Cancer Res Treat.  2005 Aug;37(4):228-232.

Expression of Maspin is associated with the Intestinal Type of Gastric Adenocarcinoma

• Kim SM
• Cho SJ
• Jang WY
• Kim DH
• Shin HS
• Jang MK
• Kim HY
• Nam ES

Abstract

PURPOSE
Maspin is known as a tumor suppressor gene, but its significance has been questioned in various human cancers. The aim of this study was to investigate the expression pattern of Maspin in human gastric adenocarcinomas and its possible correlation with clinicopathological findings. MATERIALS AND METHODS: The expression of Maspin mRNA was measured by nested RT-PCR using 60 frozen adenocarcinomas of the stomach and 31 noncancerous tissues from the proximal resection margin. Immunohistochemical study for Maspin protein expression was carried out using 62 paraffin-embedded tissues, composed of both cancer and noncancerous tissues. RESULTS: Maspin mRNA expression was detected in 80.0% (48 of 60) of the gastric adenocarcinomas, but in only 22.6% (7 of 31) of the normal gastric mucosa (p<0.001). The positive rate of Maspin protein expression was higher in the adenocarcinomas than the normal tissues (62.9% vs. 27.4%, p<0.05). In addition, the intestinal type of tumors showed significantly higher expression levels compared to the diffuse type of tumors (81.5% vs. 48.6%, p<0.05). CONCLUSION: Our results suggest that Maspin is frequently expressed in human gastric cancers, and its expression might be associated with tumorigenesis of the intestinal type of gastric cancer.

Keyword

Maspin; Gastric adenocarcinoma; Nested RT-PCR; Immunohistochemistry

MeSH Terms

Adenocarcinoma*
Carcinogenesis
Gastric Mucosa
Genes, Tumor Suppressor
Humans
Immunohistochemistry
RNA, Messenger
Stomach
Stomach Neoplasms
RNA, Messenger

Figure

• 

  Fig. 1 Expressions of maspin mRNA in normal gastric mucosa (lane 1~4) and gastric adenocarcinoma tissues (lane 5~9) using nested RT-PCR. One normal gastric mucosa (lane 4) was weakly positive. GADPH was used as an internal control.

• 

  Fig. 2 The expression of Maspin mRNA in human gastric cancer cell lines using nested RT-PCR. Maspin mRNA expression was shown in all of four human gastric cancer cell lines, SNU-719, SNU-484, SNU-620 and MKN-74. The expression of GADPH mRNA was used as an internal control.

• 

  Fig. 3 Immunohistochemical staining for Maspin in gastric adenocarcinomas. (A) Maspin was strongly expressed in the intestinal type (arrow). No staining was seen in normal non-metaplastic gastric mucosa (arrow head). Immunohistochemical stain, original magnification ×100. (B) Maspin was negative in the diffuse type of gastric adenocarcinoma (arrow). Maspin immunostaining was observed in the intestinal metaplastic epithelium (arrow head). Immunohistochemical stain, original magnification ×100.

Reference

1. Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, et al. Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science. 1994; 263:526–529. PMID: 8290962.

2. Schneider SS, Schick C, Fish KE, Miller E, Pena JC, Treter SD, et al. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc Natl Acad Sci USA. 1995; 92:3147–3151. PMID: 7724531.

3. Zhang M, Maass N, Magit D, Sager R. Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. Cell Growth Differ. 1997; 8:179–186. PMID: 9040939.

4. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci USA. 1996; 93:11669–11674. PMID: 8876194.

5. Sheng S, Pemberton PA, Sager R. Production, purification, and characterization of recombinant maspin proteins. J Biol Chem. 1994; 269:30988–30993. PMID: 7983035.

6. Sheng S, Truong B, Fredrickson D, Wu R, Pardee AB, Sager R. Tissue-type plasminogen activator is a target of the tumor suppressor gene maspin. Proc Natl Acad Sci USA. 1998; 95:499–504. PMID: 9435220.

