상피성 난소암에서 면역반응성 렙틴 (Leptin)과 그 수용체의 발현 = Expression of immunoreactive Leptin and its receptor in epithelial ovarian cancer

다국어 초록 (Multilingual Abstract)

Objective: Leptin, a secreted protein of the Ob gene by white adipose tissue, plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic breast cancer cells. However, a potential role of leptin as an endocrine regulator is unknown in ovarian cancer. In the present study, we investigated the expression of leptin and its receptors in various histologic types of ovarian cancer and immortalized ovarian cancer cell lines to find out potential effect of leptin on the cell growth and activation of ovarian cancer cell line. Methods: The ovarian cancer tissues, serous (n=18), mucinous (n=15), clear cell (n=12) and endometrioid type (n=14), were used for immuno-histochemical staining for leptin (Ob) and leptin-receptors (Ob -R). Ovrian cancer cell lines (non-mucinous: SNU-8, OVCAR-3, and SKOV-3) and mucinous: MUC) were used for RT-PCR, Western blot analysis, and [H3] thymidine incorporation assay for the cell growth and activation of mitogen-activated protein kinase. Results: Both long (Ob-Rb) and short (Ob-Rt) isoforms of leptin receptors are expressed in non-mucinous type of ovarian cancer tissues (serous, clear cell carcinoma and endometrioid cell carcinoma) and in non-mucinous ovarian cancer cell lines (SNU-8, OVCAR-3 and SKOV-3 cells). However, leptin and its receptors are not found in mucinous cancer cells and mucinous cancer cell line (MUC). In immunohistochemical staining, the immunreactive leptin is expressed on the nuclei of the stratified cuboidal-to-columnar epithelial cells whereas its receptor was sparsely expressed on the innermost epithelial cell clusters and cytoplasm in non-mucinous tumor. However, there are no immunoreactive leptin and its receptor expressions in the mucinous tumor. In addition, treatment with leptin resulted in the growth stimulation of ovarian cancer cell line, an activation of ERK 1/2 and inhibition of constitutive phosphorylation of p38 Mitogen-activated protein kinase (MAPK). Conclusion: Taken together, our data demonstrates preliminary that the expression of leptin and its receptor is different according to the cell types of the ovarian cancer. Also it canbe thought that leptin immunolocalized on the nuclei in non-mucinous type but not in mucinous possibly acts as a nuclear transcription factor. Further studies are necessary to validate whether leptin may be a potential regulator for ovarian cancer.

참고문헌 (Reference)

1 Cleary MP, "The rule of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer" 216 : 28-43, 1997

2 Tartaglia LA, "The leptin receptor" 272 : 6093-6096, 1997

3 Baumann H, "The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors" 93 : 8374-8378, 1996

4 Cioffi JA, "The expression of leptin and its receptors in pre-ovulatory human follicles" 3 : 467-472, 1997

5 Senaris R, "Synthesis of leptin in human placenta" 138 : 4501-4504, 1997

6 Lebrecht A, "Serum vascular endothelial growth factor and serum leptin in patients with cervical cancer" 85 : 32-35, 2002

7 Kitawaki J, "Progesterone inhibition of functional leptin receptor mRNA expression in human endometrium" 7 : 567-572, 2001

8 Zhang Y, "Positional cloning of the mouse obese gene and its human homologue" 372 : 425-432, 1994

9 Mink PJ, "Physical activity, waist-to-hip ratio, and other risk factors for ovarian cancer: A follow-up study of older women" 7 : 38-45, 1996

10 Bergstrom A, "Overweight as an avoidable cause of cancer in Europe" 91 : 421-430, 2001

11 Carroll K, "Obesity as a risk factor for certain types of cancer" 33 : 1055-1059, 1998

12 Calle EE, "Obesity and cancer" 23 : 6365-6378, 2004

13 Masuzaki H, "Nonadipose tissue production of leptin: leptin as a novel placentaderived hormone in humans" 3 : 1029-1033, 1997

14 Hu X, "Leptin —A growth factor in normal and malignant breast cells and for normal mammary gland development" 94 : 1704-1711, 2002

15 Dieudonne MN, "Leptin mediates a proliferative response in human MCF7 breast cancer cells" 293 : 622-628, 2002

16 Caprio M, "Leptin in reproduction" 12 : 65-72, 2001

17 Smith-Kirwin SM, "Leptin expression in human mammary epithelial cells and breast milk" 83 : 1810-1813, 1998

18 Catalano S, "Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line" 278 : 28668-28676, 2003

19 Fiedman JM, "Leptin and the regulation of body weight in mammals" 395 : 763-770, 1998

20 Moschos S, "Leptin and reproduction: a review" 77 : 433-444, 2002

21 Gonzalez RR, "Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst" 85 : 4883-4888, 2000

22 Garofalo C, "Leptin and cancer" 207 : 12-22, 2006

23 Petridou E, "Leptin and body mass index in relation to endometrial cancer risk" 46 : 147-151, 2002

24 Vaisse C, "Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice" 14 : 95-97, 1996

25 Neville MC, "Hormonal regulation of mammary differentiation and milk secretion" 7 : 49-66, 2002

26 World Cancer Research Fund, "Food, nutrition, and the prevention of cancer: a global perspective" The Institute 371-373, 1997

27 Willett WC, "Fat, energy and breast cancer" 127 (127): 921S-923S, 1997

28 Henson MC, "Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term" 92 : 1020-1028, 1998

29 Choi JH, "Expression of leptin receptors and potential effects of leptin on the cell growth and activation of mitogen-activated protein kinases in ovarian cancer cells" 90 : 207-210, 2005

30 Kitawaki J, "Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle" 85 : 1946-1950, 2000

31 Karlsson C, "Expression of functional leptin receptors in the human ovary" 82 : 4144-4148, 1997

32 Bjorbaek C, "Divergent signaling capacities of the long and short isoforms of the leptin receptor" 272 : 32686-32695, 1997

33 Somasundar P, "Differential effects of leptin on cancer in vitro" 113 : 50-55, 2003

34 Ghilardi N, "Defective STAT signaling by the leptin receptor in diabetic mice" 93 : 6231-6235, 1996

35 Peto J, "Cancer epidemiology in the last century and the next decade" 411 : 390-395, 2001

36 Dal Maso L, "Body size indices at different ages and epithelial ovarian cancer risk" 38 : 1769-1774, 2002

37 Purdie DM, "Body size and ovarian cancer: Case-control study and systematic review (Australia)" 12 : 855-863, 2001

38 Galanis DJ, "Anthropometric predictors of breast cancer incidence and survival in a multi-ethnic cohort of female residents of Hawaii, United States" 9 : 217-224, 1998

39 Yuan SS, "Aberrant expression and possible involvement of the leptin receptor in endometrial cancer" 92 : 769-775, 2004