Influence of adriamycin on changes in Nanog, Oct-4, Sox2, ARID1 and Wnt5b expression in liver cancer stem cells

AIM: To determine the influence of Adriamycin (ADM) on the changes in Nanog, Oct4, Sox2, as well as, in ARID1 and Wnt5b expression in liver cancer stem cells.

Regulators of liver cancer stem cells

Hepatocellular carcinoma(HCC)is a leading cause of cancer deaths.It is often detected at a stage when there are few therapeutic options.Liver cancer stem cells(LCSCs)are highly tumorigenic and resistant to chemotherapy and radiation therapy.Their presence in HCC is a major reason why HCC is difficult to treat.The development of LCSCs is regulated by a variety of factors.This review summarizes recent advances on the factors that regulate the development of LCSCs.Due to the importance of LCSCs in the development of HCC,a better understanding of how LCSCs are regulated will help to improve the treatments for HCC patients.

Liver cancer stem cell markers: Progression and therapeutic implications

Cancer stem cells(CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.

Research progress and prospects of markers for liver cancer stem cells

Liver cancer is a common malignancy and surgery is the main treatment strategy. However, the prognosis is still poor because of high frequencies of postoperative recurrence and metastasis. In recent years, cancer stem cell(CSC) theory has evolved with the concept of stem cells, and has been applied to oncological research. According to cancer stem cell theory, liver cancer can be radically cured only by eradication of liver cancer stem cells(LCSCs). This notion has lead to the isolation and identification of LCSCs, which has become a highly researched area. Analysis of LCSC markers is considered to be the primary method for identification of LCSCs. Here, we provide an overview of the current research progress and prospects of surface markers for LCSCs.

8-bromo-7-methoxychrysin inhibits properties of liver cancer stem cells via downregulation of β-catenin

AIM:To evaluate whether 8-bromo-7-methoxychrysin(BrMC),a synthetic analogue of chrysin,inhibits the properties of cancer stem cells derived from the human liver cancer MHCC97 cell line and to determine the potential mechanisms.METHODS:CD133+cells were sorted from the MHCC97 cell line by magnetic activated cell sorting,and amplified in stem cell-conditioned medium to obtain the enriched CD133+sphere forming cells(SFCs).The stem cell properties of CD133+SFCs were validated by the tumorsphere formation assay in vitro and the xenograft nude mouse model in vivo,and termed liver cancer stem cells(LCSCs).The effects of BrMC on LCSCs in vitro were evaluated by MTT assay,tumorsphere formation assay and transwell chamber assay.The effects of BrMC on LCSCs in vivo were determined using a primary and secondary xenograft model in Balb/c-nu mice.Expressions of the stem cell markers,epithelialmesenchymal transition(EMT)markers andβ-catenin protein were analyzed by western blotting or immunohistochemical analysis.RESULTS:CD133+SFCs exhibited stem-like cell properties of tumorsphere formation and tumorigenesis capacity in contrast to the parental MHCC97 cells.We found that BrMC preferentially inhibited proliferation and self-renewal of LCSCs(P<0.05).Furthermore,BrMC significantly suppressed EMT and invasion of LCSCs.Moreover,BrMC could efficaciously eliminate LCSCs in vivo.Interestingly,we showed that BrMC decreased the expression ofβ-catenin in LCSCs.Silencing ofβ-catenin by small interfering RNA could synergize the inhibition of self-renewal of LCSCs induced by BrMC,while Wnt3a treatment antagonized the inhibitory effects of BrMC.CONCLUSION:BrMC can inhibit the functions and characteristics of LCSCs derived from the liver cancer MHCC97 cell line through downregulation ofβ-catenin expression.

