骨形成蛋白信号通路中Smad4和Smad7在口腔鳞癌中的表达变化

上海口腔医学 ›› 2013, Vol. 22 ›› Issue (5): 492-497.

骨形成蛋白信号通路中Smad4和Smad7在口腔鳞癌中的表达变化

刘端芹¹，张君^1,2，宋洪宁¹，郑君¹，王旭霞^1,2

(1.山东大学口腔医学院口腔颌面外科，山东济南 250012；2.山东省口腔生物医学重点实验室，山东济南 250012)

收稿日期:2013-03-18 修回日期:2013-05-10 出版日期:2013-10-10 发布日期:2013-10-10
通讯作者: 王旭霞，E-mail:wxx@sdu.edu.cn
作者简介:刘端芹(1987-),女,在读硕士研究生,E-mail:liuduanqin1987@126.com
基金资助:
山东省科学技术发展项目(2010GSF10239)；山东省科学技术专项计划项目(2012G0021852)

Expression of Smad4 and Smad7 of BMP signaling pathway in oral squamous cell carcinoma

LIU Duan-qin¹, ZHANG Jun^1,2, SONG Hong-ning¹, ZHENG Jun¹, WANG Xu-xia^1,2

1.Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University. Jinan 250012; 2. Shandong Provincial Key Laboratory of Oral Biomedicine. Jinan 250012, Shandong Province, China

Received:2013-03-18 Revised:2013-05-10 Online:2013-10-10 Published:2013-10-10
Supported by:
Supported by Science and Technology Development Plan (2010GSF10239) of Shandong Province and Science and Technology Special Project of Shandong Province (2012G0021852).

摘要/Abstract

摘要： 目的：观察口腔鳞癌和癌旁正常组织中Smad4和Smad7表达量的变化，探讨Smad4和Smad7对口腔鳞癌发生和发展的影响。方法：收集临床和病理学诊断为OSCC的病例72例。取癌组织和癌旁正常组织做切片，用SP免疫组化法分别检测Smad4和Smad7在口腔鳞癌和正常组织中的表达，采用SPSS11.5软件包对数据进行统计学分析。结果：Smad4蛋白在癌旁正常组织中的阳性表达率为69.44%，在口腔鳞癌组织中的阳性表达率为45.83% (P<0.05)，且随着分化程度的降低其阳性表达率降低；有淋巴结转移者阳性表达率为22.50%，无淋巴结转移者阳性表达率为65.63% (P<0.05)。Smad7蛋白在癌旁正常组织中的阳性表达率为19.44%，在口腔鳞癌组织中的阳性表达率为83.33%(P<0.05)，且随着分化程度的降低其阳性表达率升高；有淋巴结转移者阳性表达率为92.50%，无淋巴结转移者阳性表达率为68.75% (P<0.05)。结论：Smad4在癌组织中表达明显减少，且分化程度越低，表达越少，Smad4在有淋巴结转移的组织中比在无淋巴结转移的组织中表达低；Smad7的作用则相反。Smad4的表达缺失可能促进了口腔鳞癌的发展和转移，Smad7的过表达促进了口腔鳞癌的发展和转移；BMP/Smads信号传导通路受到抑制，可能会导致口腔鳞癌的继续发生和发展。

关键词: 骨形成蛋白, 口腔鳞癌, Smad4, Smad7, 信号通路

Abstract: PURPOSE: To observe the changes of the expressions of Smad4 and Smad7 in oral squamous cell carcinoma and adjacent normal tissue, and to investigate the effects of Smad4 and Smad7 on occurrence and development of oral squamous cell carcinoma (OSCC). METHODS: Seventy-two cases with OSCC which were pathologically confirmed were included in the study. Cancer tissue and adjacent normal tissue were taken to make slices. SP immunohistochemical method was used to detect the expression of Smad4 and Smad7 in oral squamous cell carcinoma and adjacent normal tissue. SPSS11.5 software package was used for statistical analysis. RESULTS: The positive expression rate of Smad4 protein was 69.44% in adjacent normal tissues, and it was 45.83% in oral squamous cell carcinoma(P<0.05). The positive expression rate of Smad4 was lower when the degree of differentiation decreased; The positive expression rate of Smad4 with lymph node metastasis was 22.50%, while it was 65.63% without lymph node metastasis(P<0.05). The positive expression rate of Smad7 protein in adjacent normal tissues was 19.44%, and it was 83.33% (P<0.05) in oral squamous cell carcinoma, the positive expression rate of Smad7 was higher when the degree of differentiation decreased. The positive expression rate of Smad7 with lymph node metastasis was 92.50%, while it was 68.75%(P<0.05) without lymph node metastasis. CONCLUSIONS: The expression of Smad4 is significantly reduced in cancer tissues and the expression is lower when the degree of differentiation decreased; the expression rate of Smad4 with lymph node metastasis is lower compared with those without lymph node metastasis. Smad7 has the opposite effect. Loss of expression of Smad4 may contribute to the development and metastasis of oral squamous cell carcinoma；Over-expression of Smad7 may promote the development and metastasis of oral squamous cell carcinoma. The inhibition of BMP/Smads signaling pathway may result in the occurrence and development of oral squamous cell carcinoma continually.

