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The transforming growth factor beta (TGF-beta) is a vital regulator of placental development and functions. TGF-beta exerts several modulatory effects on trophoblast cells, such as inhibition of proliferation and invasiveness, and stimulation of differentiation by inducing multinucleated cell formation. In this study, we determine the expression patterns of TGF-beta signaling molecules in normal trophoblast, various hydatidiform mole types and choriocarcinoma. A total of 132 cases, including 51 normal placenta (20 first trimester, 11 second trimester, and 20 third trimester) and 81 gestational trophoblastic diseases (17 choriocarcinoma, and 64 hydatidiform moles: 39 complete, 6 partial, and 19 invasive) were immunohistochemically analyzed with anti-TGF beta1/2, TGF-beta receptor type I (TbetaRI), TbetaRII, Smad 2/3, and Smad 4 antibodies on paraffin blocks. In the case of normal placenta, maximal levels of all TGF-beta signaling molecules were observed in villous trophoblast in the first trimester, which decreased with gestational age. Expression of all the TGF-beta signaling proteins except Smad2/3, was significantly enhanced in various moles, relative to normal trophoblast. Moreover, TGF-beta signaling molecules were significantly downregulated in choriocarcinoma, compared to moles. In particular, TbetaRI and Smad2/3 levels were lower in choriocarcinoma than normal villous trophoblast (TbetaRI: p0.025, Smad2/3: p0.001). In conclusion, the TGF-beta signaling pathway plays an important role in the pathogenesis and progression of gestational trophoblastic disease, and may thus be employed as a potential therapeutic target and a diagnostic biomarker.

Gallbladder carcinomas are rare but highly lethal neoplasms. We examined the expression of five cell-cycle-related molecules (p53, RB, cyclin D1, p27, Ki-67), and MSH2, in 46 carcinomas, 14 adenomas, 15 low-grade dysplasias, 9 intestinal metaplasias and 20 normal gallbladder epithelia. The expression of these molecules was altered in gallbladder carcinomas and adenomas. In gallbladder carcinomas we observed increased expression of p53, cyclin D1, Ki-67, and MSH2 together with decreased expression of RB and p27 protein. Aberrant expression of cyclin D1 and reduced expression of RB were noted in adenomas, and expression of cyclin D1 was elevated in low-grade dysplasias. However, there was no change in the levels of these cell-cycle molecules in metaplasia. Expression of p53, p27, Ki-67, and MSH2 was correlated with clinical stage (P0.05) and there was also a correlation between the expression of Ki-67 and MSH-2 and patient age (P0.05). These results suggest that altered expression of cell-cycle molecules p53, cyclin D1, RB, p27, and of MSH-2 is involved in the progression of gallbladder carcinomas.