생명과학회지 (Journal of Life Science)

  • 제21권4호
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  • Pages.529-533
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  • 2011
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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악성 단계별 인간 전립선 암세포에서 라미닌에 의한 metallothionein 유전자 발현유도 현상 연구

Induction of Metallothionein Gene by Laminin in Normal and Malignant Human Prostate Epithelial Cells

  • 옥미선 (고신대학교 의과대학 기생충학 유전학 교실) ;
  • 차희재 (고신대학교 의과대학 기생충학 유전학 교실)
  • Ock, Mee-Sun (Department of Parasitology and Gnenetics, Kosin University College of Medicine) ;
  • Cha, Hee-Jae (Department of Parasitology and Gnenetics, Kosin University College of Medicine)
  • 투고 : 2010.12.23
  • 심사 : 2010.12.30
  • 발행 : 2011.04.30
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초록

라미닌-1에 의해 분화가 유도되는 것으로 알려져 있는 HSG 및 PC-12에서는 라미닌-1에 의해 MT 유전자의 발현이 유도되었지만 반면 분화 역량을 지니지 않은 암세포인 유방암(MDA-231, MDA-435) 세포와 전립선 암인 PC-3 세포에서는 라미닌-1의 처리가 MT 유전자의 변화에 영향을 미치지 못하는 것이 관찰되었다. 라미닌-1에 의해 분화가 유도되는 현상 및 이에 따른 MT 유전자의 발현증가가 암의 전이 능력 및 악성화와 관계가 있는지를 관찰하기 위해 정상에서부터 전이 및 악성 정도가 다른 5가지 종류의 전립선 암을 대상으로 라미닌-1에 의한 MT 유전자의 발현 변화를 관찰한 결과 정상적인 전립선 외피세포인 RWPE-1과 전이 및 악성화가 낮은 WPE1-NA22의 경우 라미닌-1에 의해 MT 유전자의 발현이 증가하였으며, 악성화 정도가 높은 WPE1-NB14, WPE1-NB11, 및 WPE1-NB26에서는 라미닌-1의 처리에도 MT 유전자의 발현이 증가하지 않는 것이 관찰되었다. 이러한 결과를 통해 라미닌-1은 정상 세포의 분화를 유도하며 이에 따라 MT 유전자를 유도하며 분화가 유도되지 않는 악성 암에서는 MT 유전자의 발현이 유도되지 않는 것으로 확인되었다.

Metallothioneins (MT) are a group of low-molecular weight, cysteine-rich, intracellular proteins that are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins is associated with protection against DNA damage, oxidative stress, and apoptosis. Many studies have shown increased expression of MT in various human tumors, whereas MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. Using Northern blot analysis, we found that laminin induced expression of MT-1 in HSG and PC12 cells, which can be differentiated by laminin, but had no effect on MB-231, MDA-435, and PC-3 cells, which cannot be differentiated by laminin. In addition, we analyzed the expression level of the MT-1 gene in five prostate cancer cell lines possessing different metastatic potential. The expression of MT-1 in normal and less malignant cells (RWPE-1 and WPE1-NA22) was high and up-regulated by laminin, whereas the expression of MT-1 in WPE1-NB14, WPE1-NB11, and WPE1-NB26 cells (malignant) was extremely low and not elevated by laminin. These results suggest that the MT-1 gene is involved in laminin-mediated differentiation and affects the metastatic potential of tumor cells.

