免疫检查点抑制剂治疗肝细胞癌的研究进展

肝癌的发病率及死亡率在全球恶性肿瘤中均位居前列。初诊的肝细胞癌（hepatocellular carcinoma，HCC）患者大多已处于晚期，失去手术根治的机会，全身治疗成为主要的治疗手段。随着免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）的出现，多种ICIs被批准用于晚期HCC患者，ICIs联合抗血管生成药物为主的靶向药物的治疗方案也被证实比ICIs单药效果更佳。但是，无论是单药ICIs还是联合治疗方案，多数患者仍不能从中获益。根据患者治疗的不同目标，通过肿瘤标记物选择不同的治疗方案是目前临床面临的挑战。本文对目前ICIs以及联合不同药物和局部治疗在HCC的临床研究进展、预测疗效和预后的生物标记物以及耐药性相关问题进行综述。      

Mcl-1蛋白在宫颈病变中的表达及意义

目的：髓样细胞白血病-1（myeloid cell leukemia-1，Mcl-1）蛋白是bcl-2家族成员，它在调控肿瘤细胞的凋亡、增殖、分化等过程中起一定作用。本研究拟检测子宫颈病变组织中Mcl-1蛋白的表达，探讨该蛋白在宫颈癌形成和演进进程中的意义。方法：采用免疫组织化学SP法检测83例石蜡包埋的子宫颈组织中Mcl-1的表达情况，并结合临床病理分型分析其表达的意义。结果：Mcl-1蛋白在慢性宫颈炎、宫颈上皮内瘤样病变（cervical intraepithelial neoplasia，CIN）和宫颈癌组织中的阳性率分别为4．0％，33．3％和74．2％，3组样本中Mcl-1的阳性率差异有统计学意义（P〈0．05），宫颈癌病理学分级G1及G2期与G3相比，差异有统计学意义（P〈0．05）。Mcl-1蛋白表达阳性率与CIN的分级、与宫颈癌临床分期、组织学分型和淋巴结转移无关（P〉0．05）。结论：Mcl-1蛋白在宫颈癌组织中表达升高，可能在宫颈癌的发生发展过程中起重要作用。     

铁死亡在酪氨酸激酶抑制剂治疗肝细胞癌及其耐药机制的研究进展

酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）是治疗晚期肝细胞癌（hepatocellular carcinoma,HCC）的一线方案,但耐药性使TKIs疗效受限。铁死亡是一种新型的非凋亡调节性细胞死亡方式,大量研究表明,铁死亡与HCC TKIs治疗耐药机制相关,而诱导HCC发生铁死亡能提高TKIs疗效,减弱其耐药性。本文就铁死亡在HCC TKIs治疗及耐药中的机制进行综述。     

肝细胞癌治疗药物研究进展

肝细胞癌（HCC）死亡率高，晚期治疗手段有限，生存期短，对多种化疗药物易产生多药耐药。近年来HCC的分子靶向药物研究取得到了很大的进展，且与其它化疗药物联合作用有着很好的研究前景。本文对目前肝细胞癌的治疗药物进行了归纳与阐述，深入探讨各类药物在未来发展的潜力以及可能面对的挑战，为延长晚期肝癌生存期寻求有效的综合治疗方案。     

肝癌的靶向治疗

肝癌（HCC）是全球最富有挑战性的恶性肿瘤之一。HCC需要综合治疗，目前尚无特效的治疗药物。分子靶向药物的发展，使HCC的全身治疗有了新的希望。阐述了分子靶向药物的现状，多激酶抑制剂、抗血管生成和抗表皮生长因子受体药物在临床上的进展，认为索拉芬尼是晚期HCC的新的标准治疗药物。     

分子靶向药物在肝细胞癌治疗中的临床研究进展

肝癌是全球第六大常见的恶性肿瘤,也是第四大肿瘤相关死亡原因,其中肝细胞癌（hepatocellular carcinoma,HCC）占90%,且80%以上的HCC发生在肝炎和肝硬化等患者中。对于HCC的治疗方面,仅20%的HCC患者可进行手术切除、肝脏移植或射频消融治疗,而晚期HCC患者无法进行根治性治疗,其生存率也逐渐下降。近年来,分子靶向药物治疗已成为研究热点,该类药物可通过特异性的与致癌位点靶向结合而发挥抗癌作用。目前,抗HCC的靶向药物主要分为一线药物与二线药物,其中一线药物主要包括索拉非尼、仑伐替尼,二线药物主要包括瑞戈非尼、卡博替尼及雷莫芦单抗等。本文对此类分子靶向药物在HCC治疗中的临床研究进展进行综述。      

