Cancer cells can develop in several ways to escape from death induced by chemotherapeutic agents, thereby weakening the anti-tumor efficacy of single-target chemotherapy. Therefore, the efficacy of conventional chemotherapy hits a single target in tumor cells subject to strict limits. In this article, an AS1411 aptamer-functionalized liposome is prepared, which can simultaneously deliver paclitaxel (PTX) and siRNA into MCF-7 cells

Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This "two-punch strategy" (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.

BACKGROUND: EarlyR gene signature uses ESPL1, SPAG5, MKI67, PLK1 and PGR to classify ER+ breast cancer (ER+ BC) into EarlyR-Low, EarlyR-Int, and EarlyR-High risk strata and is prognostic in patients treated with adjuvant chemotherapy. The ability of EarlyR to predict pathological complete response (pCR) and long-term survival following neoadjuvant chemotherapy (NACT) is evaluated herein.
MATERIALS: The ability of EarlyR gene signature to predict pCR was assessed in publicly available Affymetrix microarray datasets (Cohort A; n = 659; 74 pCR events) derived from NACT-treated ER+ BC patients. Distant relapse-free survival (DRFS) results were analyzed in patients treated with NACT and adjuvant hormone therapy (AHT) (n = 281) and compared with patients treated with AHT alone (n = 455) (Cohort B; n = 736; 142 events).
RESULTS: In cohort A, EarlyR was a significant predictor of pCR (p = 5.8 × 10
CONCLUSIONS: High EarlyR is strongly associated with pCR in patients treated with neoadjuvant chemotherapy. EarlyR also predicts poor DRFS outcomes for patients in EarlyR-High not receiving NACT, and improved survival in NACT-treated EarlyR-High patients. EarlyR is not only a prognostic assay but also a predictive assay that identifies patients, who are also likely to respond to chemotherapy.

Introduction: Specific polo-like kinase (PLK1) silencing with small interface RNA (siRNA) may be an effective approach for PLK1-overexpressed lung cancer. However, low siRNA concentration into cytoplasm of tumor tissue severely limits its application.
Materials and methods: In this study, a novel triblock copolymer methoxy poly(ethylene glycol)-poly(histidine)-poly(sulfadimethoxine) (mPEG-PHis-PSD, shorten as PHD) was synthesized and used to construct novel nonviral gene vector with cationic liposomes.
Results: The resulting hybrid nanoparticles (PHD/LR) loaded with siPLK1 possessed excellent physiochemical properties. In vitro study indicated that PHD/LR could be efficiently internalized into human lung adenocarcinoma A549 cells and downregulated PLK1 protein expression to induce cell apoptosis, which was attributed to pH-induced instantaneous dissociation, efficient endo/lysosomal escape arose from PHD copolymer. Furthermore, in vivo antitumor activity demonstrated that PHD/LR could efficiently accumulated into tumor tissue and silenced PLK1 expression to possess antitumor activity.
Conclusion: Taken all these together, PHD/LR was expected to be a suitable carrier for specific delivering siRNA for lung cancer therapy.

The oncogenic transcription factor B-Myb is an essential regulator of late cell cycle genes whose activation by phosphorylation is still poorly understood. We describe a stepwise phosphorylation mechanism of B-Myb, which involves sequential phosphorylations mediated by cyclin-dependent kinase (Cdk) and Polo-like kinase 1 (Plk1) and Pin1-facilitated peptidyl-prolyl cis/trans isomerization. Our data suggest a model in which initial Cdk-dependent phosphorylation of B-Myb enables subsequent Pin1 binding and Pin1-induced conformational changes of B-Myb. This, in turn, initiates further phosphorylation of Cdk-phosphosites, enabling Plk1 docking and subsequent Plk1-mediated phosphorylation of B-Myb to finally allow B-Myb to stimulate transcription of late cell cycle genes. Our observations reveal novel mechanistic hierarchies of B-Myb phosphorylation and activation and uncover regulatory principles that might also apply to other Myb family members. Strikingly, overexpression of B-Myb and of factors mediating its activation strongly correlates with adverse prognoses for tumor patients, emphasizing B-Myb's role in tumorigenesis.

