与不良肿瘤特征相关，这可能取决于其细胞定位和组织类型。为进一步深入了解HMGB1在结直肠癌中的潜在意义，我们通过免疫组化对一个包含3,456例结直肠癌的组织微阵列进行了核内和胞质HMGB1分析。在结直肠上皮的所有正常细胞中均可见显著的核内HMGB1免疫染色。然而，癌症中核内HMGB1的水平存在差异。在2,601例可判读的癌症中，核内HMGB1完全缺失8例（0.3%），染色1+为179例（6.9%），2+为684例（26.3%），3+为1,730例（66.5%）。强的核内HMGB1与以下因素显著相关：远处转移（p<0.0001）、淋巴结转移（p=0.0438）、血管侵犯（p=0.0365）、无BRAF V600E突变（p=0.0107）以及总生存期缩短（p=0.0118）。与错配修复（MMR）功能正常的肿瘤（73.4%强染色）相比，核内HMGB1在MMR缺陷肿瘤中明显减少（43.8%强染色，p<0.0001）。在MMR功能正常的肿瘤中，高核内HMGB1与V+（p=0.0089）和L1状态（p=0.0054）相关。胞质HMGB1较不常见（16.7%），且与组织病理学肿瘤表型无关。总之，我们的数据表明，HMGB1表达在结直肠癌中存在差异，高核内HMGB1染色水平与侵袭性肿瘤特征和不良结局相关，而核内HMGB1减少则与MMR缺陷密切相关。
查看英文原文 English abstract
High-mobility group box 1 (HMGB1) is a chromatin-associated protein with a key role in DNA damage repair and genome stability, involved in DNA replication, transcription, and chromatin remodeling. The translocation of HMGB1 from the nucleus to the cytoplasm may confer additional functions regarding the interplay between autophagy, apoptosis and mitochondrial function. By regulating multiple signaling pathways HMGB1 contributes to critical characteristics of cancer cells including inflammation, angiogenesis, proliferation, migration and invasion, as well as tumor energy metabolism. Both increased and reduced expression of HMGB1 have been found to be linked to unfavorable tumor features, presumably depending on its cellular location and tissue type. To gain further insight into the potential significance of HMGB1 in colorectal cancer, a tissue microarray containing 3,456 colorectal cancers was analyzed by immunohistochemistry for nuclear and cytoplasmic HMGB1. A significant nuclear HMGB1 immunostaining was seen in all normal cells of the colorectal epithelium. However, the level of nuclear HMGB1 was variable in cancers. Among 2,601 interpretable cancers, nuclear HMGB1 was completely lost in 8 cases (0.3%) while the staining was 1+ in 179 (6.9%), 2+ in 684 (26.3%), and 3+ in 1,730 (66.5%) tumors. Strong nuclear HMGB1 was significantly linked to distant metastasis (p<0.0001), lymph node metastasis (p=0.0438), blood vessel invasion (p=0.0365), absence of BRAF V600E mutations (p=0.0107), and shortened overall survival (p=0.0118). Nuclear HMGB1 was markedly reduced in mismatch repair (MMR) deficient (43.8% strong) as compared to MMR proficient tumors (73.4%, p<0.0001). Within MMR proficient tumors, high nuclear HMGB1 was linked to V+ (p=0.0089) and L1 status (p=0.0054). Cytoplasmic HMGB1 was less common (16.7%) and unrelated to the histopathologic tumor phenotype. In summary, our data demonstrate that HMGB1 expression is variable in colorectal cancer and that a high nuclear HMGB1 staining level is associated with aggressive tumor features and poor outcome while reduced nuclear HMGB1 is strongly linked to MMR deficiency.
利益披露 Disclosure
N. Schraps, None..
K. Möller, None..
V. Reiswich, None..
F. Viehweger, None..
M. C. Tsourlakis, None..
G. Makrypidi-Fraune, None..
C. Hube-Magg, None..
M. Kluth, None..
T. Krech, None..
C. Fraune, None..
A. Marx, None..
F. Gehrisch, None..
B. Mercanoglu, None..
N. Melling, None..
T. Hackert, None..
R. Simon, None.
G. Sauter,
MS Validated Antibodies GmbH Other, The HMGB1 antibody, clone HMV317 was provided from MS Validated Antibodies GmbH, Hamburg, Germany (owned by a family member of GS).
M. Freytag, None.