Kudo Y, Takata T, Yasui W, Ogawa I, Miyauchi M, Takekoshi T, Tahara E, Nikai H
Department of Oral Pathology, Hiroshima University School of Dentistry, Japan.
Cancer. 1998 Dec 15;83(12):2447-55. doi: 10.1002/(sici)1097-0142(19981215)83:12<2447::aid-cncr7>3.0.co;2-a.
Reduced expression of the cyclin-dependent kinase inhibitor p27Kip1 has been reported to correlate with poor survival in cohorts of breast and colorectal carcinoma patients. Posttranslational ubiquitin-mediated proteasomal proteolysis is related to p27Kip1 protein levels. However, to the authors' knowledge, no previous study has examined the expression of p27Kip1 in oral squamous cell carcinoma (OSCC).
To examine the expression of p27Kip1 and its clinicopathologic roles in OSCC, the authors studied the expression of p27Kip1 protein by immunohistochemistry in deparaffinized tissue sections of 20 normal oral mucosa specimens, 22 epithelial dysplasia specimens, and 70 OSCCs, and analyzed its correlation with clinicopathologic parameters. They also studied the expression of p27Kip1 mRNA and protein in six OSCC cell lines by Northern blot and Western blot analysis. To examine the mechanism of reduced expression of p27Kip1, OSCC cell lines were treated with the proteasome inhibitor LLnV.
All the normal oral mucosa specimens and 73% (16 of 22) of the oral epithelial dysplasia specimens expressed p27Kip1 at high levels, whereas 87% of the OSCCs (61 of 70) showed reduced expression of p27Kip1. Furthermore, the levels of expression of this protein were significantly lower in carcinomas with metastasis than those without metastasis. Although OSCC cell lines expressed p27Kip1 mRNA at various levels, most of them expressed p27Kip1 protein at lower or undetectable levels. LLnV induced the expression of p27Kip1 protein in HSC2 cells, in which p27Kip1 protein was originally undetectable.
These findings suggest that 1) reduced expression of p27Kip1 may correlate with the development and progression of OSCC and can be an indicator of malignant behavior of this neoplasm, and 2) increased proteasome-mediated degradation may play an important role in the reduction of p27Kip1 protein expression.
据报道，细胞周期蛋白依赖性激酶抑制剂p27Kip1表达降低与乳腺癌和结直肠癌患者队列的不良生存相关。翻译后泛素介导的蛋白酶体蛋白水解与p27Kip1蛋白水平有关。然而，据作者所知，以往尚无研究检测过p27Kip1在口腔鳞状细胞癌（OSCC）中的表达。
为检测p27Kip1在OSCC中的表达及其临床病理作用，作者通过免疫组织化学研究了20例正常口腔黏膜标本、22例上皮发育异常标本和70例OSCC石蜡包埋组织切片中p27Kip1蛋白的表达，并分析其与临床病理参数的相关性。他们还通过Northern印迹和Western印迹分析研究了6种OSCC细胞系中p27Kip1 mRNA和蛋白的表达。为检测p27Kip1表达降低的机制，用蛋白酶体抑制剂LLnV处理OSCC细胞系。
所有正常口腔黏膜标本和73%（22例中的16例）口腔上皮发育异常标本均高表达p27Kip1，而87%的OSCC（70例中的61例）p27Kip1表达降低。此外，有转移的癌组织中该蛋白的表达水平显著低于无转移者。虽然OSCC细胞系p27Kip1 mRNA表达水平各异，但大多数细胞系p27Kip1蛋白表达较低或无法检测到。LLnV诱导了HSC2细胞中p27Kip1蛋白表达，该细胞系原本无法检测到p27Kip1蛋白。
这些发现表明，1）p27Kip1表达降低可能与OSCC的发生和进展相关，可作为该肿瘤恶性行为的一个指标；2）蛋白酶体介导的降解增加可能在p27Kip1蛋白表达降低中起重要作用。
