ARTICLE IN PRESS Cancer Letters ■■ (2015) ■■–■■

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

Survivin in survival of hepatocellular carcinoma Changqing Su * Department of Molecular Oncology, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China

A R T I C L E

I N F O

Keywords: Survivin Hepatocellular carcinoma Survival Apoptosis Targeted therapy

A B S T R A C T

Survivin is an anti-apoptotic protein belonging to the inhibitor of apoptosis protein (IAP) family. It is involved in the regulation of important physiological and pathological processes in cells and functions to inhibit cell apoptosis and promote cell proliferation. Normally and terminally differentiated tissues are nearly negative for survivin. In contrast, survivin is highly expressed in most human tumor tissues, including hepatocellular carcinoma (HCC). The abnormal overexpression of survivin is closely related to the malignant biological behaviors of tumors. During the development and progression of HCC, the high level of survivin expression promotes cancer cell proliferation, inhibits cancer cell apoptosis, induces tumor stromal angiogenesis, reduces the sensitivity of cancer cells to radiotherapy and chemotherapy, and ultimately affects the prognosis of patients with HCC. Survivin expression is regulated by a large number of factors. The latest discovery indicated that the transcription factor octamer-binding transcription factor 4 (OCT4) enhances the expression of survivin though cyclin D1 (CCND1), which, in part, accounts for tumor cell proliferation, recurrence and metastasis. Survivin plays key roles in HCC, which renders it an ideal target for the treatment of HCC. The present article reviews the research progress on the relationship between survivin and HCC and on the HCC treatment strategies targeting survivin. © 2015 Elsevier Ireland Ltd. All rights reserved.

Introduction Primary hepatocellular carcinoma (HCC) is a malignant tumor type that arises from hepatocytes. HCC is characterized by highgrade malignancy, proneness to relapse and metastasis and poor prognosis of the patients. The occurrence, development, invasion, recurrence and metastasis of HCC are complex processes that are regulated by multiple genes and factors and involve multiple steps and pathways. The biological behaviors of HCC exhibit considerable heterogeneity. Abnormal gene expression is the initiating factor that determines the biological behaviors of cancer cells. With the continuous development of molecular biology in recent years, the effects of the altered gene expression products on the development and progression of HCC have been gradually revealed, and the early diagnosis rate and the efficacy of early treatment are improved. The development and progression of HCC depend on the continued proliferative activity of cancer cells, namely, the uncontrolled proliferation of cancer cells. A variety of factors affect the proliferation of HCC cells, including the activation of oncogenes, inactivation of tumor suppressor genes, alteration of microRNA expression profiles, expression of a number of growth factors and their receptors in cancer cells, and the enhanced activities of sulfatase and metalloproteinases in the extracellular matrix (ECM). These factors

* Corresponding author. Tel.: +86 21 8187 5351; fax: +86 21 8187 5351. E-mail address: [email protected].

affect the activation and inhibition of a series of signal transduction pathways, such as the activation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), rat sarcoma (Ras)/Raf/MEK/extracellular signal-regulated kinase (ERK), epidermal growth factor (EGF)/EGF receptor (EGFR), hepatocyte growth factor (HGF)/c-Met and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathways, which alters the biological activities of cancer cells through induction of malignant transformation, inhibition of apoptosis, enhancement of proliferative and metastatic capabilities, and eventually leads to the malignant progression of tumors and poor prognosis of the patients [1–3]. Among the various factors affecting cancer cell proliferation, the apoptosis-inhibiting factor survivin is the most potent inhibitor of apoptosis discovered to date. Survivin is a member of the inhibitor of apoptosis protein (IAP) family, and it is involved in regulating the physiological development of embryonic cells and controlling the cell cycle, with dual functions that inhibit apoptosis and promotes cell proliferation. When overexpressed, survivin inhibits apoptosis through a variety of mechanisms, which is conducive to abnormal cell proliferation and malignant transformation [4–7]. Survivin is expressed in embryonic tissues and most tumor tissues. However, normal mature tissues are negative for survivin expression. Survivin exhibits highly selective positive expression in malignant tumors, and its expression is related to the high proliferative activity, high recurrence potential and high metastatic capability of tumors, the resistance of tumors to radiotherapy and chemotherapy, and the poor prognosis of patients. Therefore, survivin

http://dx.doi.org/10.1016/j.canlet.2015.06.016 0304-3835/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Changqing Su, Survivin in survival of hepatocellular carcinoma, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.06.016