Clinical implications of microRNAs in liver cancer stem cells

The prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is often dismal, mainly due to late presentation, high recurrence rate, and frequent resistance to chemotherapy and radiotherapy. Accumulating evidence on the differential microRNA (miRNA) expression patterns between non-tumor and HCC tissues or between liver cancer stem cells (CSCs) and non-CSC subsets and the significant clinical implications of these differences suggest that miRNAs are a promising, non-invasive marker for the prognosis and diagnosis of the disease. This perspective article summarizes the current knowledge of miRNAs in liver CSCs and highlights the need for further investigations of the role of miRNAs in regulating liver CSC subsets for possible future clinical applications.

COL14A1 promotes self-renewal of human liver cancer stem cells through activation of ERK signaling

Objective:Liver cancer stem cells(CSCs)are the culprits of hepatocellular carcinoma metastasis and recurrence.Only by eliminating tumor stem cells can malignant tumors be fundamentally cured.This study aimed to identify the role and underlying mechanism of aberrant Collagen Type XIV Alpha 1 Chain(COL14A1)overexpression in liver CSCs,and improve understanding of the molecular basis of hepatocellular carcinoma metastasis and recurrence.Methods:First,quantitative real-time polymerase chain reaction was used to confirm aberrant high-expression of COL14A1 in liver CSCs.Next,interference experiments were performed to determine the key role of COL14A1.To explore the mechanism of COL14A1 overexpression in liver CSCs,putative microRNA(miRNAs)targeting COL14A1 were analyzed using the miRTarBase database.Next,quantitative real-time polymerase chain reaction,western blotting,and luciferase reporter assays were performed to verify the interaction between miR-7108-3p and COL14A1.Lastly,key target proteins of the COL14A1-extracellular-regulated signal kinase(ERK)signaling pathway were identified through western blotting analysis.This study was approved by the Ethics Committee of Shanghai Fourth People’s Hospital,Tongji University School of Medicine,China(approval No.2019tjdx17)on February 21,2019.Results:COL14A1 is abnormally highly expressed in liver CSCs,which is necessary for liver CSCs to maintain their self-renewal capability.Mechanistically,COL14A1 is post-transcriptionally regulated by miR-7108-3p in a negative manner.Low expression of miR-7108-3p increased translation of COL14A1,which subsequently activated ERK signaling,ultimately maintaining the self-renewal and stem cell-like properties of liver CSCs.Conclusion:COL14A1,which is negatively regulated by miR-7108-3p,was found to play a crucial role in maintaining the selfrenewal and stem cell-like properties of liver CSCs through activation of ERK signaling.

Establishment and identification of induced pluripotent stem cells in liver cancer patients

Objective:To induce pluripotent stem(IPS)cells from fibrocytes that are separated from liver cancer patients.Methods:The fibrocytes were reprogrammed to IPS cells by lentiviral vector,stained and identified by immunohistochemistry.Results:The IPS cells were successfully established from fibrocytes after infection,and IPS cell clones formed in round shape under a microscopy.The induction rate was 0.013%±0.007%.No tumor formed at the back of nude mice within 8 weeks after the inoculation of cell clone.However,tetatoma appeared in nude mice within 1 week after IPS inoculation.A few tumors formed in nude mice within 4 weeks after the inoculation of cell clones.However,subcutaneous tumors formed within 1 week after IPS inoculation.The induced IPS cells showed three germ layers in tetatoma.Nanog and OCT4 in the induced IPS cells showed hypomethylation.SSEA-A,TRA-1-6-,TRA-1-81 and Nanog were highly expressed in the induced IPS cells,indicating the IPS cells possessed the similar ability as the stem cells.Conclusion:The IPS cells of liver cancer patients can be established effectively from fibrocytes and can be cultured stably in vitro,which provides an approach for the treatment of intermediate or advanced stage liver cancer.

