Division Research, Central Texas Veterans Health Care System, Tempe, USA.
Am J Physiol Gastrointest Liver Physiol. 2011 Oct;301(4):G623-33. doi: 10.1152/ajpgi.00118.2011. Epub 2011 Jul 21.
Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatonin → melatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth.
胆管癌（CCA）是一种具有破坏性的胆道恶性肿瘤。褪黑素由两种酶，即 5-羟色胺 N-乙酰转移酶（AANAT）和 5-羟色胺 O-甲基转移酶（ASMT），从 5-羟色胺在松果腺和外周器官中合成。胆管细胞分泌神经内分泌因子，包括通过自分泌机制调节 CCA 生长的 5-羟色胺。褪黑素通过与褪黑素受体 1A/1B（MT1/MT2）受体相互作用发挥作用。我们提出以下假设：1）在 CCA 中，AANAT 和 ASMT 的表达减少，褪黑素分泌增加，这些变化刺激 CCA 生长；2）体外过表达 AANAT 会降低 CCA 的生长。我们评估了 1）AANAT、ASMT、褪黑素和 MT1/MT2 在人非恶性和 CCA 细胞系以及对照和 CCA 活检样本中的表达；2）非恶性和 CCA 细胞系、对照和肝内 CCA 患者的胆汁和血清中的褪黑素水平；3）褪黑素对植入裸鼠的 CCA 细胞系生长和 AANAT/ASMT 和 MT1/MT2 表达的影响；4）AANAT 过表达对 Mz-ChA-1 细胞增殖、凋亡和 MT1/MT2 表达的影响。在 CCA 细胞系和活检样本中，AANAT、ASMT 和褪黑素的表达减少，而 MT1/MT2 的表达增加。CCA 细胞系上清液和 CCA 患者胆汁中的褪黑素分泌减少。褪黑素通过增加 AANAT/ASMT 和褪黑素，同时降低 MT1/MT2 表达，减少裸鼠异种移植物 CCA 肿瘤的生长。在 Mz-ChA-1 细胞中过表达 AANAT 可抑制增殖和 MT1/MT2 表达，增加凋亡。在 CCA 中，AANAT/ASMT/褪黑素→褪黑素受体轴的调节失调，抑制褪黑素分泌，随后增强 CCA 生长。
