Download PDF
Horm Metab Res 2006; 38(3): 159-166
DOI: 10.1055/s-2006-925185
Original Basic
© Georg Thieme Verlag KG Stuttgart · New York

Restoration of Transforming Growth Factor-β Type II Receptor Reduces Tumorigenicity in the Human Adrenocortical Carcinoma SW-13 Cell Line

N.  Yamamoto1 , J.  Imai2 , M.  Watanabe2 , N.  Hiroi1 , S.  Sugano2 , G.  Yoshino1
  • 1Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine
  • 2Laboratory of Genome Structure Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Further Information

Publication History

Received 21 July 2005

Accepted after revision 23 November 2005

Publication Date:
27 April 2006 (online)

Also available at
    Permissions and Reprints

Abstract

Transforming growth factor-β (TGF-β) is a potent growth suppressor. Acquisition of TGF-β resistance has been reported in many tumors, and has been associated with reduced TGF-β receptor expression. In this study, we examined TGF-β 1, TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII) expression in SW-13 adrenocortical carcinoma cells by Northern and Western blot analysis. SW-13 cells did not express TβRII mRNA or protein. We have investigated the role of TβRII in modulating tumorigenic potential using stably transfected SW-13 cells with TβRII expression plasmid. TβRII-positive SW-13 cell growth was inhibited by exogenous human TGF-β1 (hTGF-β1) in a dose-dependent manner. In contrast, SW-13 cells and control clones transfected with empty vector remained hTGF-β1-insensitive. Xenograft examination in athymic nude mice demonstrated that TβRII-positive SW-13 cells reduced tumor-forming activity. Reconstructing the TβRII can lead to reversion of the malignant phenotype of TβRII-negative human adrenocortical carcinoma, which contains SW-13 cells. Reduced TβRII expression may play a critical role in determining the malignant phenotype of human adrenocortical carcinoma.

Key words

Transforming growth factor-β (TGF-β) - TGF-β insensitivity - TGF-β type II receptor - adrenocortical carcinoma - cell proliferation