MIR-448 Regulates MAGEA6/AMPK Signaling Pathway in Hepatocellular Carcinoma Tumor Stem Cells

Objective: To explore the role of miR-448 in regulating MAGEA6/AMPK signaling pathway in the biological study of hepatocellular carcinoma (HCC) tumor stem cells. Methods: Using the database, the hepatocellular carcinoma related expression chips were obtained and the regulatory mirnas of candidate genes were predicted, and the predicted results were analyzed. The effects of miR-448 and MAGEA6 on the pellet formation rate and clone formation rate of hepatocellular carcinoma stem cells were detected by immunofluorescence identification of stem cell markers and light microscope counting method. The effects of miR-448 and MAGEA6 on migration and invasion of hepatocellular carcinoma stem cells were detected by scratch and Transwell assay. Dual luciferase reporter assay to verify whether miR-448 targets MAGEA6. The expression and influence of miR-448 on MAGEA6 and AMPK pathway were detected by qRT-PCR and Western blot. Results: It was found that miR-448 may directly regulate the expression of MAGEA6. Overexpression of miR-448 inhibited the characteristics, proliferation, migration, and invasion of hepatocellular carcinoma stem cells in vitro, as well as the ability of xenograft tumor formation in vivo. However, inhibition of miR-448 showed opposite results. In addition, miR-448 directly targets MAGEA6 and regulates AMPK signaling. Silencing MAGEA6 and adding AMPK activator further verified that miR-448 activated AMPK signaling pathway by targeting MAGEA6, thus affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. Conclusions: Our results reveal that miR-448 activates AMPK signaling pathway by targeting MAGEA6, thereby affecting characteristics, proliferation, migration and invasion of hepatoma stem cells. It is suggested that overexpression of miR-448 may be a new therapeutic strategy for hepatocellular carcinoma.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Incomplete radiofrequency ablation provokes colorectal cancer liver metastases through heat shock response by PKCα/Fra-1 pathway

Objective: Incomplete radiofrequency ablation(ICR) has been proposed as a major cause of recurrence in the treatment of hepatic metastatic tumors.We tried to determine the mechanisms of this progression in colorectal cancer(CRC) liver metastasis(CRLMs)Methods: We have established a mouse model of radiofrequency ablation(RFA) therapy to demonstrate increased risk of recurrence of CRLMs with ICR.Here we focused on heat shock-induced CRC malignancy.Sub-lethal heat shock(HS) in CRC cell lines provoked cell growth, invasion, and tumor initiation in vitro and in vivo.Results: We found that Fra-1, which lies downstream of PKCα-ERK1/2 signaling, was significantly increased by HS compared with the untreated CRC cells.Silencing Fra-1 reversed the tumor promoting effects of HS.Furthermore, proliferation and tumor initiation inducer c-Myc, together with tumor invasion inducer matrix-metalloprotase 1(MMP-1) expression were up-regulated by AP-1/Fra-1 induced genes transcription.Conclusions: Our study demonstrated that ICR generated HS induces CRC malignancy by targeting Fra-1, which could be a potential prognostic marker and a promising therapeutic strategy to prevent disease recurrence after radiofrequency ablation treatment.

肝癌干细胞niche响应型逐级靶向脂质体处方优选及体外靶向作用评价

目的制备负载多柔比星(DOX)和XAV-939的肝癌干细胞niche响应型逐级靶向脂质体(CAP@CD133-D/X-Lip),并初步评价其体外靶向作用。方法采用薄膜分散-硫酸铵梯度法制备CAP@CD133-D/X-Lip。通过Box-Behnken设计-响应面法确定CAP@CD133-D/X-Lip的最优处方制备工艺;通过加入纤维细胞活化蛋白(FAP-α)与脂质体反应测定粒径变化考察CAP@CD133-D/X-Lip中两亲肽(CAP)的敏感性;通过细胞摄取实验考察不同制剂对肝癌干细胞(LCSCs)的体外靶向能力。结果最优处方工艺为EPC 44 mg、Chol 2 mg、XAV-9390.156 mg、DOX 1.16 mg、DSPE-PEG_(2000)2 mg、DSPE-PEG_(2000)-MAL 2 mg、DSPE-PEG_(2000)-CAP-PEG_(2000)-UAMC11102 mg,超声功率为500 W,总处方量为5 mL,两药平均包封率为79.79%±0.89%;加入重组FAP-α蛋白后CAP@CD133-D/X-Lip的平均粒径缩小至(95.56±2.32)nm,显示出CAP@CD133-D/X-Lip具有较好的微环境响应能力;细胞摄取实验显示,相比于CAP@CD133-D/X-Lip,CAP@CD133-D/X-Lip+FAP-α有着更强的摄取能力,说明其靶向LCSCs的能力明显增强。结论本研究成功制备了CAP响应型逐级靶向LCSCs的脂质体,且其具有良好的微环境响应与体外靶向能力。

