Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.
Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.
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DOI：
10.1016/j.jss.2013.07.001
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发表时间：
2014-01
影响因子：
2.2
通讯作者：
Feldstein, Ariel
中科院分区：
文献类型：
--
作者：
Bansal, Samiksha;Berk, Michael;Alkhouri, Naim;Partrick, David A.;Fung, John J.;Feldstein, Ariel
肝细胞癌通常被诊断为晚期，此时它无法接受手术切除或肝移植等积极治疗。目前的治疗方案只在一小部分病例中取得临床反应。因此，迫切需要有效的预防和治疗方法。脂代谢异常近来被认为与肝细胞癌的发病机制有关。本研究的目的是明确肝细胞中硬脂酰辅酶A去饱和酶(SCD)的细胞和分子机制，SCD是肝细胞中的限速酶和脂质平衡的基本调节因子，与肝癌的发生有关。收集肝癌组织和正常肝组织标本。人肝癌细胞株：HepG2、Hep3B和PLC/PLF/5用于免疫印迹、细胞存活率、增殖和凋亡检测。小干扰RNA用于遗传抑制，10，12共轭亚油酸用于药理抑制SCD。SCD在手术切除的肝癌(n=)和不同的人肝癌细胞系(HepG2、Hep3B和PLC/PLF/5)中有较强的表达。SCD水平与肿瘤分化程度呈负相关(P<；0.01)。用一组化疗药物处理这些肝癌细胞系，可导致时间依赖性的磷脂酰肌醇3激酶和c-jun氨基末端激酶1/2介导的SCD表达上调，这与对药物诱导的细胞凋亡的抵抗程度平行。特定的遗传或药物抑制SCD导致抑制细胞增殖(P<；0.001)，并显著增加对化疗诱导的细胞凋亡的敏感性。我们的研究结果提示，SCD的高表达在肝细胞癌的发生和对化疗诱导的细胞凋亡的抵抗中起着重要作用，这在一定程度上是通过磷脂酰肌醇3激酶/c-jun氨基末端激酶的激活来实现的。在肝细胞癌中特异性靶向阻断这一通路可能是设计新的治疗策略的理想方法。
Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC. HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition. SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2–mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis. Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.
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影响因子：
3.8
作者：
Schulze-Bergkamen H;Fleischer B;Schuchmann M;Weber A;Weinmann A;Krammer PH;Galle PR
通讯作者：
Galle PR
影响因子：
4.8
作者：
Li, Zheng Zheng;Berk, Michael;Feldstein, Ariel E.
通讯作者：
Feldstein, Ariel E.
影响因子：
3.5
作者：
Roder, Karim;Zhang, Lei;Schweizer, Michael
通讯作者：
Schweizer, Michael
影响因子：
4.8
作者：
Miyazaki, M;Kim, YC;Ntambi, JM
通讯作者：
Ntambi, JM
影响因子：
50.3
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
通讯作者：
Pasparakis, Manolis