PATHOME-Drug: a subpathway-based polypharmacology drug-repositioning method.

MOTIVATION: Drug repositioning reveals novel indications for existing drugs and in particular, diseases with no available drugs. Diverse computational drug repositioning methods have been proposed by measuring either drug-treated gene expression signatures or the proximity of drug targets and disease proteins found in prior networks. However, these methods do not explain which signaling subparts allow potential drugs to be selected, and do not consider polypharmacology, i.e. multiple targets of a known drug, in specific subparts. RESULTS: Here, to address the limitations, we developed a subpathway-based polypharmacology drug repositioning method, PATHOME-Drug, based on drug-associated transcriptomes. Specifically, this tool locates subparts of signaling cascading related to phenotype changes (e.g. disease status changes), and identifies existing approved drugs such that their multiple targets are enriched in the subparts. We show that our method demonstrated better performance for detecting signaling context and specific drugs/compounds, compared to WebGestalt and clusterProfiler, for both real biological and simulated datasets. We believe that our tool can successfully address the current shortage of targeted therapy agents. AVAILABILITY AND IMPLEMENTATION: The web-service is available at http://statgen.snu.ac.kr/software/pathome. The source codes and data are available at https://github.com/labnams/pathome-drug. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Rational design of small molecule RHOA inhibitors for gastric cancer.

Previously, we identified Ras homologous A (RHOA) as a major signaling hub in gastric cancer (GC), the third most common cause of cancer death in the world, prompting us to rationally design an efficacious inhibitor of this oncogenic GTPase. Here, based on that previous work, we extend those computational analyses to further pharmacologically optimize anti-RHOA hydrazide derivatives for greater anti-GC potency. Two of these, JK-136 and JK-139, potently inhibited cell viability and migration/invasion of GC cell lines, and mouse xenografts, diversely expressing RHOA. Moreover, JK-136's binding affinity for RHOA was >140-fold greater than Rhosin, a nonclinical RHOA inhibitor. Network analysis of JK-136/-139 vs. Rhosin treatments indicated downregulation of the sphingosine-1-phosphate, as an emerging cancer metabolic pathway in cell migration and motility. We assert that identifying and targeting oncogenic signaling hubs, such as RHOA, represents an emerging strategy for the design, characterization, and translation of new antineoplastics, against gastric and other cancers.

Differential effects, on oncogenic pathway signalling, by derivatives of the HNF4 α inhibitor BI6015.

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease with few "targeted" therapeutic options. Previously, we demonstrated involvement of the transcription factor HNF4α in human GC tumours, and the developmental signal mediator, WNT5A, as a prognostic GC biomarker. One previously developed HNF4α antagonist, BI6015, while not advancing beyond preclinical stages, remains useful for studying GC. METHODS: Here, we characterised the antineoplastic signalling activity of derivatives of BI6015, including transfer of the nitro group from the para position, relative to a methyl group on its benzene ring, to the ortho- and meta positions. We assessed binding efficacy, through surface plasmon resonance and docking studies, while biologic activity was assessed by antimitogenic efficacy against a panel of GC cell lines, and dysregulated transcriptomes, followed by pathway and subpathway analysis. RESULTS: The para derivative of BI6105 was found substantially more growth inhibitory, and effective, in downregulating numerous oncogenic signal pathways, including the embryonic cascade WNT. The ortho and meta derivatives, however, failed to downregulate WNT or other embryonic signalling pathways, unable to suppress GC growth. CONCLUSION: Straightforward strategies, employing bioinformatics analyses, to facilitate the effective design and development of "druggable" transcription factor inhibitors, are useful for targeting specific oncogenic signalling pathways, in GC and other cancers.

Effects of operational decisions on the diffusion of epidemic disease: A system dynamics modeling of the MERS-CoV outbreak in South Korea.