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has become a broad-spectrum diagnostic marker for tumors and a molecular target for effective cancer therapy [8–10]. The present article reviews the functional characteristics and expression regulation of survivin in the development and progression of HCC that have been discovered in recent years. In addition, the present article elaborates the relationship between survivin and the malignant proliferation of HCC, as well as the potential and prospects of utilization of survivin as a specific therapeutic target. Expression characteristics and biological functions of survivin in HCC Survivin is the most potent apoptosis-inhibitory protein discovered to date. It belongs to the IAP protein family, and it is capable of exerting anti-apoptotic effects by inhibiting the activities of caspase-3, caspase-7, and caspase-9 [11,12]. In addition, survivin suppresses the activity of pro-apoptotic kinases through mutual regulation between survivin and nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) or interaction with serine/ threonine kinase receptors, thereby inhibiting apoptosis [13,14]. Survivin expression is highly tissue-specific, and its expression pattern is closely related to the biological functions of survivin. The tumor specificity of survivin expression Survivin is abundantly expressed in tissues during embryonic and fetal development, as it is a regulatory factor essential for the maintenance of tissue and organ growth and differentiation. As the embryos develop to maturity, the expression of survivin is gradually decreased, and its distribution is gradually confined to a few types of adult tissues, including thymus, testis, endometrium during the secretory phase, CD34+ stem cells, and vascular endothelial cells. Survivin expression is undetectable in all other terminally differentiated tissues [15,16]. However, survivin becomes highly expressed in the vast majority of most common human cancers, including HCC, gallbladder cancer, bile duct cell cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer and non-Hodgkin’s lymphoma. Positive survivin expression is also observed in almost all human tumor cell lines [5,17]. The positive rate of survivin expression reaches approximately 80% in a variety of human tumor cell lines. Among the human tumor cell lines, breast and lung cancer cell lines show the highest levels of survivin expression, whereas renal cancer expresses survivin at a relatively low level [18,19]. Immunohistochemical assays have been employed to examine the expression of survivin in HCC tissues, and the results showed that the positive rate for survivin expression reaches 70%. In contrast, survivin is not expressed in paracancerous tissues and cirrhotic liver tissues [20]. The expression of survivin in HCC cell lines has been examined by Western blot analysis, and the results indicated that the positive rate of survivin is rather high. Among the cell lines examined, Hep3B, HepG2, PLC/PRF/5, and SK-Hep-1 express relatively high levels of survivin [21]. The findings described above demonstrate that the histological expression and distribution of survivin are highly tumor-specific, which allows survivin to serve as a broad-spectrum diagnostic marker for tumors. Influence of survivin on the biological behaviors of HCC cells The specific, high-level expression of survivin and its vital activities in mitosis and apoptosis are essential for the maintenance of tumor cell survival. Under normal conditions, cell proliferation and apoptosis coexist and maintain a dynamic balance, which is critical for the maintenance of cellular homeostasis and tissue morphology. However, during the process of tumor development and progression, the relationship between tumor cell proliferation and apoptosis becomes dysregulated, and the balance is

