Journal Article

Role of transforming growth factor α and prostaglandins in preferential growth of preneoplastic rat hepatocytes

Karin Hufnagl, Wolfram Parzefall, Brigitte Marian, Monika Käfer, Krystyna Bukowska, Rolf Schulte-Hermann and Bettina Grasl-Kraupp

in Carcinogenesis

Volume 22, issue 8, pages 1247-1256
Published in print August 2001 | ISSN: 0143-3334
Published online August 2001 | e-ISSN: 1460-2180 | DOI:
Role of transforming growth factor α and prostaglandins in preferential growth of preneoplastic rat hepatocytes

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The role of transforming growth factor α (TGFα) and prostaglandins (PGs) in the preferential growth of preneoplastic liver cells was studied. Rats received the genotoxic hepatocarcinogen N-nitrosomorpholine (NNM); placental glutathione S-transferase (GSTp) was used as a marker to identify preneoplastic foci. Preneoplastic foci expressing TGFα (TGFα+) grew more rapidly than TGFα negative (TGFα) ones. Almost all tumours studied were positive for TGFα. The key enzymes of prostaglandin synthesis, cyclooxygenase I (Cox-1) and II (Cox-2), were present in all unaltered and preneoplastic cells and tended to decrease in the later stages of hepatocarcinogenesis. Immunostaining revealed that cultures of hepatocytes, isolated from NNM-treated livers by collagenase perfusion, contained 1–2% GSTp-positive (GSTp+) and 9% TGFα+ hepatocytes; 0.6% of the cells were GSTp+/TGFα+. Cox-1 and Cox-2 were present in all cells. DNA replication was almost exclusively associated with expression of TGFα. GSTp+ hepatocytes showed a 3- to 4-fold higher probability of TGFα expression and of DNA synthesis than GSTp-negative (GSTp) cells. PGE2 or PGF increased expression of TGFα and DNA replication in GSTp cells but not in GSTp+ cells. PGA2 and PGJ2 decreased DNA synthesis in TGFα+ cells without an obvious effect on the intracellular levels of TGFα. The Cox-2 inhibitor SC236 suppressed DNA replication preferentially in GSTp+ cells; this inhibition was reversed by PGE2/F. Indomethacin had no effect. These results suggest the following conclusions. (i) Growth regulation of preneoplastic GSTp+ cells in culture exhibits distinct differences from GSTp cells and elevated expression of TGFα contributes to their growth advantage. (ii) TGFα renders preneoplastic hepatocytes sensitive to suppression of DNA synthesis by PGA2/J2. (iii) SC236, a Cox-2 inhibitor, may have preventive value in hepatocarcinogenesis.

Keywords: BSA, bovine serum albumin; Cox-1, cyclooxygenase type I; Cox-2, cyclooxygenase type II; DMSO, dimethylsulphoxide; EGF, epidermal growth factor; GSTp, placental glutathione S-transferase; GSTp–, hepatocytes negative for placental glutathione S-transferase; GSTp+, hepatocytes positive for placental glutathione S-transferase; LI, labelling index; NNM, N-nitrosomorpholine; PB, phenobarbital; PG, prostaglandin; PPARγ, peroxisome proliferator activated receptor γ; TBS, Tris-buffered saline; TGFα, transforming growth factor α; TGFα–, negative for transforming growth factor α; TGFα+, positive for transforming growth factor α.

Journal Article.  7437 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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