肝癌细胞系中circAMOTL1的表达及对肝前体细胞增殖和恶性转化的影响

目的探讨环状RNA circAMOTL1在肝癌细胞系中的表达及其对肝前体细胞(HPCs)系WB-F344的增殖迁移及恶性转化的影响。方法通过实时荧光定量PCR检测circAMOTL1在5种肝癌细胞系和正常肝细胞系L-02以及HPCs系WB-F344中的表达;同时构建过表达和敲除circAMOTL1的WB-F344的细胞系;通过CCK-8实验检测过表达或敲除cAMOTL1后HPCs的增殖变化;细胞划痕实验验证细胞迁移的变化;通过蛋白免疫印迹实验验证过表达或敲除circAMOTL1后对肝癌干细胞(LCSCs)标志物CD133的表达影响。结果5种肝癌细胞系中circAMOTL1的表达水平均高于L-02(P<0.05);过表达circAMOTL1后HPCs的增殖能力显著提高(P<0.01),敲除circAMOTL1后细胞的增殖能力显著下降(P<0.001);过表达circAMOTL1后显著提升了细胞的迁移能力(P<0.01),敲除后细胞的迁移能力明显下降(P<0.01);过表达circAMOTL1后可以检测到CD133的表达。结论circAMOTL1在5种肝癌细胞系中高表达,过表达circAMOTL1可以促进HPCs的增殖和迁移能力,诱导其向LCSCs方向恶性转化。

鳖甲煎丸含药血清通过miR-140调控肝癌干细胞增殖能力及干性的机制研究

目的 研究miR-140在肝癌干细胞(liver cancer stem cells,LCSCs)中的生物学功能,以及鳖甲煎丸含药血清抑制肝癌干细胞特性的干预效应。方法 以人肝癌细胞株(Huh7)为研究对象,无血清培养基分选法分选LCSCs,用流式细胞仪鉴定富集的LCSCs,并转染miR-140慢病毒。分为Cin组、Control组、BJJP组、miR-140 mimics NC组、miR-140 mimics组、BJJP+miR-140 inhibitor组。用CCK-8法测定细胞增殖能力,RTPCR检测miR-140、CD133、CD24、EpCAM、AFP表达,Western blot法检测CD133、CD144、EpCAM、AFP蛋白表达。结果 检测显示Con组与Control组细胞增殖能力、CD133、CD24、EpCAM、AFP的蛋白及RNA表达无统计学意义(P>0.05);与miR-140 mimics NC组相比,miR-140 mimics组的肝癌干细胞的增殖能力、CD133、CD24、EpCAM、AFP的RNA及蛋白表达水平均明显减少(P<0.01),但miR-140表达明显增强(P<0.05);与Control组相比,BJJP组和BJJP+miR-140 inhibitor组的细胞增殖能力、CD133、CD24、EpCAM、AFP的RNA及蛋白表达水平显著降低(P<0.01),且BJJP组的细胞增殖能力、CD133、CD24、EpCAM、AFP的RNA及蛋白表达水平低于BJJP+miR-140inhibitor组(均P<0.05)。结论 鳖甲煎丸能抑制LCSCs的增殖能力及干性,其机制可能通过上调miR-140的表达发挥作用。

