Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth
Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth
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DOI：
10.1152/ajpgi.00118.2011
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发表时间：
2011-10-01
影响因子：
4.5
通讯作者：
Alpini, Gianfranco
中科院分区：
文献类型：
--
作者：
Han, Yuyan;DeMorrow, Sharon;Alpini, Gianfranco
Han Y，DeMorrow S，Invernizzi P，Jing Q，Glaser S，Renzi A，Meng F，Venter J，Bernuzzi F，白色M，弗朗西斯H，Lleo A，Marzioni M，Onori P，Alvaro D，Torzilli G，Gaudio E，Alpini G.褪黑激素通过自分泌环在胆管癌中发挥抗增殖作用;其合成减少有利于胆管癌生长。美国生理学胃肠和肝脏生理学杂志301：G623-G633，2011年。首次发表于2011年7月21日; doi：10.1152/ajpgi.00118.2011。胆管癌（CCA）是一种毁灭性的胆道癌。褪黑激素在松果体和外周器官中由血清素通过两种酶合成，血清素N-乙酰转移酶（AANAT）和乙酰血清素O-甲基转移酶（ASMT）。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生长的降钙素。褪黑激素通过与褪黑激素受体1A/1B型（MT 1/MT 2）受体相互作用发挥其作用。我们提出：1）在CCA中，AANAT和ASMT的表达以及褪黑激素的分泌减少，这些变化刺激CCA生长; 2）体外过表达AANAT降低CCA生长。我们评估了1）AANAT、ASMT、褪黑激素和MT 1/MT 2在人非恶性和CCA系以及对照和CCA活检样品中的表达; 2）褪黑激素在非恶性和CCA系以及对照和肝内CCA患者的胆汁和血清中的水平; 3）褪黑激素对移植到裸鼠体内的CCA系的生长和AANAT/ASMT和MT 1/MT 2表达的影响; AANAT过表达对Mz-ChA-1细胞增殖、凋亡及MT 1/MT 2表达的影响。AANAT，ASMT和褪黑素的表达下降，而MT 1/MT 2的表达增加CCA线和活检样品。CCA细胞培养上清及CCA患者胆汁中褪黑素分泌减少。褪黑激素通过增加AANAT/ASMT和褪黑激素，沿着降低MT 1/MT 2表达，降低裸鼠异种移植CCA肿瘤生长。AANAT在Mz-ChA-1细胞中的过表达抑制增殖和MT 1/MT 2表达，并增加凋亡。CCA中存在AANAT/ASMT/褪黑素->褪黑素受体轴的失调，其抑制褪黑素分泌并随后促进CCA生长。
Han Y, DeMorrow S, Invernizzi P, Jing Q, Glaser S, Renzi A, Meng F, Venter J, Bernuzzi F, White M, Francis H, Lleo A, Marzioni M, Onori P, Alvaro D, Torzilli G, Gaudio E, Alpini G. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma; its synthesis is reduced favoring cholangiocarcinoma growth. Am J Physiol Gastrointest Liver Physiol 301: G623-G633, 2011. First published July 21, 2011; doi: 10.1152/ajpgi.00118.2011.-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.