References

  • 1 Roberts A B, Sporn M B. Transforming growth factor β.  Adv Cancer Res. 1988;  51 107-145
    PubMedGoogle Scholar
  • 2 Moses H L, Yang E Y, Pietenpol J A. TGF-β stimulation and inhibition of cell proliferation: new mechanistic insights.  Cell. 1990;  63 245-247
    CrossrefPubMedGoogle Scholar
  • 3 Derynck R, Akhurst R J, Balmain A. TGF-β signaling in tumor suppression and cancer progression.  Nature Genet. 2001;  29 117-129
    CrossrefPubMedGoogle Scholar
  • 4 Massagué J, Blain S W, Lo R S. TGFβ signaling in growth control, cancer, and heritable disorders.  Cell. 2000;  103 295-309
    CrossrefPubMedGoogle Scholar
  • 5 Wrana J L, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang X F, Massagué J. TGF-β signals through heteromeric protein kinase receptor complex.  Cell. 1992;  71 1003-1014
    CrossrefPubMedGoogle Scholar
  • 6 Derynck R, Zhang Y, Feng X H. Smads: transcriptional activators of TGF-β responses.  Cell. 1998;  95 737-740
    CrossrefPubMedGoogle Scholar
  • 7 Massegué J. How cells read TGF-β signals.  Nature Rev Mol Cell Biol. 2000;  1 169-178
    PubMedGoogle Scholar
  • 8 Shi Y, Massegué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus.  Cell. 2003;  113 685-700
    CrossrefPubMedGoogle Scholar
  • 9 Howe P H, Draetta G, Leof E B. Transforming growth factor β1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.  Mol Cell Biol. 1991;  11 1185-1194
    PubMedGoogle Scholar
  • 10 Laiho M, De Caprio J A, Ludlow J W, Livingston D M, Massagué J. Growth inhibition by TGF-β linked to suppression of retinoblastoma protein phosphorylation.  Cell. 1990;  62 175-185
    CrossrefPubMedGoogle Scholar
  • 11 Vassilopoulou-Sellin R, Schultz P N. Adrenocortical carcinoma.  Cancer. 2001;  92 1113-1121
    CrossrefPubMedGoogle Scholar
  • 12 Reincke M, Karl M, Travis W H, Mastorakos G, Allolio B, Linehan H M, Chrousos G P. p53 mutations in human adrenocortical neoplasm: immunohistochemical and molecular studies.  J Clin Endocrinol Metab. 1994;  78 790-794
    CrossrefPubMedGoogle Scholar
  • 13 Weber M M, Fottner C, Wolf E. The role of the insulin-like growth factor system in adrenocortical tumorigenesis.  Eur J Clin Invest. 2000;  30 (Suppl. 3) 69-75
    CrossrefPubMedGoogle Scholar
  • 14 Feige J J, Cochet C, Savona C, Shi D L, Keramidas M, Defaye G, Chambaz E M. Transforming growth factor β1: an autocrine regulator of adrenocortical steroidogenesis.  Endocr Res. 1991;  17 267-279
    PubMedGoogle Scholar
  • 15 Stankovic A K, Dion L D, Parker C R Jr. Effects of transforming growth factor-β on human fetal adrenal steroid production.  Mol Cell Endocrinol. 1994;  99 145-151
    CrossrefPubMedGoogle Scholar
  • 16 Riopel L, Branchaud C L, Goodyer C G, Adkar V, Lefebvre Y. Growth-inhibitory effect of TGF-β on human fetal adrenal cells in primary monolayer culture.  J Cell Physiol. 1989;  140 233-238
    CrossrefPubMedGoogle Scholar
  • 17 Parker C R Jr, Stankovic A K, Harlin C, Carden L. Adrenocorticotropin interferes with transforming growth factor-β-induced growth inhibition of neocortical cells from the human fetal adrenal gland.  J Clin Endocrinol Metab. 1992;  75 1519-1521
    CrossrefPubMedGoogle Scholar
  • 18 Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbauth J, Fan R S, Zborowska E, Kinzler K W, Vogelstein B, Brattain M, Willson K V. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability.  Science. 1995;  268 1336-1338
    PubMedGoogle Scholar
  • 19 Park K, Kim S J, Bang Y J, Park J G, Kim N K, Roberts A B, Sporn M B. Genetic changes in the transforming growth factor β (TGF-β) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-β.  Proc Natl Acad Sci U S A. 1994;  91 8772-8776
    PubMedGoogle Scholar
  • 20 Yang H K, Kang S H, Kim Y S, Won K, Bang Y J, Kim S J. Truncation of the TGF-β type II receptor gene results in insensitivity to TGF-β in human gastric cancer cells.  Oncogene. 1999;  18 2213-2219
    CrossrefPubMedGoogle Scholar
  • 21 Vincent F, Hagiwara K, Ke Y, Stoner G D, Demetrick D J, Bennett W P. Mutation analysis of the transforming growth factor β type II receptor in sporadic human cancers of the pancreas, liver, and breast.  Biochem Biophys Res Commun. 1996;  223 561-564
    CrossrefPubMedGoogle Scholar
  • 22 Furuta K, Misao S, Takahashi K, Tagaya T, Fukuzawa Y, Ishikawa T, Yoshioka K, Kakumu S. Gene mutation of transforming growth factor β1 type II receptor in hepatocellular carcinoma.  Int J Cancer. 1999;  81 851-853
    CrossrefPubMedGoogle Scholar
  • 23 Tomita S, Deguchi S, Miyaguni T, Muto Y, Tamamoto T, Toda T. Analyses of microsatellite instability and the transforming growth factor-β receptor type II gene mutation in sporadic human breast cancer and their correlation with clinicopathological features.  Breast Cancer Res Treat. 1999;  53 33-39
    CrossrefPubMedGoogle Scholar
  • 24 Matoba H, Sugano S, Yamaguchi N, Miyachi Y. Expression of transforming growth factor-β1 and transforming growth factor-β type-II receptor mRNA in papillary thyroid carcinoma.  Horm Metab Res. 1998;  30 624-628