凋亡调控基因Mcl—1和bcl—2在反应性及肿瘤性淋巴组织中的表达及其意义

目的：观察Mcl-1和bcl-2在反应性和肿瘤性淋巴组织中的表达，探讨其在肿瘤发生和发展过程中的作用。方法：收集临床资料完整的反应性淋巴组织增生石蜡包埋标本36例，非霍奇金淋巴瘤（NHL）78例和霍奇金病（HD）10例，采用免疫组化方法染色观察Mcm-1和bcl-2表达。结果：反应性淋巴组织中Mcl-1阳性细胞主要分布在生发中心和滤泡间区，而bcl-2阳性的套区淋巴细胞为Mcl-1阴性，78例NHL中，有57例不同程度地表达Mcl-1蛋白，53例表达bcl-2，B细胞肿瘤中两者阳性率高于T细胞肿瘤。10例HD中有9例Mcl-1/bcl-2阳性，结论：Mcl-1作为一种凋亡抑制基因在淋巴组织的表达不同于bcl-2；鉴于两者在淋巴组织肿瘤中的广泛分布，提示其在淋巴瘤细胞凋亡调控中可能起着重要作用。     

Mcl-1与血液恶性肿瘤

Mcl-1（myeloid cell leukemia-1）是Bcl-2家族蛋白的一个抗凋亡的成员,在凋亡的调控中具有重要作用。Mcl-1基因在翻译过程中可产生全长Mcl-1和短型Mcl-1两种具有不同作用的蛋白质。Mcl-1在胚胎形成,T和B淋巴细胞的发育和维持以及中性粒细胞的生存调节中具有重要作用。Mcl-1过表达可以抑制细胞凋亡,延长细胞寿命,使细胞获得生存优势,从而导致恶性行为的发生。进一步研究表明Mcl-1表达和调节异常与血液恶性肿瘤的发生和发展有关,因此对Mcl-1的深入研究具有重要意义。     

驱动蛋白超家族在肝细胞癌中的作用及其机制和临床意义的研究进展

肝细胞癌（HCC）是转移性极高、预后极差的恶性肿瘤之一,寻找与其发生与发展密切相关的预后标志物和治疗靶点是提高HCC预后监测和治疗的关键。驱动蛋白超家族（KIF）在HCC组织中特异性高表达,并且这种异常表达可通过激活上皮间质转化（EMT）促进HCC转移,影响HCC的预后和药物治疗的疗效,提示KIF可能是HCC预后监测和治疗中极具前景的预后标志物和分子治疗靶点。阐明KIF在HCC转移、预后和治疗中的作用及其机制,以及其作为HCC预后标志物和分子治疗靶点的临床意义,对开发HCC的预后监测及靶向治疗新策略至关重要。     

免疫检查点抑制剂在肝细胞癌治疗中的研究进展

肝细胞癌（HCC）是癌症相关死亡的最常见原因之一，大多数HCC患者在癌症晚期被诊断出来。2017年以前，治疗晚期HCC的药物主要是酪氨酸激酶抑制剂，随着免疫检查点抑制剂（ICIs）的出现，免疫治疗逐渐给此类患者带来新希望。目前，ICIs与其他全身或局部治疗的联合方案已成为治疗晚期HCC最有潜力的策略，其中一些药物已进行大规模临床试验。晚期HCC免疫治疗的主要挑战包括预测性生物标志物的探索、免疫相关不良事件（irAEs）的管理以及发掘更有效的联合方案等。本文旨在对肝细胞癌ICIs单药或联合用药以及其他免疫治疗的最新进展进行综述，并讨论目前研究与临床应用的限制和未来发展方向。     

Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma

Defects in apoptosis signaling in hepatocytes contribute to tumorigenesis in hepatocellular carcinoma (HCC). In addition, treatment with chemotherapeutic drugs is often ineffective in HCC patients due to the apoptosis resistance of cancer cells. Anti-apoptotic members of the Bcl-2 family, including myeloid cell leukemia-1 (Mcl-1), which regulate intrinsic apoptosis induction at the mito-chondrial level, are often overexpressed in human cancer, and are implicated with disease grade and prognosis. Yet, little is known about the role of Mcl-1 in HCC. In this study, we analyzed the relevance of Mcl-1 expression for the apop-tosis resistance of human HCC. Mcl-1 protein expression was considerably enhanced in human HCC tissue compared to adjacent non-tumor tissue. In addition, Mcl-1 was prominently expressed in various HCC cell lines. Mcl-1 basal expression is dependent on a functional phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway; treatment of the cells with a specific PI3 kinase inhibitor led to both decreased Mcl-1 expression and a sensitization towards chemotherapeutic drug-induced apoptosis. Furthermore, the hepatocyte growth factor and epidermal growth factor induced Mcl-1 expression in an Akt- and ERK-dependent manner. Finally, specific upregulation of Mcl-1 in HCC cells inhibited chemotherapeutic drug-induced apoptosis. Our data suggest that Mcl-1 is an important factor for the apoptosis resistance of human HCC, and constitutes an interesting target for HCC therapy.     

