微小RNA调控肝细胞癌索拉非尼耐药的分子机制北大核心CSCD

肝细胞癌是全球最致命的恶性肿瘤之一,侵袭性强,治愈率低,转移率高,预后极差。索拉非尼是治疗晚期肝细胞癌最主要且有效的一线治疗药物,但原发和获得性耐药,严重限制其临床疗效。微小RNA是一种小非编码RNA,在肝细胞癌的发生、发展,以及索拉非尼耐药进展中扮演着关键的调控角色。该文总结了微小RNA在肝细胞癌索拉非尼耐药的起始和发展中的作用,旨在进一步了解索拉非尼抗肝癌的机制,并为肝细胞癌的临床靶向治疗,及预后改善提供有价值的理论依据。     

雄激素及其受体在肝细胞癌中的研究进展

肝细胞癌是最常见的原发性肝癌,也是激素敏感性肿瘤之一。在人类及啮齿类动物中肝癌发生均表现出一定的性别差异。这种差异可能与性激素有关,雄激素受体对肝癌发生、进展、转移具有一定的作用。本文阐述了雄激素受体与肝癌发生、进展、转移的关系及其可能的分子机制。雄激素受体可作为肝癌个性化治疗的一个潜在靶标,辅助现有治疗药物或为临床诊断、预后评估、肿瘤分级提供理论参考。     

索拉非尼引起移植肝肝功能异常1例

[摘要]索拉非尼是近年来研制的一个口服多靶点抗肿瘤药物,它可显著延长晚期肝细胞癌患者生存时间,但其对肝功能是否有影响尚不清楚。给予索拉非尼治疗1例原发性肝细胞癌行肝移植术后11个月出现双肺转移的患者,服用索拉非尼3个月后肺内转移灶数目减少、体积缩小,但服药2周后患者转氨酶开始持续升高,此期间胆红素水平正常,无巨细胞病毒感染及乙肝活动证据。肝组织学检查见类似急性排斥反应表现。停用索拉非尼后转氨酶开始下降,3周后恢复正常。提示索拉非尼可抑制肺转移性肝癌的生长,但可能导致移植肝肝功能的损害。     

热休克转录因子1在肝细胞癌中的表达及意义

目的:用半定量逆转录聚合酶链反应(RT-PCR)方法显示肝癌组织中热休克转录因子1(HSF1)的表达情况,探讨HSF1在肝细胞癌中的表达及意义.方法:收集肝癌患者40 例手术肝癌标本及相应的癌旁组织作为对照.采用半定量逆转录聚合酶链反应(RT-PCR)方法检测肝癌标本及相应的癌旁组织HSF1的表达,分析比较它们分别在肝癌标本及相应癌旁组织的表达情况及其与肝癌临床和病理特征的关系.结果:肝细胞癌肿瘤组织HSF1 mRNA表达显著高于癌旁组织,但HSF1表达水平与患者的性别、年龄、肿瘤大小、包膜的完整与否、分级、癌栓形成及血清AFP水平未见明显相关性(P＞0.05).结论:HSF1在肝癌组织中的表达显著高于癌旁组织,HSF1可能与PHC的发生密切相关.进一步探讨HSF1在PHC中的表达机制,有望为原发性肝癌的临床诊断与治疗提供依据.     

肝细胞癌组织中 IL-18BPc 和 VEGF 的表达及与肿瘤血管形成的关系

目的 探讨IL-18BPc和VEGF在原发性肝细胞癌组织中的表达及其与肿瘤血管形成之间的关系。方法 应用免疫组织化学SP法检测IL-18BPc和VEGF在34例肝细胞癌组织、34例癌旁肝组织及12例正常肝组织的表达,通过CD34免疫组织化学染色评价肿瘤组织MVD值,分析IL-18BPc表达与VEGF表达及MVD的关系。结果 IL-18BPc在肝癌组织中的表达阳性率高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01),且肝癌出现侵袭转移者较未出现侵袭转移者其IL-18BPc表达阳性率高(P＜0.01);VEGF在肝癌组织中的表达高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01);IL-18BPc和VEGF在肝细胞癌中表达呈正相关(r=0.357, P=0.037);肝癌组织MVD值与高于癌旁肝组织(P＜0.01)及正常肝组织(P＜0.01);肝癌组织中, IL-18BPc阳性表达者MVD值高于阴性表达者(P=0.004)。结论 IL-18BPc可能通过上调VEGF的表达促进肝细胞癌血管形成。     