鳖甲煎丸调控miR-140对肝癌干细胞致瘤性及干性的影响

目的 探讨鳖甲煎丸对裸鼠皮下成瘤、肝癌干细胞(liver cancer stem cells,LCSCs)干性的抑制作用及其相关机制。方法 选取12只BALB/c裸鼠,随机分为4组,即肝癌干细胞皮下成瘤+生理盐水灌胃组(A组)、肝癌干细胞皮下成瘤+鳖甲煎丸灌胃组(B组)、miR-140过表达慢病毒肝癌干细胞皮下成瘤+生理盐水灌胃(C组)、miR-140干扰慢病毒肝癌干细胞皮下成瘤+鳖甲煎丸灌胃(D组),将分选出肝癌干细胞种植于裸鼠皮下形成瘤体,记录瘤体体积大小,并进行多组间对比。苏木精-伊红(HE)染色观察瘤体组织的病理学变化。PCR和Western Bolt分别检测肝癌组织中CD133、CD24、EpCAM、AFP的mRNA表达、蛋白表达以及miR-140的基因表达。结果B组、C组瘤体体积均小于A组,D组瘤体体积大于B组;HE染色结果提示瘤体组织呈恶性后进行PCR与Western Bolt检测,结果提示B组、C组的CD133、CD24、EpCAM、AFP的mRNA以及蛋白表达相对含量均小于A组,D组以上检测指标小于B组;予鳖甲煎丸灌胃后,瘤体中miR-140的表达升高。结论 鳖甲煎丸能抑制肝癌干细胞的致瘤能力以及降低肝癌组织中CD133、CD24、EpCAM、AFP,其作用机制可能与促进LCSCs中miR-140的表达有关。

Targeting Wnt/β-catenin pathway in hepatocellularcarcinoma treatment

Hepatocellular carcinoma(HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or Cinfection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase Ⅰ clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.

HSP90 and SIRT3 expression in hepatocellular carcinoma and their effect on invasive capability of human hepatocellular carcinoma cells

Objective:To vexplore expression of HSP90,SIRT3 in liver cancer tissue and its effect on liver cancer cell invasion ability.Methods:Moderate expression of HSP90 in SMMC-7721,HepG2,LO2 and Hep-3B cell lines were screened,which was validated by RT-PCR.Overexpression of HSP90 cell line and lentivirus packaging HSP90-RNAi were established,which was validated by RT-PCR and western blot.The level of epithelial-mesenchymal transition(EMT)related gene was detected by western blot.The percentage of cancer stem cells was assayed by flow cytometry.Results:RT-PCR demonstrated the highest expression of HSP90mRNA in SMMC-7721 cells,the lowest expression of HSP90 mRNA in Hep3B and LO2 and the moderate expression of HSP90 mRNA in Hep-G2.Therefore,HepG2 was selected as a follow-up experiment cell lines.Compared with the blank control group,expression of HSP90in HSP overexpression group was increased obviously,and expression of HSP90 in HSP90shRNA group was significantly decreased,which indicated successful establishment of HSP overexpression and shRNA group.The apoptotic cell in hsp-siRNA group was higher than the blank control group,while the HSP overexpression group showed opposite results.Western blot results showed transfection HSP promoted cells EMT transformation,up-regulated the level of E-cadherin,and down-regulated the level of Vimentin;meanwhile,shRNA group showed opposite results.Conclusions:Carcinoma HepG2 cell transfeeted high expression of HSP can promote the transformation of EMT,improve the expression of Vimentin,reduce the expression of E-cadherin,and inhibit apoptosis of cancer stem cells,which improve the invasive ability of cancer of the liver cells.While hsp-siRNA group presents opposite results.In summary,the expression of HSP is closely related to the occurrence,development and invasion of cancer of the liver tissue.