destroyed. Cell proliferation becomes predominant, and apoptosis is inhibited, resulting in accelerated malignant progression of tumors. The expression level of survivin is enhanced in HCC, inhibiting cancer cell apoptosis and promoting cancer cell proliferation. In addition, survivin may act in synergy with other factors that are capable of promoting tumor development and progression, thereby further affecting the biological behaviors of HCC cells and promoting the malignant progression of HCC. The effects of survivin on the biological behaviors of HCC are mainly reflected in the following aspects: 1 Inhibiting the apoptosis of HCC cells: Survivin exerts its strong anti-apoptotic effect through a variety of regulatory mechanisms [22,23]. Caspases are effectors in apoptotic pathways that are capable of sensing various apoptotic signals. The vast majority of cell types rely upon these apoptotic proteases to initiate the apoptotic program. Survivin protein binds to caspase-3 and caspase-7 and inhibits the catalytic activities of the caspases, thereby blocking the apoptotic program [24]. Survivin is also capable of binding to caspase-9, which is mediated by second mitochondria-derived activator of caspases (SMAC) [25]. The interaction between survivin and SMAC enables the release of IAPs from the SMAC/IAP complexes, thus achieving its apoptosisinhibitory effect [26]. Survivin protein also inhibits apoptosis via the Bax pathway [27]. Survivin also can bind to hepatitis B X-interacting protein (HBXIP), thereby exerting its anti-apoptotic effects [28–30]. HBXIP is a cytoplasmic protein capable of binding to hepatitis B virus X (HBX) protein, and it is widely expressed in human tissues. Survivin binds to HBXIP, forming the complex survivin–HBXIP. Survivin–HBXIP further blocks the caspase-9driven mitochondria/cytochrome C pathway of apoptosis through inhibiting the binding of procaspase-9 to its ligand apoptotic protease-activating factor 1 (Apafl). When HBX protein is expressed after hepatitis B virus infection, it is capable of binding to the survivin–HBXIP complex. Following the binding, HBX protein inhibits caspase cascades and regulates the apoptosis of HCC cells in a survivin-dependent manner [28,31]. Therefore, it can be concluded that the development and progression of hepatitis-B-related HCC are closely related to the survivinmediated apoptotic mechanisms. 2 Promoting the proliferation of HCC cells: Survivin not only inhibits apoptosis but also promotes aberrant proliferation and cell cycle progression of HCC cells [32–34]. The expression level of survivin is positively correlated with the proliferative activities of cancer cells. Survivin is an important effector molecule that regulates the balance between cell proliferation and death. Survivin is specifically expressed in the G2/M phase of the cell cycle, and its expression exhibits clear periodicity. In the early stage of mitosis, survivin binds to microtubules that constitute the mitotic spindles. Binding of survivin to microtubules stabilizes the structure of microtubules and prevents the hydrolysis of spindles, thereby protecting the integrity of mitotic organelles and contributing to continuous mitosis. Therefore, survivin exhibits persistent anti-apoptotic and proliferation-promoting effects [35,36]. Under the induction of basic fibroblast growth factor (bFGF), HCC cells express high levels of survivin protein, which promotes the proliferation of cancer cells through activating the PI3K signaling pathway [37]. 3 Enhancing the resistance of HCC cells to radiotherapy and chemotherapy: Most antitumor drugs and radiation therapies exert their therapeutic effects through inducing apoptosis and inhibiting cell proliferation, and an enhanced anti-apoptotic capability is the key reason behind the development of resistance to radiotherapy and chemotherapy in cancer cells. Survivin is overexpressed in HCC, which inhibits spontaneous apoptosis as well as radiotherapy- and chemotherapy-induced apoptosis in