This case/control study is aimed at investigating the expression of CEP55, PLK1 and FOXM1 in bladder cancer tissues and comparing it with healthy tissue and their relationship with clinicopathological features of BC. Total RNA was extracted; then, gene expression was performed using real-time PCR relative to 18 s rRNA. 2

Cholangiocarcinoma (CCA) is one of the most common epithelial cell malignancies worldwide. However, its prognosis is poor. The aim of the present study was to examine the prognostic landscape and potential therapeutic targets for CCA. RNA sequencing data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) dataset and processed. A total of 172 genes that were significantly associated with overall survival of patients with CCA were identified using the univariate Cox regression method. Bioinformatics tools were applied using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO). It was identified that 'Wnt signaling pathway', 'cytoplasm' and 'AT DNA binding' were the three most significant GO categories of CCA survival-associated genes. 'Transcriptional misregulation in cancer' was the most significant pathway identified in the KEGG analysis. Using the Drug-Gene Interaction database, a drug-gene interaction network was constructed, and 31 identified genes were involved in it. The most meaningful potential therapeutic targets were selected via protein-protein and gene-drug interactions. Among these genes, polo-like kinase 1 (PLK1) was identified to be a potential target due to its significant upregulation in CCA. To rapidly find molecules that may affect these genes, the Connectivity Map was queried. A series of molecules were selected for their potential anti-CCA functions. 0297417-0002B and tribenoside exhibited the highest connection scores with PLK1 via molecular docking. These findings may offer novel insights into treatment and perspectives on the future innovative treatment of CCA.

The centrosomal protein, CEP55, is a key regulator of cytokinesis, and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/cyclin B activation and CDK1 caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in

Acute leukemia is a common malignancy among children and adults worldwide and many patients suffer from chronic health issues using current therapeutic approaches. Therefore, there is a great need for the development of novel and more specific therapies with fewer side effects. The family of Polo-like kinases (Plks) is a group of five serine/threonine kinases that play an important role in cell cycle regulation and are critical targets for therapeutic invention. Plk1 and Plk4 are novel targets for cancer therapy as leukemic cells often express higher levels than normal cells. In contrast, Plk2 and Plk3 are considered to be tumor suppressors. Several small molecule inhibitors have been developed for targeting Plk1 inhibition. Despite reaching phase III clinical trials, one of the ATP-competitive Plk1 inhibitor, volasertib, did not induce an objective clinical response and even caused lethal side effects in some patients. In order to improve the specificity of the Plk1 inhibitors and reduce off-target side effects, novel RNA interference (RNAi)-based therapies have been developed. In this review, we summarize the mechanisms of action of the Plk family members in acute leukemia, describe preclinical studies and clinical trials involving Plk-targeting drugs and discuss novel approaches in Plk targeting.

Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis.

BACKGROUND: Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-β-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear.
METHODS: The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA-induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model.
RESULTS: AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model.
CONCLUSIONS: Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM.

Previous studies have shown that high levels of PLK1 are expressed in HCC, and PLK1 inhibitors are being tested in clinical trials. However, the mechanisms, which regulate PLK1 expression in HCC, have not been clarified. Here, we show that induction of let-7b over-expression inhibits the PLK1-regulated luciferase activity in HEK-293T cells, and decreases the levels of PLK1 expression in HCC cells. Furthermore, the levels of let-7b expression were negatively correlated with PLK1 expression in HCC tissues. Let-7b over-expression inhibited the proliferation of HCC cells and promoted their apoptosis, which were partially rescued by increased PLK1 expression. Let-7b over-expression decreased the levels of PLK1, CDC25C and Survivin phosphorylation and CDC2, β-catenin, TCF-4 expression, which were mitigated by increased PLK1 expression in MHCC-97H cells. Let-7b over-expression inhibited the development and growth of implanted HCC tumors in mice by decreasing PLK1 and Survivin expression in the tumors. Together, our data indicated that let-7b targeted PLK1 to inhibit HCC growth and induce their apoptosis by attenuating the PLK1-mediated Survivin phosphorylation. Our findings may provide new insights into the pathogenesis of HCC.

