Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
J Cancer Res Clin Oncol. 2010 Oct;136(10):1573-83. doi: 10.1007/s00432-010-0815-x. Epub 2010 Feb 25.
This study aimed to assess the protein level of inhibitor of growth gene 5 (ING5) in head and neck squamous cell carcinoma (HNSCC) and to explore its roles in tumorigenesis and cancer progression.
ING5 expression was assessed in 172 cases of HNSCC by immunohistochemistry using tissue microarray, and in 3 oral SCC cell lines by immunohistochemistry and Western blot. Expression of ING5 was compared with clinicopathological variables, TUNEL assay staining, and the expression of several tumorigenic markers. In addition, double immunofluorescence labeling was performed in order to analyze the colocalization of ING5 with p300 and p21.
ING5 expression was primarily observed in the nuclei, but was also occasionally found in the cytoplasm of both SCC cell lines and tissue samples of HNSCC. Nuclear expression of ING5 in HNSCC was significantly lower than that of non-cancerous epithelium, and was positively correlated with a well-differentiated status. In contrast, cytoplasmic expression of ING5 was significantly increased in HNSCC, and was inversely correlated with a well-differentiated status and nuclear ING5 expression. In addition, nuclear expression of ING5 was positively correlated with p21 and p300 expression, and with the apoptotic index. In contrast, cytoplasmic expression of ING5 was negatively correlated with the expression of p300, p21, and PCNA. Although no statistical association was found between the expression of nuclear ING5 and mutant p53 in HNSCC, patients with high expression of nuclear ING5 tended to have converse prognoses when grouped according to mutant p53 expression.
Our results suggest that a decrease in nuclear ING5 localization and cytoplasmic translocation are involved in tumorigenesis and tumor differentiation in HNSCC. Nuclear ING5 may modulate the transactivation of target genes, and may promote apoptosis and cell cycle arrest by interacting with the p300 and p21 proteins. ING5 may function as a tumor suppressor gene or oncogene tightly linked with p53 status, and may play an important role in the prognosis of HNSCC patients. Therefore, we propose that ING5 represents a novel potential molecular therapeutic target for HNSCC.
本研究旨在评估头颈部鳞状细胞癌（HNSCC）中生长抑制基因 5（ING5）的蛋白水平，并探讨其在肿瘤发生和癌症进展中的作用。
采用组织微阵列免疫组化法检测 172 例 HNSCC 组织中 ING5 的表达，采用免疫组化和 Western blot 法检测 3 种口腔 SCC 细胞系中 ING5 的表达。比较 ING5 的表达与临床病理变量、TUNEL 检测染色以及几种致癌标记物的表达。此外，还进行了双重免疫荧光标记，以分析 ING5 与 p300 和 p21 的共定位。
ING5 表达主要位于 SCC 细胞系和 HNSCC 组织样本的细胞核中，但偶尔也位于细胞质中。HNSCC 中 ING5 的核表达明显低于非癌上皮，且与分化程度较好呈正相关。相反，HNSCC 中 ING5 的细胞质表达显著增加，且与分化程度较好的核 ING5 表达呈负相关。此外，核 ING5 的表达与 p21 和 p300 的表达呈正相关，与凋亡指数呈正相关。相反，细胞质 ING5 的表达与 p300、p21 和 PCNA 的表达呈负相关。尽管在 HNSCC 中未发现核 ING5 表达与突变型 p53 之间存在统计学关联，但根据突变型 p53 的表达对核 ING5 高表达的患者进行分组时，其预后呈相反趋势。
我们的研究结果表明，核 ING5 定位减少和细胞质易位参与了 HNSCC 的肿瘤发生和肿瘤分化。核 ING5 可能通过与 p300 和 p21 蛋白相互作用，调节靶基因的反式激活，并促进细胞凋亡和细胞周期阻滞。ING5 可能作为与 p53 状态紧密相关的肿瘤抑制基因或癌基因发挥作用，并可能在 HNSCC 患者的预后中发挥重要作用。因此，我们提出 ING5 是 HNSCC 的一个新的潜在分子治疗靶点。