Key words: BMP, Oral squamous cell carcinoma, Smad4, Smad7, Signaling pathway

中图分类号:

R739.8

刘端芹, 张君, 宋洪宁, 郑君, 王旭霞,. 骨形成蛋白信号通路中Smad4和Smad7在口腔鳞癌中的表达变化[J]. 上海口腔医学, 2013, 22(5): 492-497.

LIU Duan-qin, ZHANG Jun, SONG Hong-ning, ZHENG Jun, WANG Xu-xia,. Expression of Smad4 and Smad7 of BMP signaling pathway in oral squamous cell carcinoma[J]. Shanghai Journal of Stomatology, 2013, 22(5): 492-497.

参考文献

[1] Urist MR, DeLange RJ, Finerman GA. Bone cell differentiation and growth factors[J]. Science, 1983, 220(4598): 680-686.
[2] Wen XZ, Miyake S, Akiyama Y, et al. BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells [J]. Biochem Biophys Res Commun, 2004, 316(1): 100-106.
[3] Heikinheimo KA, Laine MA, Ritvos OV, et al. Bone morphogenetic protein 6 is a marker of serous acinar cell differentiation in normal and neoplastic human salivary gland[J]. Cancer Res, 1999, 59(22): 5815-5821.
[4] 傅升, 金岩, 何黎升, 等. 骨形成蛋白(BMP)-2/4与IA型BMP受体在口腔鳞癌中的表达[J]. 实用口腔医学杂志, 2001, 17(6): 476-478.
[5] Sekelsky JJ, Newfeld SJ, Raftery LA, et al. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic functionin Drosophila melanogaster[J]. Genetics, 1995, 139(3): 1347-1358.
[6] Arai T, Akiyama Y, Okabe S, et al. Genomic structure of the human Smad3 gene and its infrequent alteration in colorectal cancers[J]. Cancer Lett, 1998, 122(1-2): 157-163.
[7] Zhang Y, Feng X, We R, et al. Receptor-associated Mad homologues synergize as effectors of the TGF-β responses[J]. Nature, 1996, 383(6596): 168-172.
[8] Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation[J]. Science, 2000, 287(5450): 92-97.
[9] Sirard C, Kim S, Mirtsos C, et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling[J]. J Biol Chem,2000,275(3): 2063-2070.
[10] Lin X, Liang M, Liang YY, et al. Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4[J]. J Biol chem, 2003, 278(21): 18714-18719.
[11] Muro-Cacho CA, Rosario-Ortiz K, Livingston S, et al. Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2[J]. Clin Cancer Res, 2001, 7(6): 1618-1626.
[12] Schutte M, Hruban RH, Hedrick L, et al. DPC4 gene in various tumor types[J]. Cancer Res, 1996, 56(11): 2527-2530.
[13] Tanaka T, Watanabe T, Kazama Y, et al. Loss of Smad4 protein expression and 18qLOH as molecular markers indicating lymph node metastasis in colorectal cancer a study matched for tumor depth and pathology[J]. J Surg Oncol, 2008, 97(1): 69-73.
[14] Kim SK, Fan Y, Papadimitrakopoulou V, et al. DPC4, a candidate tumor suppression gene, is altered infrequently in head and neck squamous cell carcinoma[J]. Cancer Res, 1996, 56(11): 2519-2521.
[15] Deng H, Ravikumar TS, Yang WL. Overexpression of bone morphogenetic protein 4 enhances the invasiveness of Smad4-deficient human colorectal cancer cells[J]. Cancer Lett,2009,281(2): 220-231.
[16] 蔡传宝,陶学金,朱声荣,等. TGF-β1、Smad4和CyclinD1在口腔鳞癌中的表达和意义[J].口腔医学研究,2007,23(1):14-16.
[17] Inamoto S, Iwata S, Inamoto T, et al. Crk-associated substrate lymphocyte type regulates transforming growth factor-β signaling by inhibiting Smad6 and Smad7[J]. Oncogene, 2007, 26(6): 893-904.
[18] Kim YH, Lee HS, Lee HJ, et al. Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas[J]. Ann Oncol, 2004, 15(4): 574-580.
[19] Kleeff J, shiwata T, Maruyama H, et al. The TGF-β signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer[J]. Oncogene, 1999, 18(39): 5363-5372.