TRAIL、TRAIL-R在原发性肝癌及其癌旁组织中的表达

目的 检测肿瘤坏死因子相关凋亡诱导配体（TRAIL）及其受体在原发性肝癌（PHC）及癌旁组织中的表达。方法 收集PHC及癌旁组织各30例，采用半定量RT-PCR方法，对TRAIL及其受体的表达作半定量检测。结果 （1）30例痈组织度癌旁组织中均有TRAIL及其死亡受体4（DR4）、死亡受体5（DR5）、“诱骗”受体1，2（DcR1、DeR2）的表达。（2）TRAIL、DcR1及DcR2在癌组织中的表达量较之癌旁组织明显降低（P〈0．01），而DR4、DR5的表达量则高于癌旁组织；（3）PHC组织中4种受体之间，DR4及DR5的表达量明显高于DcR1及DcR2，且PHC组织中4种受体间的表达量存在相关性。结论 PHC及其癌旁组织中均存在TRAIL及其受体的表达，且有表达量的差异。     

ICAM-1和VEGF在原发性肝细胞癌中的表达及其临床意义

目的探讨血管内皮生长因子（Vascular endothelial growth factor，VEGF）和细胞间粘附分子-1（Intercellular adhesion molecule，ICAM-1）的表达与原发性肝细胞癌侵袭和转移的关系。方法采用免疫组织化学LSAB法对36例原发性肝癌和其癌旁组织手术切除后的石蜡标本组织中的VEGF和ICAM-1的表达及微血管密度（MVD）进行检测。结果①VEGF、ICAM-1在原发性肝癌组织中的表达明显高于癌旁组织。②在原发性肝癌中，有转移者及包膜不完整者VEGF、ICAM-1和MVD明显高于无转移者及包膜完整者。③VEGF的表达与MVD呈正相关。结论原发性肝细胞癌组织中的VEGF、ICAM-1表达与肿瘤的侵袭和转移密切相关，可作为判断转移及预后的指标     

P53、P63在原发性肝细胞癌的表达及临床意义

目的探讨P53、P63与原发性肝癌临床病理特征的关系,探讨其在肿瘤发生、发展中的作用。方法收集手术切除后经病理证实为原发性肝癌标本46例、另选肿瘤旁肝硬化组织包埋蜡块20例和肝良性病切除肝组织12例作为对照组,应用免疫组织化学方法检测肝癌组织、肝硬化、正常肝组织中P53和P63的表达,并进行对比研究。结果 P63在原发性肝细胞癌中起癌基因的作用,在低分化肝细胞癌及有淋巴转移组中呈高水平表达,P53在原发性肝细胞癌中起抑癌基因的作用,并与肿瘤分化程度、有无门脉癌栓浸润及有无淋巴结转移有关,肝细胞癌中P53和P63蛋白的表达无相关性。结论 P63在原发性肝细胞癌中起癌基因的作用,P53在原发性肝细胞癌中起抑癌基因的作用,P53基因突变是原发性肝细胞癌的发生发展中的一个重要事件。     

Expression and clinical significance of P53 and P63 in primary hepatocellular carcinoma

目的 探讨P53、P63与原发性肝癌临床病理特征的关系,探讨其在肿瘤发生、发展中的作用.方法 收集手术切除后经病理证实为原发性肝癌标本46例、另选肿瘤旁肝硬化组织包埋蜡块20例和肝良性病切除肝组织12例作为对照组,应用免疫组织化学方法检测肝癌组织、肝硬化、正常肝组织中P53和P63的表达,并进行对比研究.结果 P63在原发性肝细胞癌中起癌基因的作用,在低分化肝细胞癌及有淋巴转移组中呈高水平表达,P53在原发性肝细胞癌中起抑癌基因的作用,并与肿瘤分化程度、有无门脉癌栓浸润及有无淋巴结转移有关,肝细胞癌中P53和P63蛋白的表达无相关性.结论 P63在原发性肝细胞癌中起癌基因的作用,P53在原发性肝细胞癌中起抑癌基因的作用,P53基因突变是原发性肝细胞癌的发生发展中的一个重要事件.     