BACKGROUND: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule-associated proteinrequired for mitosis and spindle assembly. It has been revealed that TPX2 is overexpressedin various human cancers and promotes cancer progression.
METHODS: The expression of TPX2 was examined in ovarian cancer (OC) tissues and by Western blotting, quantitative real-time reverse transcription PCR (qRT-PCR) and immunohistochemistry. The effects of TPX2 on proliferation and migration of two OC cell lines SKOV3and RMG1 were analyzed using the methylthiazol tetrazolium (MTT) assay, flow cytometry and transwell assay. The mechanisms underlying the effects of TPX2 on OC cells were explored by qRT-PCR and Western blot.
RESULTS: In this study, we found that TPX2 was upregulated in OC tissues. We observed knockdown of TPX2 inhibited the expression of Polo-like kinase 1 (PLK1), which has an important role in the regulation of M phase of the cell cycle, and the activity of Cdc2, induced cell arrested at the G2/M phase and decreased proliferation. Moreover, our data revealed that the levels of PLK1, β-catenin, MMP7 and MMP9 were inhibited following TPX2 knockdown, leading to decrease of cell migration. Finally, we showed that the restoration of PLK1 expression attenuated the anti-proliferation and anti-migration effects of TPX2 knockdown in OC cells.
CONCLUSIONS: TPX2 promotes the proliferation and migration of human OC cells by regulating PLK1 expression.

BACKGROUND: Liver carcinoma is a major cause of cancer-related death worldwide. Up to date, the mechanisms of liver cancerigenesis and development have not been fully understood. Multi-genes and pathways were involved in the tumorigenesis of liver cancer.
OBJECTIVE: The aim of the present study was to screen key genes and pathways in liver cancerigenesis and development by using bioinformatics methods.
METHODS: A dataset GSE64041 were retrieved from GEO database and the differentially expressed genes (DEGs) were screened out. Then the DEG functions were annotated by gene ontology (GO) and pathway enrichment analysis, respectively. The hub genes were further selected by protein-protein interaction (PPI) analysis. Afterwards, the mRNA and protein expressions as well as the prognostic values of the hub genes were assessed.
RESULTS: As a result, 208 up-regulated and 82 down-regulated genes were screened out. These DEGs were mainly enriched in cell cycle and metabolism-related pathways. Through PPI analysis, TOP2A, PRDM10, CDK1, AURKA, BUB1, PLK1, CDKN3, NCAPG, BUB1B and CCNA2 were selected as hub genes, which were all over-expressed in liver cancers relative to those in normal tissues, respectively. Among them, PLK1 and CCNA2 were suggested to be prognostic factors for liver carcinoma.
CONCLUSION: In conclusion, the present study identified several hub genes, and cell cycle and metabolism-related pathways that may play critical roles in the tumorigenesis of liver cancer. Future validation laboratory experiments are required to confirm the results.

BACKGROUND/AIMS: Liver cancer has the second highest cancer-related death rate globally and has relatively few targeted therapeutics. Polo-like kinase 1 (PLK1) is a fascinating trigger of the cell cycle; however, the still-rudimentary understanding of PLK1 at present is a significant barrier to its clinical applications. Here, we comprehensively clarified the clinicopathological value and potential functions of PLK1 in hepatocellular carcinoma (HCC).
METHODS: HCC-related microarrays, RNA-sequencing datasets and published studies were deeply mined and integrated from The Cancer Genome Atlas, Gene Expression Omnibus, ArrayExpress, Oncomine, literature databases, and immunohistochemistry experiments. Meanwhile, the associations between PLK1 expression and its clinicopathological implications and prognostic value in HCC patients were assessed. The standardized mean difference, summary receiver operating characteristic curve and the corresponding area under the curve, hazard ratios, odds ratios (ORs), and their 95% confidence intervals (CIs) were examined by STATA 12.0. Additionally, several bioinformatics methods were used to identify the potential function of PLK1 in HCC.
RESULTS: Comprehensive analyses revealed that PLK1 was significantly increased in HCC (standardized mean difference = 1.34, 95% CI: 1.03-1.65, P < 0.001). The results of diagnostic tests specified that in the summary receiver operating characteristic curve, the area under the curve was 0.88 (95% CI: 0.85-0.90). Furthermore, an elevated PLK1 level significantly predicted unfavorable overall survival (hazard ratio = 1.78, 95% CI: 1.10-2.88, P = 0.019) and was correlated with female gender (OR = 0.73, 95% CI: 0.56-0.95, P = 0.017), tumor thrombus (OR = 3.97, 95% CI: 1.46-10.78, P < 0.001), metastasis (OR = 3.46, 95% CI: 1.33-9.01, P = 0.011), pathologic stage (OR = 1.56, 95% CI: 1.17-2.07, P = 0.002), Barcelona Clinic Liver Cancer stage (OR = 5.76, 95% CI: 2.17-15.28, P < 0.001) and histologic grade (OR = 2.33, 95% CI: 1.12-487, P = 0.024). Through bioinformatics methods, we determined that enhancing the proliferative effect of PLK1 in HCC was associated with a series of hub genes and the activation of the cell cycle pathway.
CONCLUSIONS: These findings substantiated that PLK1 may be an independent prognostic biomarker in HCC and may facilitate the development of targeted precision oncology.