7. Maass N, Hojo T, Ueding M, Luttges J, Kloppel G, Jonat W, et al. Expression of the tumor suppressor gene Maspin in human pancreatic cancers. Clin Cancer Res. 2001; 7:812–817. PMID: 11309327.

8. Lim YJ, Lee JK, Jang WY, Song SY, Lee KT, Paik SW, et al. Prognostic significance of maspin in pancreatic ductal adeno carcinoma. Korean J Intern Med. 2004; 19:15–18. PMID: 15053038.

9. Sood AK, Fletcher MS, Gruman LM, Coffin JE, Jabbari S, Khalkhali-Ellis Z, et al. The paradoxical expression of maspin in ovarian carcinoma. Clin Cancer Res. 2002; 8:2924–2932. PMID: 12231537.

10. Ogasawara S, Maesawa C, Yamamoto M, Akiyama Y, Wada K, Fujisawa K, et al. Disruption of cell-type-specific methylation at the Maspin gene promoter is frequently involved in undifferentiated thyroid cancers. Oncogene. 2004; 23:1117–1124. PMID: 14743202.

11. Umekita Y, Ohi Y, Sagara Y, Yoshida H. Expression of maspin predicts poor prognosis in breast-cancer patients. Int J Cancer. 2002; 100:452–455. PMID: 12115529.

12. Wada K, Maesawa C, Akasaka T, Masuda T. Aberrant expression of the maspin gene associated with epigenetic modification in melanoma cells. J Invest Dermatol. 2004; 122:805–811. PMID: 15086568.

13. Umekita Y, Yoshida H. Expression of maspin is up-regulated during the progression of mammary ductal carcinoma. Histopathology. 2003; 42:541–545. PMID: 12786889.

14. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, et al. Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet. 2002; 31:175–179. PMID: 12021783.

15. Akiyama Y, Maesawa C, Ogasawara S, Terashima M, Masuda T. Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Am J Pathol. 2003; 163:1911–1919. PMID: 14578190.

16. Son HJ, Sohn TS, Song SY, Lee JH, Rhee JC. Maspin expression in human gastric adenocarcinoma. Pathol Int. 2002; 52:508–513. PMID: 12366809.

17. Terashima M, Maesawa C, Oyama K, Ohtani S, Akiyama Y, Ogasawara S, et al. Gene expression profiles in human gastric cancer: expression of maspin correlates with lymph node metastasis. Br J Cancer. 2005; 92:1130–1136. PMID: 15770218.

18. Wang MC, Yang YM, Li XH, Dong F, Li Y. Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer. World J Gastroenterol. 2004; 10:634–637. PMID: 14991928.

19. Fleming I, Cooper J, Henson D. Stomach. AJCC cancer staging manual. 1997. 5th ed. Philadelphia: Lippincott-Raven;p. 71–76.

20. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965; 64:31–49. PMID: 14320675.

21. Song SY, Lee SK, Kim DH, Son HJ, Kim HJ, Lim YJ, et al. Expression of maspin in colon cancers: its relationship with p53 expression and microvessel density. Dig Dis Sci. 2002; 47:1831–1835. PMID: 12184537.

22. Yin T, Ji XL, Shen MS. Relationship between lymph node sinuses with blood and lymphatic metastasis of gastric cancer. World J Gastroenterol. 2003; 9:40–43. PMID: 12508348.

23. Xin Y, Li XL, Wang YP, Zhang SM, Zheng HC, Wu DY, et al. Relationship between phenotypes of cell-function differentiation and pathobiological behavior of gastric carcinomas. World J Gastroenterol. 2001; 7:53–59. PMID: 11819733.

24. Correa P. Human gastic carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992; 52:6735–6740. PMID: 1458460.

25. Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, et al. Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 2004; 64:7740–7747. PMID: 15520178.