金属硫蛋白1G通过抑制铁死亡促进肝癌细胞索拉非尼耐药

正【据《Hepatology》2016年8月报道】题:金属硫蛋白1G通过抑制铁死亡促进肝癌细胞索拉非尼耐药(作者Sun X等)肝细胞癌是引起全球癌症相关死亡的主要原因,近年来其发病率有增高趋势。索拉非尼是一种多致癌激酶抑制剂,是近年来唯一用于治疗晚期肝细胞癌的系统性治疗药物,然而,在肝细胞癌患者中出现索拉非尼耐药,     

瑞戈非尼治疗肝细胞癌的机制及临床效果

索拉非尼作为原发性肝癌治疗的一线药物已被临床广泛使用,耐药性及毒副作用日渐显现,且疗效有限。近几年来瑞戈非尼在肝细胞癌治疗方面的研究成为热点。RESORCE试验表明瑞戈非尼可显著延长索拉非尼治疗失败的晚期肝细胞癌患者的总生存期至10. 6个月,2017年已被美国食品药品监督管理局批准作为肝癌二线治疗用药。综述了近几年瑞戈非尼治疗肝细胞癌的分子机制、疗效评估、联合用药以及患者的选择标准,为未来的进一步研究提供方向。     

环状RNA在肝细胞癌发生发展调控及诊断治疗中的作用研究进展

肝细胞癌（HCC）是消化系统的常见恶性肿瘤,临床治疗效果及预后较差。环状RNA(circRNA)是近几年非编码RNA研究领域中的新兴热点之一,可以通过调控HCC的肿瘤干细胞干性维持、细胞周期、细胞凋亡及肿瘤血管生成等多个生物学进程而影响HCC的发生及进展。由于circRNA有一定保守性且具有特殊的闭环结构使得它们在真核生物的血液、唾液、尿液等体液中较为稳定,具有作为HCC的诊断标志物及治疗靶点的潜在可能。同时,circRNA还通过多种机制参与HCC耐药并调节HCC细胞对抗癌药物的反应程度。     

索拉非尼联合肝移植、射频消融、肝动脉化疗栓塞治疗肝细胞癌的研究进展

肝细胞癌(HCC)是世界上最常见的恶性肿瘤之一,传统的手术及化疗效果局限。多酶抑制剂索拉非尼在HCC的Ⅲ期临床试验中证明对晚期肝癌有效,开创了肝癌治疗新领域。近年来,索拉非尼联合其他方法治疗HCC的研究正在世界各地开展,并取得令人鼓舞的结果。总结了索拉非尼联合肝移植、射频消融术及肝动脉化疗栓塞术治疗肝癌的研究进展,认为索拉非尼与其他抗肝癌治疗的综合运用,有望成为肝癌靶向治疗的新途径。     

MLN4924对索拉非尼耐药肝细胞癌细胞中neddylation修饰的抑制作用

目的 索拉非尼是美国FDA于2007年批准的治疗肝细胞癌(hepatocellular carcinoma,HCC)的一线小分子抑制剂。然而,其在HCC患者中的反应率不高。本研究旨在进一步了解索拉非尼在HCC治疗中的作用机理,为HCC靶向治疗方法的优化提供理论基础。方法 使用蛋白印迹方法检测经索拉非尼治疗前后HCC细胞中与neddylation修饰相关蛋白的表达水平。通过CCK实验检测HCC细胞的增殖速率。结果 本研究发现索拉非尼能激活neddylation修饰相关的蛋白的表达。神经前体细胞表达的发育性下调蛋白8(neuronal precursor cell-expressed developmentally down-regulated protein8,NEDD8)激活酶抑制剂MLN4924通过抑制neddylation修饰来抑制索拉非尼耐药细胞的增殖。结论 索拉非尼能引起neddylation通路的活化。泛素激活酶NAE抑制剂可以进一步抑制对索拉非尼耐药的HCC细胞的增殖。     