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cancer cells and reduces the sensitivity of cancer cells to radiotherapy and chemotherapy [37–40]. Studies have demonstrated that the expression level of survivin affects drug sensitivity. The HCC cell lines Hep3B, Huh7, and PLC5 were selected and subjected to single-drug intervention or multidrug joint intervention using a group of targeted drugs, and the human umbilical vein endothelial cells (HUVECs) were used as a control. The targeted drugs included NVP-AEW541 (insulin-like growth factor receptor kinase inhibitor), MK2206 (Akt inhibitor), BEZ235 (PI3K/mTOR inhibitor) and RAD001 (mTOR inhibitor). Distinct combinations of the targeted drugs differ in their effectiveness to induce cancer cell apoptosis and reduce the survival rate of cancer cells. The difference is closely correlated with the expression status of survivin. High levels of survivin expression impair the synergistic antitumor effect of NVP-AEW541 and MK2206. Knockdown of survivin expression using small interfering RNA (siRNA) significantly enhances the synergistic effect of the targeted drugs [41]. Studies have shown that survivin may serve as a downstream effector molecule in cell signaling pathways, particularly the PI3K/Akt/mTOR pathway. Therefore, survivin may be used to determine the drug sensitivity to the targeted therapies [41,42]. The HCC cell line PLC/PRF/5 was used to establish a stable, survivin-knockout sub-cell line PLC-k3. It has been found that knockout of the survivin gene significantly enhances the cell-killing effect of platinum-based chemotherapy drugs toward HCC cells [43]. In SMMC-7721 cells, specific siRNA-mediated downregulation of survivin expression inhibits cell proliferation, induces cell cycle arrest at the G2/M phase, and increases the percentage of apoptotic cells. In a nude mouse xenograft model, downregulation of survivin expression significantly enhances the radiosensitivity and prolongs the survival time in tumor-bearing mice [44]. Therefore, survivin is an important factor that contributes to the development of resistance to chemotherapy and the loss of sensitivity to radiation therapy in tumors. Targeted therapies against survivin significantly enhance the efficacy of cancer chemotherapy and radiotherapy. 4 Inducing the tumor stromal angiogenesis: In addition to inhibiting apoptosis, survivin facilitates the proliferation and migration of endothelial cells to promote the survival of tumor cells [45]. The formation of tumor neovasculature is dependent on the proliferative divisions of vascular endothelial cells. VEGF is the most important factor in the promotion of endothelial cell proliferation, maintenance of vascular stability, and formation of a vascular lumen. One study showed that survivin expression is upregulated in the process of vascular endothelial cell proliferation and threedimensional lumen formation, which inhibits the activity of caspase-3 and abolishes tumor necrosis factor (TNF)-alpha- and cycloheximide-induced apoptosis [45]. High-level survivin expression in tumor tissues increases the level of β-catenin protein, enhances the transcriptional activity of β-catenin/T cell factor (Tcf)/lymphoid enhancer-binding factor (Lef), and promotes the expression of VEGF, thus contributing to angiogenesis in tumor stroma [46]. 5 Affecting the prognosis of HCC patients: Survivin expression promotes the proliferative activity of HCC cells, inhibits apoptosis, induces stromal angiogenesis, and enhances resistance to radiation therapy and chemotherapy. Therefore, survivin expression will inevitably affect the efficacy of clinical surgery and radiochemotherapy in the treatment of HCC, thereby affecting the prognosis of HCC patients. Statistical analysis of 305 HCC patients has shown that the positive rate of survivin is 75.7% in HCC tissues, which is significantly higher than the positive rate in paracancerous liver tissues (13.4%). The positive rate of survivin is closely related to tumor size, capsular invasion, portal vein tumor thrombosis, lymph node metastasis, and clinical stage of

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the tumors. Survivin expression in HCC tissues is positively correlated with NF-κB expression. Both survivin and NF-κB are associated with poor prognosis in patients with HCC. These results indicated that survivin may be used as a reference index to determine the malignant biological behaviors of HCC and predict the prognosis of patients [2]. A meta-analysis of 14 independent studies that included a total of 890 patients with HCC showed that the combined hazard ratio (HR) for the overall survival of all patients with HCC was 2.33 (95% CI: 1.65–3.31), while the combined HR for relapse-free survival was 2.13 (95% CI: 1.65–2.75). Grouped comparison was performed based on the expression status of survivin. It has been found that the positive expression of survivin, especially the positive expression of survivin in the cytoplasm of cancer cells, is closely related to the overall survival and the relapse-free survival rate of HCC patients [47]. Molecular regulation of survivin expression and function in HCC The abnormal survivin expression and activation in HCC indicate that a large number of factors are related to the regulation of survivin expression and activity. Survivin expression is precisely regulated at the transcriptional and post-transcriptional levels. It has been confirmed that the functional binding sites for signal transducer and activator of transcription 3 (STAT-3), β-catenin-activated TCF transcription factor, Kruppel-like factor 5 (KLF5), hypoxia-inducible factor 1-alpha (HIF-1α), transcription factor specificity protein 1 (Sp1), retinoblastoma protein (Rb)/E2F, TCF4 and early growth response 1 (Egr1) are present in the survivin promoter. Their bind mediates the activation of the survivin promoter, thereby enhancing the expression level of survivin [48–51]. A number of important protein molecules activate the SP1 promoter and SP1 expression and indirectly promote survivin expression, including cyclin-dependent kinase 4 (CDK4), s-phase kinase-associated protein 2 (SKP2), Rad51, breast cancer 2 (BRCA2), E2F-DP1, cyclin D1 (CCND1), Stat3, Rb and p21 [52]. SP1-mediated survivin expression can be inhibited by p53 [53]. Alteration of the stability and intracellular localization of survivin protein represents another mechanism by which survivin function is regulated. Phosphorylation of survivin by cdc2 kinase prevents the proteasome-mediated clearance or degradation of survivin [54,55]. Survivin can be phosphorylated at multiple sites, including threonine 34 (Thr34), threonine 53 (Thr53), threonine 117 (Thr117) and serine 20 (Ser20). Survivin contains an IAP-specific baculovirus IAP repeat (BIR) domain, which includes Thr34. Therefore, when phosphorylated at Thr34, survivin displays significant apoptosis-inhibiting and cell-protecting activities [56,57]. Survivin undergoes phosphorylation and activation by cytoplasmic protein kinases and is ready to exert its biological activities only if survivin is translocated from the nucleus to the cytoplasm [58–60]. Therefore, the functional status of survivin is related to the phosphorylation state, while the phosphorylation status of survivin determines the intracellular localization. High level of survivin expression in the cytoplasm is a marker for poor prognosis of cancer patients, whereas the accumulation of nuclear survivin is a marker for good prognosis [58,61]. Survivin expression is significantly decreased in the embryonic stem cells derived from OCT4-knockout mice, indicating that OCT4 is a regulatory factor for survivin expression [62]. However, no OCT4 binding sites are detected in the survivin promoter region, indicating that OCT4 indirectly regulates survivin [63]. Studies have further shown that OCT4 activates the CCND1 promoter and promotes CCND1 expression through the octamer motif located in the CCND1 promoter region. The survivin promoter region contains a CCND1 binding sequence and can be activated by CCND1 [21,64]. OCT4 is a marker of cancer stem cells. OCT4-positive tumor cells that possess