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참고문헌

  1. Alimirah, F., J. Chen, Z. Basrawala, H. Xin, and D. Choubey. 2006. DU-145 and PC-3 human prostate cancer cell lines express androgen receptor: implications for the androgen receptor functions and regulation. FEBS Lett. 580, 2294-2300. https://doi.org/10.1016/j.febslet.2006.03.041
  2. Andrews, G. K., E. D. Adamson, and L. Gedamu. 1984. The ontogeny of expression of murine metallothionein: comparison with the alpha-fetoprotein gene. Dev. Biol. 103, 294-303. https://doi.org/10.1016/0012-1606(84)90317-8
  3. Bello-DeOcampo, D., H. K. Kleinman, N. D. Deocampo, and M. M. Webber. 2001. Laminin-1 and alpha6beta1 integrin regulate acinar morphogenesis of normal and malignant human prostate epithelial cells. Prostate 46, 142-153. https://doi.org/10.1002/1097-0045(20010201)46:2<142::AID-PROS1018>3.0.CO;2-B
  4. Bello, D., M. M. Webber, H. K. Kleinman, D. D. Wartinger, and J. S. Rhim. 1997. Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. Carcinogenesis 18, 1215-1223. https://doi.org/10.1093/carcin/18.6.1215
  5. Cha, H. J., M. J. Jeong, and H. K. Kleinman. 2003. Role of thymosin beta4 in tumor metastasis and angiogenesis. J. Natl. Cancer Inst. 95, 1674-1680. https://doi.org/10.1093/jnci/djg100
  6. Cherian, M. G., A. Jayasurya, and B. H. Bay. 2003. Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat. Res. 533, 201-209. https://doi.org/10.1016/j.mrfmmm.2003.07.013
  7. Clarkson, J. P., M. E. Elmes, B. Jasani, and M. Webb. 1985. Histological demonstration of immunoreactive zinc metallothionein in liver and ileum of rat and man. Histochem. J. 17, 343-352. https://doi.org/10.1007/BF01004596
  8. Colognato, H. and P. D. Yurchenco. 2000. Form and function: the laminin family of heterotrimers. Dev. Dyn. 218, 213-234. https://doi.org/10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R
  9. Danielson, K. G., S. Ohi, and P. C. Huang. 1982. Immunochemical detection of metallothionein in specific epithelial cells of rat organs. Proc. Natl. Acad. Sci. USA 79, 2301-2304. https://doi.org/10.1073/pnas.79.7.2301
  10. Graner, E., A. F. Mercadante, S. M. Zanata, V. R. Martins, D. G. Jay, and R. R. Brentani. 2000. Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett. 482, 257-260. https://doi.org/10.1016/S0014-5793(00)02070-6
  11. Hecht, D., D. Jung, V. V. Prabhu, P. J. Munson, M. P. Hoffman, and H. K. Kleinman. 2002. Metallothionein promotes laminin-1-induced acinar differentiation in vitro and reduces tumor growth in vivo. Cancer Res. 62, 5370-5374.
  12. Hoffman, M. P., M. C. Kibbey, J. J. Letterio, and H. K. Kleinman. 1996. Role of laminin-1 and TGF-beta 3 in acinar differentiation of a human submandibular gland cell line (HSG). J. Cell Sci. 109, 2013-2021.
  13. Hoffman, M. P., M. Nomizu, E. Roque, S. Lee, D. W. Jung, Y. Yamada, and H. K. Kleinman. 1998. Laminin-1 and laminin-2 G-domain synthetic peptides bind syndecan-1 and are involved in acinar formation of a human submandibular gland cell line. J. Biol. Chem. 273, 28633-28641. https://doi.org/10.1074/jbc.273.44.28633
  14. Kleinman, H. K., M. L. McGarvey, J. R. Hassell, V. L. Star, F. B. Cannon, G. W. Laurie, and G. R. Martin. 1986. Basement membrane complexes with biological activity. Biochemistry 25, 312-318. https://doi.org/10.1021/bi00350a005
  15. Kleinman, H. K., M. L. McGarvey, L. A. Liotta, P. G. Robey, K. Tryggvason, and G. R. Martin. 1982. Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. Biochemistry 21, 6188-6193. https://doi.org/10.1021/bi00267a025
  16. Lee, J. H. and D. R. Welch. 1997. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res. 57, 2384-2387.
  17. Lichtlen, P. and W. Schaffner. 2001. Putting its fingers on stressful situations: the heavy metal-regulatory transcription factor MTF-1. Bioessays 23, 1010-1017. https://doi.org/10.1002/bies.1146
  18. Malinda, K. M. and H. K. Kleinman. 1996. The laminins. Int. J. Biochem. Cell Biol. 28, 957-959. https://doi.org/10.1016/1357-2725(96)00042-8
  19. Nartey, N., M. G. Cherian, and D. Banerjee. 1987. Immunohistochemical localization of metallothionein in human thyroid tumors. Am. J. Pathol. 129, 177-182.
  20. Nishimura, H., N. Nishimura, and C. Tohyama. 1989. Immunohistochemical localization of metallothionein in developing rat tissues. J. Histochem. Cytochem. 37, 715-722. https://doi.org/10.1177/37.5.2703706
  21. Shirasuna, K., M. Sato, and T. Miyazaki. 1981. A neoplastic epithelial duct cell line established from an irradiated human salivary gland. Cancer 48, 745-752. https://doi.org/10.1002/1097-0142(19810801)48:3<745::AID-CNCR2820480314>3.0.CO;2-7
  22. Timpl, R. and J. C. Brown. 1994. The laminins. Matrix Biol. 14, 275-281. https://doi.org/10.1016/0945-053X(94)90192-9
  23. Timpl, R., H. Rohde, P. G. Robey, S. I. Rennard, J. M. Foidart, and G. R. Martin. 1979. Laminin--a glycoprotein from basement membranes. J. Biol. Chem. 254, 9933-9937.
  24. Weaver, V. M., A. H. Fischer, O. W. Peterson, and M. J. Bissell. 1996. The importance of the microenvironment in breast cancer progression: recapitulation of mammary tumorigenesis using a unique human mammary epithelial cell model and a three-dimensional culture assay. Biochem. Cell Biol. 74, 833-851. https://doi.org/10.1139/o96-089
  25. Webber, M. M., D. Bello, H. K. Kleinman, and M. P. Hoffman. 1997. Acinar differentiation by non-malignant immortalized human prostatic epithelial cells and its loss by malignant cells. Carcinogenesis 18, 1225-1231. https://doi.org/10.1093/carcin/18.6.1225
  26. Zeng, J., B. L. Vallee, and J. H. Kagi. 1991. Zinc transfer from transcription factor IIIA fingers to thionein clusters. Proc. Natl. Acad. Sci. USA 88, 9984-9988. https://doi.org/10.1073/pnas.88.22.9984