环状RNA在肝细胞癌发生发展及诊疗中的作用

肝细胞癌(HCC)作为原发性肝癌最常见的类型,是一种具有侵袭性且致命的恶性肿瘤,其发生发展是一个多基因参与、多步骤、多阶段的过程。环状RNA(circRNA)作为一类内源性非编码RNA,主要通过吸附微小RNA(miRNA)或者RNA结合蛋白(RBP)发挥“海绵作用”,进而调控下游靶基因表达。本文全面介绍了circRNA在HCC信号转导、免疫、代谢、耐药、HBV相关HCC中的作用及意义,及其作为HCC的生物标志物或治疗靶点的潜在价值,为HCC的诊断和治疗提供新思路。     

microRNA在肝癌发生和发展中的作用及其机制

肝细胞肝癌(HCC)是我国常见的恶性肿瘤,其发生、发展是多因素、多基因和多步骤的复杂过程[1].miRNA(microRNA)是一类内源性非编码小分子RNA,可经序列特异性翻译抑制或mRNA裂解来调控基因表达,参与细胞发育、增殖、分化、凋亡等,约有1/3以上基因在转录后受其调控[2].新近研究结果表明,多种miRNA通过调节其靶基因参与HCC的细胞生物程序调控,间接发挥癌基因和抑癌基因的功能[3].了解miRNA的调控机制,可为肝细胞恶性转化及HCC的诊治提供理论依据.本文综述了miRNA在肝癌发生、发展中作用与机制的研究进展.     

铁死亡在索拉非尼治疗肝癌中的作用及机制

晚期肝癌患者基础状况差,可供选择的治疗方式有限,预后不良。索拉非尼作为被FDA批准用于晚期肝癌治疗的一线用药,具有多激酶抑制活性,能延长肝癌患者生存期。近年来研究发现索拉非尼也是一种铁死亡诱导剂,其对肝癌细胞的毒性作用部分依赖于诱导肿瘤细胞的铁死亡,通过促进索拉非尼诱导的铁死亡,能提高索拉非尼治疗肝癌的疗效,同时铁死亡在索拉非尼的耐药机制中也扮演重要角色,铁死亡途径中的某些关键蛋白也可以用来提示索拉非尼效用及肝癌预后。综述了铁死亡在索拉非尼治疗肝癌中发挥的作用以及相关最新研究进展。     

MicroRNAs治疗肝癌的方法及相关肝癌模型的研究进展

正微小RNA(MicroRNAs)由长度大约为20～24个核苷酸构成,其主要功能是调节蛋白质编码基因的表达。过去十多年中的研究表明它们在肝癌发生中起重要的作用。因此,它们已经成为治疗肝癌潜在的分子和靶标。微小RNA很容易通过全身给药的方法作用于肝脏,因此,肝癌是测试MicroRNAs治疗方法的优秀平台。近年来,人们广泛开展了MicroRNAs治疗肝细胞癌(HCC)的研究,并且建立了这方面的动物模型。这些研究     

长链非编码RNA HOTAIR在肝癌细胞生物学行为中的调节作用及其机制研究进展

反义转录长链非编码RNA-同源盒基因转录反义RNA(HOTAIR)是在肝癌细胞中第一个被发现的长链非编码RNA，其可通过调控表观遗传和染色质状态来调节其基因的表达水平，并影响肝癌细胞的生物学行为。其中，HOTAIR可通过与PRC2转录抑制复合物结合，使其相应靶基因甲基化，从而诱导和促进肝癌细胞的激活与增殖，或者通过竞争同种miRNA，参与靶基因的水平表达调节，来促进肝癌细胞的侵袭与转移。沉默HOTAIR可通过调控miR-217-5p活化磷酸化-磷脂酰肌醇3-激酶/磷酸化-苏氨酸蛋白激酶/基质金属蛋白酶-2/9信号通路及降低磷酸化信号转导和转录激活因子3的表达水平，促进肝癌细胞凋亡现象的发生。     

环状RNA在肝细胞癌发生发展中的作用

肝细胞癌(HCC)是世界上常见的恶性肿瘤之一,研究调控HCC的侵袭迁移机制对于其临床诊断和治疗具有重要意义。环状RNA(circRNA)作为非编码RNA家族的重要成员,因其环状结构高度稳定,在肝细胞中起microRNA(miRNA)海绵作用,以竞争内源性RNA机制调控miRNA或促进靶基因表达,在HCC进展中起重要作用。探讨circRNA在HCC发病中的作用机制,将有助于筛选HCC诊断标志物和研发治疗的有效靶点。     

Long non-coding RNA highly up-regulated in liver cancer promotes exosome secretion