Please cite this article in press as: Changqing Su, Survivin in survival of hepatocellular carcinoma, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.06.016

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the characteristics of stem cells express survivin, which is an important mediator of the proliferation, recurrence and metastasis of tumor cells. Survivin is a substrate for AKT kinase. AKT kinase promotes survivin phosphorylation, thereby activating survivin. Restoration of P16 expression or PH domain leucine-rich repeat protein phosphatase (PHLPP) activity in tumor cells can inhibit AKT activity, resulting in the dephosphorylation of survivin. Dephosphorylated survivin becomes unstable and prone to degradation, leading to the loss of its biological function [8,65].

Survivin-targeting biological treatment strategies for HCC Survivin is a potentially important oncogene. It plays important roles in the occurrence, development, diagnosis, treatment and prognosis of liver and other types of cancers, which provide a theoretical basis for the development of novel strategies for targeted cancer therapy. The main advantages of survivin-targeting treatment techniques are mainly reflected in two aspects. First, survivin displays specificity in its histological distribution. Therapeutic genetic interventions that target survivin can be precisely located in cancerous tissues, which allow for the effective destruction of survival mechanisms unique to cancer cells without causing damage to normal tissues. Second, survivin expression exhibits evident cell cycle-dependence. Blocking survivin expression during the corresponding cell cycle phase induces apoptosis, reduces the survival potential of tumor cells, and enhances their sensitivity to radiochemotherapy. Many survivin-targeting therapeutic strategies are currently being evaluated in clinical trials or have been employed in clinical applications.

Strategies based on the inhibition of survivin expression Small molecule inhibitors, antisense oligonucleotides (ASOs), and siRNAs that target survivin are all capable of inhibiting survivin expression and eliciting antitumor effects. YM155 is a small molecule inhibitor of survivin that acts directly on the promoter region of the survivin gene in a cell cycle-independent manner to suppress its promoter activity or induce local DNA damage, thereby inhibiting the transcription of the survivin gene [66–68]. In the in vitrocultured HCC cell lines, YM155 effectively inhibits cell proliferation and induces cell cycle arrest and apoptosis. In addition, YM155 induces DNA damage through promoting the dysregulation of cellcycle checkpoint-regulatory genes. In a mouse model of HCC xenografts established using clinical HCC specimens with high levels of survivin and phosphorylated survivin expression, YM155 exhibits more pronounced antitumor effects compared to those of sorafenib [69]. ASOs bind to the mRNAs of their target genes, forming DNA–RNA hybrid molecules; as a result, ribonuclease H (RNase H) is activated, causing the degradation of mRNAs. In addition, ASOs prevent the binding of ribosomes through steric hindrance, thus inhibiting the translation of target mRNAs. LY2181308 is a survivintargeting ASO with 18 bases in length. By specifically inhibiting survivin expression, LY2181308 induces caspase-3-dependent apoptosis of HCC cells, G2/M cell cycle arrest, and appearance of multinucleated cells. In addition, LY2181308 enhances the sensitivity of cancer cells to gemcitabine, paclitaxel, and docetaxel [70]. siRNA is another effective approach for inhibiting survivin expression. Transfection of HepG2 and SMMC-7721 HCC cells with survivinsiRNA results in increased sensitivity to cisplatin [38]. One study found that, following siRNA-mediated inhibition of survivin, cancer cells undergo autophagy to protect themselves. Therefore, the combined application of survivin siRNA and the autophagy inhibitor 3-MA may enhance the apoptosis-inducing effect of survivin siRNA and improve its antitumor efficacy [71].