Telomerase-dependent virotherapy overcomes resistance of hepatocellular carcinomas against chemotherapy and tumor necrosis factor-related apoptosis-inducing ligand by elimination of Mcl-1

Hepatocellular carcinomas (HCC) are drug-resistant tumors that frequently possess high telomerase activity. It was therefore the aim of our study to investigate the potential of telomerase-dependent virotherapy in multimodal treatment of HCC. In contrast to normal liver, HCC xenografts showed high telomerase activity, resulting in tumor-restricted expression of E1A by a telomerase-dependent replicating adenovirus (hTERT-Ad). Neither tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or chemotherapy alone nor the combined treatment with both agents resulted in significant destruction of HCC cells. Application of hTERT-Ad at low titers was also not capable to destroy HCC cells, but telomerase-dependent virotherapy overcame the resistance of HCC against TRAIL and chemotherapy. The synergistic effects are explained by a strong down-regulation of Mcl-1 expression through hTERT-Ad that sensitizes HCC for TRAIL- and chemotherapy-mediated apoptosis. To investigate whether down-regulation of Mcl-1 alone is sufficient to explain synergistic effects observed with virotherapy, Mcl-1 expression was inhibited by RNA interference. Treatment with Mcl-1-siRNA significantly enhanced caspase-3 activity after chemotherapy and TRAIL application, confirming that elimination of Mcl-1 is responsible for the drug sensitization by hTERT-Ad. Consistent with these results, heterologous overexpression of Mcl-1 significantly reduced the sensitization of hTERT-Ad transduced cells against apoptosis-inducing agents. Chemotherapy did not interfere with quantitative hTERT-Ad production in HCC cells. Whereas hTERT-Ad virotherapy alone was only capable to inhibit the growth of Hep3B xenografts, virochemotherapy resulted in vast destruction of the drug-resistant HCC. In conclusion our data indicate that telomerase-dependent virotherapy is an attractive strategy to overcome the natural resistance of HCC against anticancer drugs by elimination of Mcl-1.     

PI3K/AKT/mTOR信号通路介导索拉非尼治疗原发性肝癌耐药机制的研究进展

索拉非尼（sorafenib）作为原发性肝癌（hepatocellular carcinoma,HCC）靶向治疗的一线药物已广泛应用于临床,然而部分HCC患者对索拉非尼治疗耐药导致临床疗效欠佳,联合其他靶向药物的临床实验仍未取得突破,故深入研究索拉非尼耐药机制,逆转索拉非尼耐药对于改善肝癌治疗的预后具有重要意义。最新研究发现,PI3K/AKT/mTOR信号通路在索拉非尼耐药机制中起重要作用,本文将从PI3K/AKT/mTOR信号通路促进肿瘤血管生成、参与细胞自噬、抑制肿瘤细胞凋亡并促进其增殖、与RAS/RAF/ERK/MEK信号通路交联及其促进上皮-间质转化等几个方面,概述其在索拉非尼治疗原发性肝癌时产生耐药的机制,为进一步开发治疗原发性肝癌的新型药物提供研究方向。     

雄激素受体在乳腺癌他莫昔芬耐药中的作用和机制研究进展

他莫昔芬(tamoxifen,TAM)为人工合成的非甾体类抗雌激素药物,被普遍的应用于雌激素受体(estrogen receptor,ER)阳性的乳腺癌患者中。但大约一半的ER阳性的患者会出现耐药。可见内分泌耐药是当前临床迫切需要解决的问题。随着对耐药机制的深入研究:发现雄激素受体(androgen receptor,AR)在 72.9%的原发性乳腺癌病例中表达,并在约65%的乳腺癌中与ER同时表达。有研究显示:AR/ER越高预示着TAM治疗率越低;AR与人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）之间所形成的正反馈循环能够增加TAM耐药;AR、髓样细胞白血病-1蛋白(myeloid cell leukemia-1,Mcl-1)与TAM耐药有可能相关。所以探讨AR在TAM耐药中的作用和机制是非常有意义的。为乳腺癌的靶向治疗掀开了新的一页。     

Restoration of miR-193b sensitizes Hepatitis B virus-associated hepatocellular carcinoma to sorafenib

Background

Chronic infection with Hepatitis B virus (HBV) is the major risk factor of Hepatocellular Carcinoma (HCC). This study is to explore the mechanism of sorafenib resistance and find an effective strategy to sensitize HBV-associated HCC to sorafenib.