    PubMedGoogle Scholar
  • 25 Takada T, Iida K, Awaji T, Itoh K, Takahashi R, Shibui A, Yoshida K, Sugano S, Tujimoto G. Selective production of transgenic mice using green fluorescent protein as a marker.  Nat Biotechnol. 1997;  15 458-461
    PubMedGoogle Scholar
  • 26 Matzuk M M, Finegold M J, Mather J P, Krummen L, Lu H, Bradley A. Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice.  Proc Natl Acad Sci U S A.. 1994;  91 8817-8821
    PubMedGoogle Scholar
  • 27 Beuschlein F, Looyenga B D, Bleasdale S E, Mutch C, Bavers D L, Parlow A F, Nilson J H, Hammer G D. Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice.  Mol Cell Biol. 2003;  23 3951-3964
    CrossrefPubMedGoogle Scholar
  • 28 Arnaldi G, Freddi S, Mancini T, Kola B, Mantero F. Transforming growth factor β1: implications in adrenocortical tumorigenesis.  Endocr Res. 2000;  26 905-910
    PubMedGoogle Scholar
  • 29 Boccuzzi A, Terzolo M, Cappia S, De Giuli P, De Risi C, Leonardo E, Bovio S, Borriero M, Paccotti P, Angeli A. Different immunohistochemical patterns of TGF-β1 expression in benign and malignant adrenocortical tumours.  Clin Endocrinol (Oxf). 1999;  50 801-808
    CrossrefPubMedGoogle Scholar
  • 30 Le Roy C, Maisnier-Patin K, Leduque P, Li J Y, Saez J M, Langlois D. Overexpression of a dominant-negative type II TGFβ receptor tagged with green fluorescent protein inhibits the effects of TGFβ on cell growth and gene expression of mouse adrenal tumor cell line Y-1 and enhances cell tumorigenicity.  Mol Cell Endocrinol. 1999;  158 87-98
    CrossrefPubMedGoogle Scholar
  • 31 Sun L, Wu G, Willson J K, Zborowska E, Yang J, Rajkarunanayake I, Wang J, Gentry L E, Wang X F, Brattain M G. Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 Cells.  J Biol Chem. 1994;  269 26 449-26 455
    PubMedGoogle Scholar
  • 32 Chang J, Park K, Bang Y J, Kim W S, Kim D, Kim S J. Expression of transforming growth factor β type II receptor reduces tumorigenicity in human gastric cancer cells.  Cancer Res. 1997;  57 2856-2859
    PubMedGoogle Scholar
  • 33 Turco A, Coppa A, Aloe S, Baccheschi G, Morrone S, Zupi G, Colletta G. Overexpression of transforming growth factor β -type II receptor reduces tumorigenicity and metastastic potential of K-ras-transformed thyroid cells.  Int J Cancer. 1999;  80 85-91
    CrossrefPubMedGoogle Scholar
  • 34 Weiss L M, Medeiros L J, Vickery A L Jr. Pathologic features of prognostic significance in adrenocortical carcinoma.  Am J Surg Pathol. 1989;  13 202-206
    CrossrefPubMedGoogle Scholar
  • 35 Sasano H, Suzuki T, Moriya T. Discrening malignancy in resected adrenocortical neoplasms.  Endocr Pathol. 2001;  12 397-406
    CrossrefPubMedGoogle Scholar
  • 36 Wachenfeld C, Beuschlein F, Zwermann O, Mota P, Fassnacht M, Alloloi B, Reincke M. Discerning malignancy in adrenocortical tumors: are molecular makers useful?.  Eur J Endocrinol. 2001;  145 335-341
    CrossrefPubMedGoogle Scholar
  • 37 Miyajima A, Asano T, Seta K, Asano T, Kakoi N, Hayakawa M. Loss of expression of transforming growth factor-β receptor as a prognostic factor in patients with renal cell carcinoma.  Urology. 2003;  61 1072-1077
    CrossrefPubMedGoogle Scholar
  • 38 Kim I Y, Ahn H J, Lang S, Oefelein M G, Oyasu R, Kozlowski J M, Lee C. Loss of expression of transforming growth factor-β receptor is associated with poor prognosis in prostate cancer patients.  Clin Cancer Res. 1998;  4 1625-1630
    PubMedGoogle Scholar
  • 39 Muñoz-Antonia T, Li X, Reiss M, Jackson R, Antonia S. A mutation in the transforming growth factor β type II receptor gene promoter associated with loss of gene expression.  Cancer Res. 1996;  56 4831-4835
    PubMedGoogle Scholar
  • 40 Hahm K B, Cho K, Lee C, Im Y H, Chang J, Choi S G, Sorensen P H, Thiele C J, Kim S J. Repression of the gene encoding the TGF-β type II receptor is a major target of the EWS-FLI1 oncoprotein.  Nat Genet. 1999;  23 222-227
    CrossrefPubMedGoogle Scholar
  • 41 Yamamoto N. Reduced expression of transforming growth factor β type II receptor mRNA in the human adrenocortical carcinoma cell line SW-13.  J Med Soc Toho Univ. 2002;  49 336-346
    PubMedGoogle Scholar
  • 42 Vassilopoulou-Sellin R, Guinee V F, Klein M J, Taylor S H, Hess K R, Schultz P N, Samaan N A. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer.  Cancer. 1993;  71 3119-3123
    PubMedGoogle Scholar
  • 43 Bukowski R M, Wolfe M, Levine H S, Crawford D E, Stephens R L, Gaynor E, Harker W G. Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study.  J Clin Oncol. 1993;  11 161-165
    PubMedGoogle Scholar

Natsuko Yamamoto, M. D., Ph. D.

Division of Diabetes, Metabolism and Endocrinology · Department of Medicine · Toho University School of Medicine

6-11-1 Omorinishi · Ota-ku · Tokyo · 143-8541 Japan ·

Phone: +81 (3) 3762-4151/6565

Fax: +81 (3) 3765-6488

Email: n-yamamoto@med.toho-u.ac.jp