Strategies based on interference with survivin functions The dominant negative mutant of survivin is a protein that has lost its normal biological functions due to mutation. This protein form can competitively inhibit the function of wild-type survivin. The mechanism of this action involves the formation of nonfunctional dimers between the mutant and the wild-type proteins, which results in the inhibition of the functions of the wild-type protein. It has been proven that the dominant negative single-point mutants of survivin, T34A and C84A, significantly inhibit the functions of survivin, induce the activation of caspase family of proteases, and promote apoptosis [72,73]. The dominant negative double-point mutants of survivin, TC34 and 84AA, enhance the sensitivity of wild-type survivin to ubiquitin–proteasome pathway-mediated degradation and exhibit more potent apoptosis-inducing activity toward HCC cells [74]. In addition, the heat shock protein HSP90 is highly expressed in HCC tissues. HSP90 is crucial for the post-translational processing and folding of survivin protein and for the maintenance of survivin protein stability. Treatment of HCC cells with an inhibitor of HSP90 activity, 17-DMAG, inhibits cancer cell proliferation and induces apoptosis (especially early apoptosis) in a timeand concentration-dependent manner. The main mechanisms of 17DMAG action include the inhibition of survivin activity, downregulation of cyclin D1 and NF-κB expression, and simultaneous enhancement of p53 expression [75]. Oncolytic viral therapeutic strategies targeting the survivin-positive cancer cells HCC and other types of tumor cells generally express high levels of survivin, the expression of which is closely related to the characteristics of tumor cells including high proliferative activity, high metastatic capacity, and resistance to radiation therapy and chemotherapy. The subset of survivin-positive cells in tumor tissues is an important source for tumor recurrence and metastasis. Therefore, timely removal of survivin-positive cancer cells may rapidly reduce the proliferation and growth rate of tumors and create an opportunity for complete, comprehensive treatment. In HCC cells that express survivin, the survivin promoter is regulated by a number of trans-acting factors produced by the cancer cells and is in a highly active state. Placing the genes essential for the viral replication under the regulation of the survivin promoter allows the virus to selectively replicate in the survivin-positive tumor cells. A large number of replicated viruses will thus lyse the cancer cells. The destroyed cancer cells release progeny virions that continue to infect and destroy the surrounding cancer cells. Therefore, this type of virus is known as an oncolytic virus. As a viral vector is specifically replicated, the copy number of the antitumor gene carried by the viral vector increases accordingly. The expression level of the antitumor factor is elevated, which may significantly enhance the antitumor efficacy while having no effect on normal tissues and cells. Such therapeutic strategy displays better reliability and safety [76]. The tumor suppressor in lung cancer 1 (TSLC1) gene, originally identified in non-small cell lung cancer, is involved in cell adhesion, immunological surveillance, cell motility, and signal transduction. Absent or low expression of TSLC1 has been observed in a variety of malignancies, including HCC and lung cancer, and is closely related to the occurrence, invasion, and metastasis of tumors. The survivin promoter-regulated oncolytic adenovirus SD55-TSLC1 carries the TSLC1 gene that exhibits highly potent tumor-suppressive effects on the survivin-positive Huh7 HCC cells and the Huh7 xenograft tumor model. Its tumor-suppressive effect is achieved by the activation of caspase-mediated apoptotic signaling pathways and viral replicationinduced oncolysis. In contrast, SD55-TSLC1 has little effect on normal liver cells [77]. Another study employed the patient-derived tumor xenograft (PDTX) model in nude mice to verify the targeting activity

