Riehle Kimberly J, Kenerson Heidi L, Riggle Kevin M, Turnham Rigney, Sullivan Kevin, Bauer Renay, Scott John D, Yeung Raymond S
Department of Surgery, University of Washington, Seattle, WA, USA.
Department of Pharmacology, University of Washington, Seattle, WA, USA.
Oncotarget. 2019 Aug 20;10(49):5092-5102. doi: 10.18632/oncotarget.27149.
Fibrolamellar hepatocellular carcinomas (FL-HCCs) possess a unique mutation that encodes a chimeric form of protein kinase A (DNAJ-PKAc), which includes a chaperonin binding domain. DNAJ-PKAc retains most of the biochemical properties of the native enzyme, however, and activity remains dependent on cAMP. We thus speculated that a persistent source of cAMP is necessary to promote FL-HCC carcinogenesis, and that neurotensin (NTS) may drive cAMP production in this setting, given that NS serum and tumor levels are elevated in many patients with FL-HCC. We examined expression of NTS pathway components in human FL-HCCs and paired normal livers, and determined the role of NTS in driving proliferation in tumor slice cultures. Cultured hepatocytes were used to determine interactions between NTS and other proliferative pathways, and to determine the effects of NTS on cAMP production and PKA activity. We found that the NTS pathway is up-regulated in human FL-HCCs, and that NTS activates cAMP and PKA in hepatocytes. NTS increases proliferation in the presence of epidermal growth factor (EGF), and NTS-induced proliferation is dependent on NTSR1 and the EGFR/MEK pathway. We conclude that NTS serves as a co-mitogen in FL-HCC, and provides a source of cAMP to facilitate ongoing activation of DNAJ-PKAc.
纤维板层型肝细胞癌（FL - HCC）具有一种独特的突变，该突变编码一种蛋白激酶A的嵌合形式（DNAJ - PKAc），其中包含一个伴侣蛋白结合结构域。然而，DNAJ - PKAc保留了天然酶的大部分生化特性，其活性仍然依赖于cAMP。因此，我们推测持续的cAMP来源对于促进FL - HCC的癌变是必要的，并且鉴于许多FL - HCC患者血清和肿瘤中的神经降压素（NTS）水平升高，神经降压素可能在此情况下驱动cAMP的产生。我们检测了人FL - HCC及其配对的正常肝脏中NTS信号通路成分的表达，并确定了NTS在肿瘤切片培养中驱动细胞增殖的作用。使用培养的肝细胞来确定NTS与其他增殖信号通路之间的相互作用，并确定NTS对cAMP产生和PKA活性的影响。我们发现NTS信号通路在人FL - HCC中上调，并且NTS在肝细胞中激活cAMP和PKA。在表皮生长因子（EGF）存在的情况下，NTS增加细胞增殖，并且NTS诱导的增殖依赖于NTSR1和EGFR/MEK信号通路。我们得出结论，NTS在FL - HCC中作为一种协同促有丝分裂原，并提供cAMP来源以促进DNAJ - PKAc的持续激活。