Methods

Cytotoxicity to sorafenib was evaluated in HBV-positive/negative HCC cell lines. Expression of miR-193b and myeloid cell leukemia-1 (Mcl-1) protein were assessed by Q-PCR, in situ hybridization and western blot, immunohistochemistry, respectively. A luciferase reporter of Mcl-1 3’-UTR was used for validation as a target of miR-193b. Cell apoptosis was measured by flow cytometry, caspase-3 activity assay and DAPI staining.

Result

The IC50 to sorafenib was significantly higher in HBV-positive HCC cells than those without HBV infection. Significant downregulation of miR-193b and a higher level of Mcl-1 were observed in HBV-positive HCC cells and tissues. The activity of Mcl-1 3′-UTR reporter was inhibited by co-transfection with miR-193b mimic. Restoring the expression of miR-193b sensitized HBV-associated HCC cells to sorafenib treatment and facilitated sorafenib-induced apoptosis.

Conclusions

Modulation of miRNAs expression might be a potential way to enhance response to sorafenib in HBV-associated HCC.     

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction

Background  

Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro.     

STAT3 regulates 5-Fu resistance in human colorectal cancer cells by promoting Mcl-1–dependent cytoprotective autophagy

Chemoresistance to 5-fluorouracil (5-Fu)-based chemotherapy is one of the primary reasons for the failure of colorectal cancer (CRC) management. STAT3 can mediate tumor drug resistance through a variety of diverse mechanisms. Nonetheless, the underlying mechanisms of STAT3-induced 5-Fu resistance in CRC are still poorly understood. Here, we aimed to investigate the potential mechanism(s) of STAT3-induced 5-Fu resistance in CRC. Quantitative RT-PCR and Western blot were used to test the expression of STAT3 and Mcl-1 in chemosensitive and chemoresistant CRC tissues and cell lines. After overexpression or knockdown of STAT3 or Mcl-1, and/or treatment with or without 5-Fu or chloroquine (CQ), we tested cell viability, inhibitory concentration 50% (IC₅₀) value of 5-FU, cell apoptosis, proliferation, migration, and autophagy. STAT3 and Mcl-1 were significantly upregulated in the chemoresistant CRC tissues and cell lines, and STAT3 positively regulated Mcl-1. Functional studies demonstrated that STAT3 promoted 5-Fu resistance in CRC. Mechanistically, STAT3 triggered autophagy via Mcl-1 to induce cancer chemoresistance. Our results show that STAT3 regulates 5-Fu resistance in CRC by promoting Mcl-1–dependent cytoprotective autophagy. Our results provide a novel role of STAT3 and may offer a new approach for managing CRC 5-Fu resistance.     

ADAM10 overexpression confers resistance to doxorubicin-induced apoptosis in hepatocellular carcinoma

Chemoresistance represents a major obstacle to successful treatment of hepatocellular carcinoma (HCC). A disintegrin and metalloproteinase 10 (ADAM10) is known to be frequently upregulated in many cancers. We aimed to determine the biological function of ADAM10 in the chemoresistance of HCC cells. Overexpression of ADAM10 in three HCC cell lines (HepG2, Hep3B, and Huh7) conferred protection against doxorubicin-induced apoptosis, as determined by Annexin V staining. Western blot analysis revealed that ADAM10-overexpressing cells had a significantly lower amount of cleaved caspase-3 and an elevated expression of myeloid cell leukemia-1 (Mcl-1), a prosurvival member of the Bcl-2 family. Conversely, RNA interference-mediated silencing of endogenous ADAM10 potentiated doxorubicin-induced apoptosis in HepG2 and Hep3B cells, which was coupled with increased cleavage of caspase-3 and decreased expression of Mcl-1. Ectopic expression of ADAM10 resulted in a marked increase in the phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and Akt. Most interestingly, the pretreatment with the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and diminished the Mcl-1 expression in ADAM10-overexpressing Huh7 cells. Our data provide evidence that ADAM10 plays an important role in modulating the chemosensitivity of HCC cells, which, at least partially, involves the activation of the PI3-K/Akt pathway. ADAM10 may be a promising target for the improvement of chemotherapeutic efficacy in HCC.