BACKGROUND Highly upregulated in liver cancer(HULC) is a long non-coding RNA(lnc RNA)which has recently been identified as a key regulator in hepatocellular carcinoma(HCC) progression. However, its role in the secretion of exosomes from HCC cells remains unknown.AIM To explore the mechanism by which HULC promotes the secretion of exosomes from HCC cells.METHODS Serum and liver tissue samples were collected from 30 patients with HCC who had not received chemotherapy, radiotherapy, or immunotherapy before surgery.HULC expression in serum exosomes and liver cancer tissues of patients was measured, and compared with the data obtained from healthy controls and tumor adjacent tissues. The effect of HULC upregulation in HCC cell lines and the relationship between HULC and other RNAs were studied using q PCR and dualluciferase reporter assays. Nanoparticle tracking analysis was performed to detect the quantity of exosomes.RESULTS HULC expression in serum exosomes of patients with HCC was higher than that in serum exosomes of healthy controls, and HULC levels were higher in liver cancer tissues than in tumor adjacent tissues. The expression of HULC in serum exosomes and liver cancer tissues correlated with the tumor-node-metastasis(TNM) classification, and HULC expression in tissues correlated with that in serum exosomes. Upregulation of HULC promoted HCC cell growth and invasion and repressed apoptosis. Notably, it also facilitated the secretion of exosomes from HCC cells. Moreover, q PCR assays showed that HULC repressed micro RNA-372-3 p(mi R-372-3 p) expression. We also identified Rab11 a as a downstream target of mi R-372-3 p. Dual-luciferase reporter assays suggested that mi R-372-3 p could directly bind both HULC and Rab11 a.CONCLUSION Our findings illustrate the importance of the HULC/mi R-372-3 p/Rab11 a axis in HCC and provide new insights into the molecular mechanism regulating the secretion of exosomes from HCC cells.     

Sorafenib response in hepatocellular carcinoma: MicroRNAs as tuning forks

Hepatocellular carcinoma (HCC) is the primary liver malignancy that contributes towards the second most common cause of cancer‐related mortality. The targeted chemotherapeutic agent, sorafenib, is known to show a statistically significant but limited overall survival advantage in advanced HCC. However, the individual patient response towards sorafenib varies drastically, with most experiencing stable disease and few with partial response; complete response is very rare. Progressive disease despite the treatment is also evident in many patients, indicating drug resistance. These varied responses have been linked with the modulation of several intracellular signaling pathways. Notably, the regulation of these pathways through diverse operating biomolecules, including microRNAs (miRNAs), is the focus of recent studies. MicroRNAs are tiny, non‐coding RNA molecules that regulate the expression of several target genes. In addition, miRNAs are known to play a role in the progression of HCC carcinogenesis. Interestingly, miRNAs have also been identified to play differential roles in terms of sorafenib response in HCC such as biomarkers and functional modulation of cellular response to sorafenib, hence, they are also being therapeutically evaluated. This review outlines the role of reported miRNAs in different aspects of sorafenib response in HCC.     

CircRNA-001241 mediates sorafenib resistance of hepatocellular carcinoma cells by sponging miR-21-5p and regulating TIMP3 expression

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and its incidence is on the rise, closely related to advanced liver disease. Sorafenib chemotherapy is one of the main treatment options for patients with advanced HCC. Despite several reports on HCC multidrug resistance, the underlying regulatory mechanisms are still unclear. In this study, we found circ-001241 was significantly upregulated in HCC tissues and cells. Knockdown of circ-001241 markedly inhibited HCC cell proliferation and decreased sorafenib-resistance. More importantly, circRNA acts as a ceRNA to suppress the expression and activity of miR-21-5p, leading to the increase in TIMP3 expression. In addition, circRNA-001241 facilitated HCC sorafenib-resistance by regulating the miR-21-5p/TIMP3 axis. Taken together, our study elucidated the oncogenic role of circ-001241 in mediating sorafenib resistance in HCC, providing insights and opportunities to overcome sorafenib resistance in patients with advanced hepatocellular carcinoma.     

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma

BACKGROUNDSorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.AIMTo explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.METHODSThe protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq).RESULTSYB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.CONCLUSIONOverall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.     