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and effectiveness of a therapeutic strategy using a survivin promoterregulated oncolytic adenovirus, AdSurp-Hsp70. AdSurp-Hsp70 expresses the antitumor immunomodulatory factor 70-kD heat shock protein (HSP70). The cytokine-induced killer cells (CIK cells) were simultaneously infused intravenously into nude mice to partially reconstruct the immune function. The model was then treated with the oncolytic adenovirus AdSurp-Hsp70, and the results showed that the synergistic tumor inhibitory effect induced by the combined therapy with AdSurp-Hsp70 and CIK cells was significantly more profound. The oncolytic adenovirus-mediated specific expression of HSP70 in cancer tissues stimulates the chemotaxis of CIK cells and induces the infiltration of CD3+ T cells in tumor stroma, thereby exerting antitumor activities. The study has demonstrated that the treatment strategy described above is capable of synergizing multiple antitumor mechanisms to achieve a better effective antitumor activity. The strategy is especially excellent to destroy the survivinpositive HCC cells [78]. A series of studies have found that the human sulfatase 1 (hSulf-1) catalyzes the desulfation of cell surface heparan sulfate proteoglycans (HSPGs), thereby inhibiting HSPG-mediated activation of receptor tyrosine kinases. As a result, the signal transduction pathways activated by multiple cell growth factors and their receptors are negatively regulated, directly exerting inhibitory effects on the proliferation, invasion, and metastasis of HCC cells and enhancing the sensitivity of cancer cells to radiotherapy and chemotherapy [79–81]. On the basis of studies of the survivin promoter-regulated adenoviral vectors, the radiation-inducible tumor-targeting adenoviral vector Ad.eSurp-hSulf1 was constructed. This adenoviral vector employed the radiation-sensitive CArG regulatory element of the early growth response-l (Egr-l) gene as an enhancer, and it was fused with the survivin promoter to generate an enhanced radiation-inducible promoter. The virus under the control of the enhanced radiationinducible promoter is capable of mediating high-level, cancerspecific expression of hSulf-1, thereby exerting anticancer effects. In addition, the virus can be used jointly with the anti-HCC drug I131-metuximab (I131-mab, trade name “Licartin”), resulting in a more powerful synergistic anticancer activity. I131-mab is a monoclonal anti-human HCC antibody that specifically recognizes the HAbG/CD147 in HCC cells. The antibody is conjugated with radioisotope I131 and has been used in hepatic artery intervention to provide localized radioimmunotherapy. When Ad.eSurp-hSulf1 is used in conjunction with I 131 -mab, I 131 -mab exerts an immunoradiotherapeutic effect. I131 radiation activates the CArG regulatory element, increases the activity of the enhanced radiationinducible survivin promoter, promotes the replicative activity of adenovirus, and further enhances the expression level of hSulf-1. The combined application of Ad.eSurp-hSulf1 and I131-mab exhibits extremely potent tumor-suppressive effects toward HCC cells and xenograft tumors in nude mice [39]. This novel biotherapeutic strategy involves the synergistic effect of multiple mechanisms including targeted gene therapy and antibody-based radioimmunotherapy and has application value in cancer treatment. Summary and outlook Survivin is the most potent inhibitor of apoptosis identified to date; it possesses both apoptosis-inhibiting and cell proliferationpromoting activities. Abnormally high expression of survivin is closely related to the high degree of tumor malignancy and poor prognosis of patients. The specificity of survivin expression and biological function of survivin in HCC provide ideal molecular targets for the treatment of HCC. With respect to the selection of an optimal treatment strategy, one option is to directly inhibit the expression of survivin, thereby inducing the apoptosis and inhibiting the growth of cancer cells. Another option is to interfere with the functional activity of survivin, thus enhancing the sensitivity of tumors to