多激酶抑制药——索拉非尼的临床研究

［摘要］索拉非尼是强有力的多激酶抑制药，靶向两种特殊的受体：RAF激酶和血管内皮生长因子（VEGF）受体。通过阻断RAF激酶缓慢下调细胞分化和肿瘤生长。VEGF受体负责血管生成或者促进肿瘤的新生血管发生。索拉非尼通过阻断这些受体影响肿瘤的营养来源。在临床研究中，索拉非尼治疗晚期或转移性肝细胞癌和肾细胞癌有明显效果，已被美国食品药品管理局（FDA）批准治疗这两种疾病。索拉非尼治疗其他肿瘤，如恶性黑色素瘤、甲状腺癌和前列腺癌等也正在研究。用索拉非尼作为单药治疗和联合细胞毒药物治疗不同的实体瘤值得进一步研究。     

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Liver tumor cells show several molecular alterations which favor pro-survival signaling. Among those, we have proposed the NADPH oxidase NOX1 as a prosurvival signal for liver tumor cells. On the one side, we have described that FaO rat hepatoma cells show NOX1-dependent partial resistance to apoptosis induced by Transforming Growth Factor beta (TGF-β). On the other side, we have shown that FaO cells, as well as different human hepatocellular carcinoma (HCC) cell lines, are able to proliferate in the absence of serum through the activation of a NOX1-dependent signaling pathway. The aim of this work was to analyze the effects of NADPH oxidase pharmacological inhibition in liver tumor cells using the inhibitor VAS2870. This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 μM. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-α (Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-β. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.     

原发性肝细胞癌OSM、OSMR表达与临床资料关系及意义

目的探讨原发性肝癌(HCC)及癌旁组织中OSM、OSMR表达与临床资料的关系及意义。方法用固相夹心法酶联免疫吸附法(ELISA)检测30例HCC及其癌旁组织中OSM、OSMR表达水平,常规检测患者术前血清AFP、AST、ALT、TBIL水平,并同时将30例肝癌患者按性别、年龄、Child分级、AFP、乙型肝炎表面抗原、肝硬化、TNM分期、肿瘤有无假包膜情况进行分组,通过方差分析与Logistic回归对肝癌及癌旁组织OSM、OSMR表达与以上临床资料进行分析,研究原发性肝细胞癌中OSM OSMR表达与临床资料关系及意义。结果 1肝癌及癌旁组织中OSM、OSMR表达与年龄、性别、乙型肝炎表面抗原阳性、Child分级、肝硬化、AST、ALT、TBIL等因素无关(P>0.05);2肝癌及癌旁组织中OSM、OSMR表达与AFP、TNM分期、肿瘤有无假包膜相关(P<0.05)。结论 OSM、OSMR与HCC发生、发展密切相关;肝癌及癌旁组织中OSM、OSMR表达与AFP、TNM分期、肿瘤无假包膜密切相关。     

Sorafenib in non-small cell lung cancer

Introduction: Conventional chemotherapy has reached a plateau of effectiveness for the treatment of non-small cell lung cancer (NSCLC). Patients with EGFR mutation or ALK translocations will benefit significantly from agents targeting these pathways, however, only 20% of western NSCLC patients have these mutations. Anti-VEGF antibody bevacizumab was approved for advanced NSCLC, but the clinical benefits are modest and all patients eventually develop resistance. Multi-targeted tyrosine kinase inhibitors (TKI) may offer more efficient inhibition of angiogenesis by blocking overlapping pathways and they may also have direct anti-tumor effects. Sorafenib is approved in the treatment of renal cell carcinoma and hepatocellular carcinoma and is now under investigation in the treatment of NSCLC. Areas covered: This review summarizes recent studies evaluating sorafenib in the treatment of NSCLC. Expert opinion: Sorafenib has shown anti-tumor activity in NSCLC. However, because NSCLC is complex and molecularly heterogeneous, it is very likely that only a subset of NSCLC patients will benefit from sorafenib, and so it is imperative to discover biomarkers to select patients who will probably benefit from sorafenib. Combination with other agents targeting parallel and compensatory pathways, such as EGFR inhibitors, may offer broader coverage and better disease control.     