The present study aimed to explore the effects and underlying mechanisms of microRNA (miR)‑23a on pancreatic cancer (PC) cells progression. Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were used to detect the mRNA and protein miR‑23a and PLK‑1 level. Cell viability, cell cycle, migration and invasion assasy, and in vivo tumorigenicity assay were used to investigate the effects of miR‑204. Further luciferase reporter assay was used to explore the mechanisms contributing to miR‑204 effects. It was observed that miR‑23a expression was upregulated and negatively associated with polo‑like kinase‑1 (PLK‑1) expression in human PC tissues. PLK‑1 was a direct target of miR‑23a in PC cells. Functional analysis demonstrated that miR‑23a overexpression suppressed cell proliferation, inhibited cell migration and invasion and promoted cell apoptosis in vitro. When PC cells were transfected with has‑miR‑23a PLK‑1 was downregulated and its downstream molecules were deregulated, including decreased expression of B‑cell lymphoma‑2, cyclin B1 and vimentin, and increased expression of Bax and E‑cadherin. The inhibitory effect of miR‑23a on PC cell progression was observed in vivo tumor xenografts. The results of the study suggest that miR‑23a inhibits PC cell progression by directly targeting PLK‑1‑associated signaling and promoting miR‑23a expression may be a potential method for treating patients with PC.

BACKGROUND Long non-coding RNAs (lncRNAs) have a role in physiological and pathological processes, including cancer. The aim of this study was to investigate the expression of the long intergenic non-protein coding RNA 665 (LINC00665) gene and the cell cycle in hepatocellular carcinoma (HCC) using database analysis including The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and quantitative real-time polymerase chain reaction (qPCR). MATERIAL AND METHODS Expression levels of LINC00665 were compared between human tissue samples of HCC and adjacent normal liver, clinicopathological correlations were made using TCGA and the GEO, and qPCR was performed to validate the findings. Other public databases were searched for other genes associated with LINC00665 expression, including The Atlas of Noncoding RNAs in Cancer (TANRIC), the Multi Experiment Matrix (MEM), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) networks. RESULTS Overexpression of LINC00665 in patients with HCC was significantly associated with gender, tumor grade, stage, and tumor cell type. Overexpression of LINC00665 in patients with HCC was significantly associated with overall survival (OS) (HR=1.47795%; CI: 1.046-2.086). Bioinformatics analysis identified 469 related genes and further analysis supported a hypothesis that LINC00665 regulates pathways in the cell cycle to facilitate the development and progression of HCC through ten identified core genes: CDK1, BUB1B, BUB1, PLK1, CCNB2, CCNB1, CDC20, ESPL1, MAD2L1, and CCNA2. CONCLUSIONS Overexpression of the lncRNA, LINC00665 may be involved in the regulation of cell cycle pathways in HCC through ten identified hub genes.

Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling.

Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA-β-Gal staining and p21

The purpose of the present study was to investigate the underlying molecular mechanism of hepatocellular carcinoma (HCC) using bioinformatics approaches. The microarray dataset GSE64041 was downloaded from the Gene Expression Omnibus database, which included 60 tumor liver samples and 60 matched control samples. Differentially expressed genes (DEGs) between HCC and control groups were identified. Then functional enrichment analyses, protein‑protein interaction (PPI) network, sub‑network and integrated transcription factor (TF)‑microRNA (miRNA)‑target network analyses were performed for these DEGs. A total of 378 DEGs were obtained, including 101 upregulated and 277 downregulated DEGs. In addition, functional enrichment analysis for DEGs in the sub‑network revealed 'cell division' and 'cell cycle' as key Gene Ontology (GO) terms and pathways. Topoisomerase (DNA) IIα (TOP2A) and integrin subunit α2 (ITGA2) were hub nodes in the PPI network. TOP2A, cyclin dependent kinase 1 (CDK1) and polo like kinase 1 (PLK1) were revealed to be hub nodes in the sub‑network. Finally, 4 TFs including forkhead box M1 (FOXM1), E2F transcription factor 4 (E2F4), SIN3 transcription regulator family member A (SIN3A) and transcription factor 7 like 1 (TCF7L1) were obtained through integrated network analysis. TOP2A, ITGA2, PLK1 and CDK1 may be key genes involved in HCC development. 'Cell division' and 'cell cycle' were indicated to act as key GO terms and Kyoto Encyclopedia of Genes and Genomes pathways in HCC. In addition, FOXM1, TCF7L1, E2F4 and SIN3A were revealed to be key TFs associated with HCC.

Context: Polo-like kinase 1 (PLK1) is a critical molecule in the proliferation of several human cancers. Overexpression of PLK1 has been correlated with cancer cell proliferation and lower overall survival rates. Although PLK1 has been studied in various tumors, information regarding its expression in oral cancer and precancer is limited. Aims: This study is aimed at evaluating the expression of PLK1 in a potentially malignant and malignant disorder of the oral cavity, namely, oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively, using the immunohistochemistry technique. It also intended to evaluate the association of the various histological grades of OSCC with the intensity of PLK1 expression.
Subjects and Methods: Thirty OSMF, thirty OSCC tissues, and thirty control tissues were obtained, and the expression of PLK1 was detected by immunohistochemistry using rabbit antihuman PLK1 polyclonal antibodies (Abcam Ab47867). The association between staining intensity and histological grade of OSCC was evaluated.
Statistical Analysis Used: Using SPSS 20 version, a test for proportions, nonparametric Chi-square/correlation analysis was used to compare differences in proportions of categorical variables of interest between groups. Results: PLK1 was positively expressed in 27 (90%) OSCC tissues. OSMF showed no detectable staining in 27 (90%) tissues and positive staining in 3 (10%) tissues. PLK1 showed no staining (0%) in normal tissues. Statistically significant associations were not found between staining intensity and histological grade of OSCC.
Conclusions: PLK1 could be a promising progression marker for OSCC. Therapeutically, targeting PLK1 may be a new approach to fight oral cancer.

Studies have shown that transforming acidic coiled-coil protein 3 (TACC3), a key component of centrosome-microtubule dynamic networks, is significantly associated with various types of human cancer. We have recently reported that high levels of TACC3 are found in breast cancer, lead to the accumulation of spontaneous DNA damage due to defective DNA damage response signaling, and confer cellular sensitivity to radiation and poly(ADP-ribose) polymerase (PARP) inhibitors. Although our study suggests a potential role of TACC3 as a biomarker in breast cancer detection and prediction of therapy outcome, its role as a therapeutic target in breast cancer is not well studied. In this study, we show that a small molecule TACC3 inhibitor, KHS101, suppresses cell growth, motility, epithelial-mesenchymal transition (EMT), and breast cancer cell stemness while it induces apoptotic cell death. Quantitative multiplexed proteomic analysis using tandem mass tags (TMTs) revealed that KHS101 alters multiple biological processes and signaling pathways, and significantly reduces the expression of mitotic kinases Aurora A and Polo-like kinase 1 (PLK1), which are closely associated with TACC3. Our findings therefore provide a new insight into the potential mechanisms of the action of KHS101 and suggest its possible use as a dual or multi-targeting mitotic inhibitor in breast cancer.