We evaluated the nosocomial outbreak of Middle East Respiratory Syndrome (MERS) Coronavirus (CoV) in the Republic of Korea, 2015, from a healthcare operations management perspective. Establishment of healthcare policy in South Korea provides patients' freedom to select and visit multiple hospitals. Current policy enforces hospitals preference for multi-patient rooms to single-patient rooms, to lower financial burden. Existing healthcare systems tragically contributed to 186 MERS outbreak cases, starting from single "index patient" into three generations of secondary infections. By developing a macro-level health system dynamics model, we provide empirical knowledge to examining the case from both operational and financial perspectives. In our simulation, under base infectivity scenario, high emergency room occupancy circumstance contributed to an estimated average of 101 (917%) more infected patients, compared to when in low occupancy circumstance. Economic patient room design showed an estimated 702% increase in the number of infected patients, despite the overall 98% savings in total expected costs compared to optimal room design. This study provides first time, system dynamics model, performance measurements from an operational perspective. Importantly, the intent of this study was to provide evidence to motivate public, private, and government healthcare administrators' recognition of current shortcomings, to optimize performance as a whole system, rather than mere individual aspects.

HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer.

BACKGROUND: Worldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. OBJECTIVE: To determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. METHODS: We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. RESULTS: Hepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. CONCLUSIONS: Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.

Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems.

BACKGROUND: "Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. METHOD: To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. RESULTS: The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network. CONCLUSION: Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.

Detection of PIWI and piRNAs in the mitochondria of mammalian cancer cells.

Piwi-interacting RNAs (piRNAs) are 26-31 nt small noncoding RNAs that are processed from their longer precursor transcripts by Piwi proteins. Localization of Piwi and piRNA has been reported mostly in nucleus and cytoplasm of higher eukaryotes germ-line cells, where it is believed that known piRNA sequences are located in repeat regions of nuclear genome in germ-line cells. However, localization of PIWI and piRNA in mammalian somatic cell mitochondria yet remains largely unknown. We identified 29 piRNA sequence alignments from various regions of the human mitochondrial genome. Twelve out 29 piRNA sequences matched stem-loop fragment sequences of seven distinct tRNAs. We observed their actual expression in mitochondria subcellular fractions by inspecting mitochondrial-specific small RNA-Seq datasets. Of interest, the majority of the 29 piRNAs overlapped with multiple longer transcripts (expressed sequence tags) that are unique to the human mitochondrial genome. The presence of mature piRNAs in mitochondria was detected by qRT-PCR of mitochondrial subcellular RNAs. Further validation showed detection of Piwi by colocalization using anti-Piwil1 and mitochondria organelle-specific protein antibodies.

An electroactive biotin-doped polypyrrole substrate that immobilizes and releases EpCAM-positive cancer cells.

The specific capture and remotely controlled release of the EpCAM-positive cancer cells from biotin-doped polypyrrole (Ppy) films in response to an electrical potential is presented. As Ppy allows the direct incorporation of biotin molecules during the electrochemical process, densely packed biotin molecules can serve as the binding sites for streptavidin-tagged biomolecular complexes. This study demonstrates not only the enhanced capture and enrichment of EpCAM-positive cancer cells but also "on-demand" release of the viable cells from conductive Ppy in an electrical-potential-dependent way. This novel approach is of great importance in a diverse range of applications, and in particular in cancer diagnostics and screening.

High Expression of PRNP Predicts Poor Prognosis in Korean Patients with Gastric Cancer.

Gastric cancer (GC) has the highest occurrence and fourth-highest mortality rate of all cancers in Korea. Although survival rates are improving with the development of diagnosis and treatment methods, the five-year survival rate for stage 4 GC in Korea remains <10%. Therefore, it is important to identify candidate prognostic factors for predicting poor prognosis. PRNP is a gene encoding the prion protein PrP, which has been noted for its role in the nervous system and is known to be upregulated in various cancers and associated with both cell proliferation and metastasis. However, the value of PRNP as a prognostic factor for Korean GC patients remains unclear. Here, we analyzed the relationship between PRNP expression and survival in three independent datasets for Korean patients with GC as well as the TCGA-STAD dataset. Survival analysis indicates that high levels of PRNP expression are associated with poor overall survival of patients with GC. Gene set enrichment analysis showed that PRNP is associated with epithelial mesenchymal transition and Hedgehog signaling. In addition, proliferation of GC cell lines was inhibited after siRNA-mediated knockdown of PRNP. In conclusion, our study suggests a potential role for PRNP as a candidate prognostic factor for patients with GC.

Second-Generation JK-206 Targets the Oncogenic Signal Mediator RHOA in Gastric Cancer.