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radiochemotherapy and improving the prognosis of patients with HCC. In cytological studies and animal xenograft models, the survivin promoter-regulated, oncolytic virus-mediated anti-HCC gene therapies have demonstrated excellent antitumor efficacy. Therefore, these therapies have great potential to become novel approaches for the treatment of HCC. Acknowledgments We gratefully acknowledge the support from the National Natural Science Foundation of China (81370552, 81402565), and the National Science and Technology Major Significant Projects of New Drugs Creation (2014ZX09101003). Conflict of interest None declared. References [1] X. Jiang, L. Zeng, J. Huang, H. Zhou, Y. Liu, Arctigenin, a natural lignan compound, induces apoptotic death of hepatocellular carcinoma cells via suppression of PI3-K/Akt signaling, J. Biochem. Mol. Toxicol. (2015) doi:10.1002/jbt.21712. [2] Y. Jin, J. Chen, Z. Feng, W. Fan, Y. Wang, J. Li, et al., The expression of survivin and NF-κB is associated with prognostically worse clinicopathologic variables in hepatocellular carcinoma, Tumour Biol. 35 (2014) 9905–9910. [3] R. Galuppo, E. Maynard, M. Shah, M.F. Daily, C. Chen, B.T. Spear, et al., Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/ MAPK and WNT/β-catenin pathways, Anticancer Res. 34 (2014) 1709–1713. [4] R. Zhang, S. Jin, W. Rao, F. Song, Q. Yin, Y. Wang, et al., OVA12, a novel tumor antigen, promotes cancer cell growth and inhibits 5-fluorouracil-induced apoptosis, Cancer Lett. 357 (2015) 141–151. [5] K. Athanasoula, H. Gogas, K. Polonifi, A.G. Vaiopoulos, A. Polyzos, M. Mantzourani, Survivin beyond physiology: orchestration of multistep carcinogenesis and therapeutic potentials, Cancer Lett. 347 (2014) 175–182. [6] G. Salzano, R. Riehle, G. Navarro, F. Perche, G. De Rosa, V.P. Torchilin, Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer, Cancer Lett. 343 (2014) 224–231. [7] J. Wang, Z. Li, Z. Lin, B. Zhao, Y. Wang, R. Peng, et al., 17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation, Cancer Lett. 362 (2015) 83–96. [8] Y. Qiu, X. Li, B. Yi, J. Zheng, Z. Peng, Z. Zhang, et al., Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting survivin phosphorylation and nuclear export in gallbladder cancer, Oncotarget (2015) . [9] M. Pennati, M. Folini, N. Zaffaroni, Targeting survivin in cancer therapy, Expert Opin. Ther. Targets 12 (2008) 463–476. [10] D.C. Altieri, Targeting survivin in cancer, Cancer Lett. 332 (2013) 225–228. [11] Y. Hu, K. Xu, E. Yagüe, MiR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer, Breast Cancer Res. Treat. 151 (2015) 269–280. [12] S. Trabulo, A.M. Cardoso, T. Santos-Ferreira, A.L. Cardoso, S. Simões, M.C. Pedroso de Lima, Survivin silencing as a promising strategy to enhance the sensitivity of cancer cells to chemotherapeutic agents, Mol. Pharm. 8 (2011) 1120–1131. [13] M. Tsubaki, T. Takeda, N. Ogawa, K. Sakamoto, H. Shimaoka, A. Fujita, et al., Overexpression of survivin via activation of ERK1/2, Akt, and NF-κB plays a central role in vincristine resistance in multiple myeloma cells, Leuk. Res. 39 (2015) 445–452. [14] X. Gao, Y. Liu, D. Deeb, A.S. Arbab, S.C. Gautam, Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-κB/mTOR signaling, J. Exp. Ther. Oncol. 10 (2014) 275–283. [15] G. Ambrosini, C. Adida, D.C. Altieri, A novel anti-apoptosis gene, survivin, is expressed in cancer and lymphoma, Nat. Med. 3 (1997) 917–921. [16] G. Han, H. Gong, Y. Wang, S. Guo, K. Liu, AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cells, Cancer Biol. Ther. 16 (2015) 77–87. [17] R. Necochea-Campion, C.S. Chen, S. Mirshahidi, F.D. Howard, N.R. Wall, Clinicopathologic relevance of survivin splice variant expression in cancer, Cancer Lett. 339 (2013) 167–174. [18] M.M. Asuncion Valenzuela, I. Castro, A. Gonda, C.J. Diaz Osterman, J.M. Jutzy, J.R. Aspe, et al., Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase, Onco. Targets Ther. 8 (2015) 495–507. [19] I. Tamm, Y. Wang, E. Sausville, D.A. Scudiero, N. Vigna, T. Oltersdorf, et al., The IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs, Cancer Res. 58 (1998) 5315– 5320.

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