Curcumin (1) and resveratrol (2) are bioactive natural compounds that display wide pharmacological properties, including antitumor activity. However, their clinical application has been limited due to their low solubility and bioavailability. Nevertheless, independent studies have considered these compounds as interesting prototypes for developing new chemical structures useful for anticancer therapy. Here in, we report the synthesis of novel curcumin-like hydrazide analogues (3a and 3b), and a series of curcumin-resveratrol hybrid compounds (4a-f), and the evaluation of their cytotoxic potential on three tumor cell lines MCF-7 (breast), A549 (lung), and HepG2 (liver). Cell viability was significantly reduced in all tested cell lines when compounds 4c-4e were used. The IC

OBJECTIVE: An increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways.
METHODS: The correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA. In addition, the potential molecular mechanism of survivin in ovarian cancer was also determined.
RESULTS: The pooled sensitivity and specificity were 0.71 (95%CI: 0.68-0.74) and 0.97 (95%CI: 0.94-0.98), respectively. The AUC of sROC was 0.8765. The results showed that there was also a significant relationship between survivin expression and poor overall survival (HR: 1.24, 95%CI: 1.14-1.35, p < 0.001), disease-free survival (HR: 1.53, 95%CI: 0.57-4.09, p < 0.001), as well as higher recurrence rate (HR: 1.11, 95%CI: 0.97-1.27). Moreover, survivin expression was also associated with tumor progression (cancerous vs. benign, OR: 11.29, 95%CI: 8.96-14.24, p < 0.001), TNM stage (III + IV vs. I + II, OR: 5.38, 95%CI: 4.16-6.97, p < 0.001), histological grades (G3 vs. G1 ∼ G2, OR: 4.36, 95%CI: 3.29-5.77, p < 0.001), and lymphatic metastasis (metastasis vs. non-metastasis, 3.35, 95%CI 2.36-4.75, p < 0.001). Bioinformatics analysis revealed the 50 most frequently altered neighboring genes of survivin in OC, and then Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. GO analysis showed that these genes were related to signal conduction, cell cycle, apoptosis, and metabolism. KEGG pathways analysis indicated that these genes were primarily enriched in mitotic prometaphase, PLK1 signaling events and the regulation of glucokinase by the glucokinase regulatory protein.
CONCLUSION: Survivin (BIRC5) expression might become a specific but low-sensitivity biomarker in ovarian cancer patients, and its presence indicated poor prognosis and worse TNM stages. This protein might function as an oncoprotein by influencing specific pathways involving the 50 genes identified herein. Additional studies are needed to confirm these results.

An ideal gene-carrying vector is supposed to exhibit outstanding gene-condensing capability with positively charged macromolecules to protect the carried gene during in vivo circulation and a rapid dissociation upon microenvironmental stimuli at the aimed sites to release the escorted gene. Currently, it still remains a challenge to develop an ideal gene carrier with efficient transfection ability and low toxicity for clinical applications. Herein, we have innovatively introduced a reactive oxygen species (ROS)-biodegradable boric acid ester linkage in elaborating the design of a gene carrier. In virtue of the featured intracellular characteristics such as the high level of ROS in tumor cells, an ROS-biodegradable electropositive polymer derived from branched polyethylenimine (BPEI) with a low molecular weight (1.2k) through a cross-linking reaction by the boric acid ester bond was developed in this study to achieve condensation and escorting of carried genes. Furthermore, the polymer was modified with substance P (SP) peptide as the targeting ligand through polyethylene glycol. The final fabricated SP-cross-linked BPEI/plasmid DNA nanoparticles exhibit favorable biocompatibility, ROS-cleavability, and fine targeting ability as well as high transfection efficiency compared with parental BPEI

Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment. In vitro combination of both compounds leads to a decrease in S-Phase and to increased apoptosis. In vitro scheduling experiments guided in vivo experiments in disseminated AML mouse models. Co-administration of BI 894999 and volasertib dramatically reduces tumor burden accompanied by long-term survival of tumor-bearing mice and eradication of AML cells in mouse bone marrow. Together, these preclinical findings provide evidence for the strong synergistic effect of BI 894999 and volasertib, warranting future clinical studies in patients with AML to investigate this paradigm.

The most common therapy for estrogen receptor-positive breast cancer is antihormone therapy, such as tamoxifen. However, acquisition of resistance to tamoxifen in one third of patients presents a serious clinical problem. Polo-like kinase 1 (Plk1) is a key oncogenic regulator of completion of G

Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC.

The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.