苦龙胆酯苷对热消融不全的残存肝癌干细胞的影响及机制初探

目的探讨苦龙胆酯苷(Amarogentin)在热消融不全的残存肝癌细胞对肝癌干细胞的影响及其作用机制。方法水浴法建立HepG2肝癌细胞热消融不全的残存模型,流式细胞术检测细胞中CD133阳性细胞比例,qRT-PCR和Western blot法检测肝癌细胞中CD133的mRNA和蛋白的表达水平。分别用低、中和高剂量的苦龙胆酯苷处理上述HepG2细胞24 h后,流式细胞术分别检测细胞中CD133阳性肝癌细胞比例、肝癌细胞的增殖率和凋亡率,qRT-PCR和蛋白印记法检测肝癌细胞中CD133、TBC1D15和p53的mRNA和蛋白的表达水平。结果随培养时间的延长,热消融不全的残存肝癌细胞中CD133阳性细胞比例、CD133和TBC1D15 mRNA和蛋白的表达水平显著提高,而p53磷酸化水平显著下降。苦龙胆酯苷处理后,热消融不全的残存肝癌细胞中CD133阳性细胞比例、细胞增殖率以及肿瘤干细胞相关分子CD133和TBC1D15的mRNA和蛋白表达水平显著降低(均P<0.05);凋亡率和p53磷酸化水平提高(均P<0.05)。结论苦龙胆酯苷可降低热消融不全的残存肝癌干细胞的比例和肿瘤细胞的增殖,促进细胞的凋亡,这可能与其提高肝癌干细胞p53磷酸化和抑制TBC1D15蛋白相关。

敷和备化方对肝癌干细胞Wnt/β-catenin通路的影响

目的探讨敷和备化方对CD+133HepG2肝癌干细胞Wnt/β-catenin通路的影响。方法通过免疫磁珠法分筛出CD+133HepG2肝癌干细胞后,在干细胞培养液中诱导和培养,流式细胞术鉴定CD+133HepG2细胞比例,将CD+133HepG2肝癌干细胞分为血清对照组、空白对照组、XVV939阳性药对照组、敷和备化方组。血清对照组加入体积分数为16%正常大鼠血清培养基,空白对照组加入相同剂量正常培养基,阳性对照组加入相同剂量含1μmol/L XVV939的培养基,敷和备化方组加入体积分数为16%敷和备化方含药血清培养基,药物作用6 d后采用RT-PCR以及Western blot检测Wnt/β-catenin通路相关因子Wnt1、β-catenin、PI3K、AKT的mRNA以及蛋白表达。结果与空白对照组和血清对照组相比,阳性药对照组和敷和备化方组皆可下调Wnt1、β-catenin、PI3K、Akt的mRNA水平(P<0.05),其中阳性药对照组对Wnt1、Akt的抑制力最强,敷和备化方组对β-catenin的抑制力最强;与空白对照组和血清对照组相比,阳性药对照组和敷和备化方组皆可下调Wnt1、PI3K、Akt的蛋白水平(P<0.05),敷和备化方组能明显下调β-catenin的蛋白水平(P<0.05)。结论相较于PI3K/Akt通路,敷和备化方可以更有效下调Wnt/β-catenin通路相关因子的mRNA和蛋白表达水平,从而降低肝癌干细胞的胚系干性水平。

阿伐曲泊帕的临床应用进展

阿伐曲泊帕(avatrombopag)是一种口服第2代血小板生成素受体激动剂(TPO-RA),被批准用于治疗难治性或对其他治疗反应不足的成人慢性原发免疫性血小板减少症(cITP),以及择期行侵入性检查或手术的成人慢性肝病(CLD)相关性血小板减少症,在治疗化疗引起的血小板减少症(CIT)方面被授予孤儿药资格。Ⅲ期临床研究数据表明,阿伐曲泊帕在此3种适应证中的安全性及耐受性良好。目前,阿伐曲泊帕治疗再生障碍性贫血(AA)和造血干细胞移植(HSCT)后血小板减少的疗效和安全性研究正在进行中。本文就其临床应用进展作一综述。