Kleeff J, Ishiwata T, Friess H, Büchler M W, Korc M
Department of Medicine, University of California, Irvine 92697, USA.
Int J Cancer. 1998 Sep 11;77(6):860-8. doi: 10.1002/(sici)1097-0215(19980911)77:6<860::aid-ijc11>3.0.co;2-5.
Activins and inhibins belong to the transforming growth factor-beta (TGF-beta) superfamily of multifunctional cytokines that bind to transmembrane receptors with serine/threonine kinase activity. In this study, we characterized the levels of expression of 3 activin/inhibin subunits (betaA, betaB, alpha), and 2 type I and type II activin receptors (actRI/Ib, actRII/IIb) in pancreatic cancer cell lines and in human pancreatic tissues. In addition, we assessed the growth responsiveness to activin A in these cell lines. All 6 cell lines (ASPC-1, CAPAN-1, COLO-357, MIA-PaCa-2, PANC-1 and T3M4) expressed the activin/inhibin betaA subunit, whereas expression levels of the activin/inhibin betaB and alpha subunits were undetectable. Furthermore, actRI, actRII and actRIIb were expressed in all cell lines and actRIb mRNA was evident in ASPC-1, CAPAN-1, COLO-357 and PANC-1 cells. CAPAN-I and COLO-357 cells were growth-stimulated by activin A in the presence of 10% serum, whereas the other cell lines were resistant to activin A. In contrast, in serum-free medium activin A inhibited the growth of CAPAN-1, COLO-357 and MIA-PaCa-2 cells. Pancreatic cancer samples markedly over-expressed the activin/inhibin betaA subunit, whereas the betaB subunit was only moderately increased in comparison to normal pancreatic samples. Pancreatic cancer tissues also markedly over-expressed actRI, actRIb and actRII. By in situ hybridization, activin/inhibin betaA, actRI, actRIb and actRII were strongly expressed in diffuse infiltrative and duct-like cancer cells. Both the ligand and its receptors were often co-expressed in these cells. Together, our findings suggest that activin A may participate in autocrine activation of pancreatic cancer cells in vivo.
激活素和抑制素属于多功能细胞因子的转化生长因子-β（TGF-β）超家族，它们与具有丝氨酸/苏氨酸激酶活性的跨膜受体结合。在本研究中，我们对3种激活素/抑制素亚基（βA、βB、α）以及2种I型和II型激活素受体（激活素受体I/Ib、激活素受体II/IIb）在胰腺癌细胞系和人胰腺组织中的表达水平进行了表征。此外，我们评估了这些细胞系对激活素A的生长反应性。所有6种细胞系（ASPC-1、CAPAN-1、COLO-357、MIA-PaCa-2、PANC-1和T3M4）均表达激活素/抑制素βA亚基，而激活素/抑制素βB和α亚基的表达水平未检测到。此外，激活素受体I、激活素受体II和激活素受体IIb在所有细胞系中均有表达，激活素受体Ib mRNA在ASPC-1、CAPAN-1、COLO-357和PANC-1细胞中明显可见。在10%血清存在的情况下，激活素A刺激CAPAN-I和COLO-357细胞生长，而其他细胞系对激活素A具有抗性。相反，在无血清培养基中，激活素A抑制CAPAN-1、COLO-357和MIA-PaCa-2细胞的生长。胰腺癌样本中激活素/抑制素βA亚基明显过度表达，而与正常胰腺样本相比，βB亚基仅适度增加。胰腺癌组织中激活素受体I、激活素受体Ib和激活素受体II也明显过度表达。通过原位杂交，激活素/抑制素βA、激活素受体I、激活素受体Ib和激活素受体II在弥漫性浸润性和导管样癌细胞中强烈表达。配体及其受体在这些细胞中常共同表达。总之，我们的研究结果表明激活素A可能参与体内胰腺癌细胞的自分泌激活。