Role and mechanism of circ-PRKCI in hepatocellular carcinoma

BACKGROUND The circular RNA circ-PRKCI is an endogenous non-coding RNA that forms a covalently closed ring after reverse splicing, which plays a key role in the occurrence and development of multiple digestive system tumors.AIM To investigate the role and mechanism of circ-PRKCI in the occurrence and development of hepatocellular carcinoma(HCC).METHODS This study used real-time polymerase chain reaction to detect the expression of circ-PRKCI in tumor tissues, tumor adjacent tissues, and blood in patients with HCC and other digestive system tumor cells. A series of functional tests were performed to explore whether circ-PRKCI affects the growth of HCC cells and what is its mechanism in HCC. Meanwhile, fluorescence in situ hybridization was used to detect the subcellular localization of circ-PRKCI. Survival analysis was performed to predict the correlation between circ-PRKCI and the prognosis of HCC. Chi-square test and t-test were performed for statistical analyses.RESULTS The level of circ-PRKCI was significantly higher in HCC tissues than in tumor adjacent tissues, and in HCC cell lines than in cells lines of esophageal, liver,stomach, and colon cancers. A series of functional tests showed that circ-PRKCI substantially inhibited cell apoptosis and promoted cell invasion. It was foundthat circ-PRKCI can act as the sponge of miRNA-545 to reduce the expression of AKT3 protein. Moreover, the result of survival analysis showed that circ-PRKCI target gene E2 F7 can reduce liver cancer patients' survival rate. And clinical data suggested that the distribution of circ-PRKCI rose with the depth of invasion,lymph node metastasis, distant metastasis, and TNM stage, indicating that circPRKCI may affect the survival and prognosis of patients with HCC by regulating E2 E7.CONCLUSION This study explores the role and mechanism of circ-PRKCI in HCC, which provides a new research direction and theoretical basis for the treatment of HCC.     

LncRNA-ATB promotes autophagy by activating Yes-associated protein and inducing autophagy-related protein 5 expression in hepatocellular carcinoma

BACKGROUND Long non-coding RNAs(lnc RNAs) play important roles in many diseases,including hepatocellular carcinoma(HCC). Autophagy is a metabolic pathway that facilitates cancer cell survival in response to stress. The relationship between autophagy and the lnc RNA-activated by transforming growth factor beta(lnc RNA-ATB) in HCC remains unknown.AIM To explore the influence of lnc RNA-ATB in regulating autophagy in HCC cells and the underlying mechanism.METHODS In the present study, we evaluated lnc RNA-ATB expression in tumor and adjacent non-tumor tissues from 72 HCC cases by real-time PCR. We evaluated the role of lnc RNA-ATB in the proliferation and clonogenicity of HCC cells in vitro. The effect of lnc RNA-ATB on autophagy was determined using a LC3-GFP reporter and transmission electron microscopy. Furthermore, the mechanism by which lnc RNA-ATB regulates autophagy was explored by immunofluorescence staining, RNA immunoprecipitation(RIP), and Western blot.RESULTS The expression of lnc RNA-ATB was higher in HCC tissues than in normal liver tissues, and lnc RNA-ATB expression was positively correlated with tumor size,TNM stage, and poorer survival of patients with HCC. Moreover, ectopic overexpression of lnc RNA-ATB promoted cell proliferation and clonogenicnity of HCC cells in vitro. Lnc RNA-ATB promoted autophagy by activating Yesassociated protein(YAP). Moreover, lnc RNA-ATB interacted with autophagy-related protein 5(ATG5) m RNA and increased ATG5 expression.CONCLUSION Lnc RNA-ATB regulates autophagy by activating YAP and increasing ATG5 expression. Our data demonstrate a novel function for lnc RNA-ATB in autophagy and suggest that lnc RNA-ATB plays an important role in HCC.     

Molecularly targeted therapies for hepatocellular carcinoma: sorafenib as a stepping stone

Since sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials, it has changed the treatment paradigm and become the standard first-line treatment for patients with advanced HCC. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance, and thus the survival advantage was modest, even in patients with preserved liver function. Furthermore, there is currently no biomarker for monitoring the response or resistance to sorafenib. Currently, various kinds of molecularly targeted agents have been developed and are being evaluated in clinical trials. There are several steps required to improve the outcome from sorafenib therapy. First, a reliable predictive and prognostic biomarker is urgently needed. Second, a compelling indication of sorafenib treatment for HCC needs more clinical studies and consensus. Third, the actual benefits of sorafenib to patients with advanced liver dysfunction should be clarified and a more effective strategy for targeted therapy needs to be developed, for example, using a combination of targeted agents acting on different pathways or different levels of a key pathway. Finally, sorafenib could be used with other treatment modalities, such as local ablation or transarterial chemoembolization, to synergize efficacy. Based on the successful introduction of sorafenib, future studies should focus on plans to further improve the outcome of HCC patients by overcoming resistance and maximizing the efficacy of molecularly targeted therapy.