Haloperidol可以增敏索拉非尼诱导的肝癌细胞铁死亡

目的探讨haloperidol对肝癌细胞铁死亡进程的影响,为肝细胞癌的治疗提供新策略。方法索拉非尼处理肝癌细胞株HepG2,Huh-7,SMMC-7721和PLC/PRF/5,在体外构建铁死亡模型,利用CCK-8实验对细胞活性进行检测;用RT-qPCR实验以及Western-blot实验对SlR的mRNA水平及蛋白水平进行检测;向培养基中同时添加haloperidol和索拉非尼,利用CCK-8实验和克隆形成实验对细胞活性进行检测;最后,利用RT-qPCR实验以及Western-blot实验对铁死亡中相关分子GSH以及GPX4的变化进行进一步的检测。结果索拉非尼处理肝癌细胞株HepG2,Huh-7,SMMC-7721和PLC/PRF/5可以导致细胞铁死亡的发生,并且能够被铁死亡的特异性抑制剂Fer-1挽救;在索拉非尼诱导肝癌细胞发生铁死亡的过程中,SlR的表达升高,并且具有统计学意义;和索拉非尼组进行比较,haloperidol+索拉非尼组的细胞活性进一步降低且具有统计学意义;haloperidol能够进一步促进索拉非尼导致的GSH及GPX4表达减少并且具有统计学意义。结论Haloperidol促进索拉非尼导致的GSH及GPX4表达来促进肝癌细胞铁死亡进程,加快肝癌细胞死亡。     

黄芪甲苷逆转耐药肝癌细胞株HepG2/GCS多药耐药的研究

目的探讨黄芪甲苷对耐药肝癌细胞株HepG2/GCS多药耐药的逆转作用及可能机制。方法以噻唑蓝(MTT)法测定黄芪甲苷的细胞毒作用和处理前后肝癌细胞对阿霉素的敏感性变化,通过Westernblot法检测细胞GCS蛋白的表达。结果黄芪甲苷在实验浓度范围内对HepG2、HepG2/GCS细胞均无明显毒性;浓度为40μg/ml的黄芪甲苷可逆转HepG2/GCS细胞对阿霉素的耐药性,逆转倍数为1.50,同时细胞内GCS蛋白的表达下降。结论黄芪甲苷具有逆转HepG2/GCS细胞多药耐药的作用,可能与下调细胞内GCS基因表达有关。     

Synergistic effects of the combination of β-ionone and sorafenib on metastasis of human hepatoma SK-Hep-1 cells

The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and β-ionone (BI), a precursor of carotenoids. We found that SF (1 μM) in combination with BI (1 μM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP-2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 μM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells.     

索拉非尼研究进展

索拉非尼（sorafenib）是一种口服的多激酶抑制荆，可以抑制肿瘤细胞增殖和血管增生，对肾癌和肝细胞癌均有效，对非小细胞肺癌、恶性黑色素瘤、甲状腺癌、乳腺癌、前列腺癌等的临床试验均在进行中。本文就索拉非尼的药代动力学、临床试验研究现状进行综述。     

多靶点抗肿瘤新药索拉非尼的研究进展

索拉非尼是一种口服多激酶抑制药,靶向作用于肿瘤细胞和肿瘤血管丝氨酸和(或)苏氨酸及受体酪氨酸激酶,具有抑制肿瘤细胞增殖和血管形成的双重作用。Ⅰ期临床的推荐剂量为400mg,每日两次。Ⅱ及Ⅲ期临床实验表明索拉非尼对肾癌、肝癌、黑素瘤和非小细胞肺癌都有一定的治疗作用。FDA已批准索拉非尼用于肾癌、肝癌的治疗。     

Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.     

超声引导下经皮经肝无水乙醇注射联合索拉非尼口服治疗原发性肝癌临床评价

目的 探讨超声引导下经皮经肝无水乙醇注射联合索拉非尼治疗原发性肝癌的临床效果及对术后复发情况的影响。方法 选取沧州市传染病医院2014年1月至2015年12月收治的原发性肝癌患者92例,按随机数字表法分为观察组和对照组,各46例。两组患者均予超声引导下经皮经肝无水乙醇注射治疗,观察组患者加服甲苯磺酸索拉非尼片。统计并比较两组患者的近期疗效、血清肿瘤标志物水平、不良反应发生率,并门诊随访3年以观察肿瘤复发率、远端转移率、死亡率。结果 观察组近期有效率为86.96%,明显高于对照组的69.57%(P<0.05);治疗后,观察组患者的甲胎蛋白(AFP)、癌胚抗原(CEA)、血管内皮生长因子(VEGF)水平均明显低于对照组(P<0.05);治疗期间,观察组不良反应发生率为21.74%,与对照组的13.04%相当(P>0.05)。门诊随访3年,观察组肿瘤复发率、远端转移率、死亡率均明显低于对照组(P<0.05)。结论 超声引导下经皮经肝无水乙醇注射联合索拉非尼口服治疗原发性肝癌,能提高近期疗效,降低患者体内血清肿瘤标志物水平和复发率。