Ras homologous A (RHOA), a signal mediator and a GTPase, is known to be associated with the progression of gastric cancer (GC), which is the fourth most common cause of death in the world. Previously, we designed pharmacologically optimized inhibitors against RHOA, including JK-136 and JK-139. Based on this previous work, we performed lead optimization and designed novel RHOA inhibitors for greater anti-GC potency. Two of these compounds, JK-206 and JK-312, could successfully inhibit the viability and migration of GC cell lines. Furthermore, using transcriptomic analysis of GC cells treated with JK-206, we revealed that the inhibition of RHOA might be associated with the inhibition of the mitogenic pathway. Therefore, JK-206 treatment for RHOA inhibition may be a new therapeutic strategy for regulating GC proliferation and migration.

The homeobox gene Hex regulates hepatocyte differentiation from embryonic stem cell-derived endoderm.

We investigated the role of the hematopoietically expressed homeobox (Hex) in the differentiation and development of hepatocytes within embryonic stem cell (ESC)-derived embryoid bodies (EBs). Analyses of hepatic endoderm derived from Hex(-/-) EBs revealed a dramatic reduction in the levels of albumin (Alb) and alpha-fetoprotein (Afp) expression. In contrast, stage-specific forced expression of Hex in EBs from wild-type ESCs led to the up-regulation of Alb and Afp expression and secretion of Alb and transferrin. These inductive effects were restricted to c-kit(+) endoderm-enriched EB-derived populations, suggesting that Hex functions at the level of hepatic specification of endoderm in this model. Microarray analysis revealed that Hex regulated the expression of a broad spectrum of hepatocyte-related genes, including fibrinogens, apolipoproteins, and cytochromes. When added to the endoderm-induced EBs, bone morphogenetic protein 4 acted synergistically with Hex in the induction of expression of Alb, Afp, carbamoyl phosphate synthetase, transcription factor 1, and CCAAT/enhancer binding protein alpha. These findings indicate that Hex plays a pivotal role during induction of liver development from endoderm in this in vitro model and suggest that this strategy may provide important insight into the generation of functional hepatocytes from ESCs.

CANcer-specific Evaluation System (CANES): a high-accuracy platform, for preclinical single/multi-biomarker discovery.

The recent creation of enormous, cancer-related "Big Data" public depositories represents a powerful means for understanding tumorigenesis. However, a consistently accurate system for clinically evaluating single/multi-biomarkers remains lacking, and it has been asserted that oft-failed clinical advancement of biomarkers occurs within the very early stages of biomarker assessment. To address these challenges, we developed a clinically testable, web-based tool, CANcer-specific single/multi-biomarker Evaluation System (CANES), to evaluate biomarker effectiveness, across 2,134 whole transcriptome datasets, from 94,147 biological samples (from 18 tumor types). For user-provided single/multi-biomarkers, CANES evaluates the performance of single/multi-biomarker candidates, based on four classification methods, support vector machine, random forest, neural networks, and classification and regression trees. In addition, CANES offers several advantages over earlier analysis tools, including: 1) survival analysis; 2) evaluation of mature miRNAs as markers for user-defined diagnostic or prognostic purposes; and 3) provision of a "pan-cancer" summary view, based on each single marker. We believe that such "landscape" evaluation of single/multi-biomarkers, for diagnostic therapeutic/prognostic decision-making, will be highly valuable for the discovery and "repurposing" of existing biomarkers (and their specific targeted therapies), leading to improved patient therapeutic stratification, a key component of targeted therapy success for the avoidance of therapy resistance.

Clinical Relevance and Molecular Phenotypes in Gastric Cancer, of TP53 Mutations and Gene Expressions, in Combination With Other Gene Mutations.

While altered TP53 is the most frequent mutation in gastric cancer (GC), its association with molecular or clinical phenotypes (e.g., overall survival, disease-free survival) remains little known. To that end, we can use genome-wide approaches to identify altered genes significantly related to mutated TP53. Here, we identified significant differences in clinical outcomes, as well as in molecular phenotypes, across specific GC tumor subpopulations, when combining TP53 with other signaling networks, including WNT and its related genes NRXN1, CTNNB1, SLITRK5, NCOR2, RYR1, GPR112, MLL3, MTUS2, and MYH6. Moreover, specific GC subpopulations indicated by dual mutation of NRXN1 and TP53 suggest different drug responses, according to the Connectivity Map, a pharmacological drug-gene association tool. Overall, TP53 mutation status in GC is significantly relevant to clinical or molecular categories. Thus, our approach can potentially provide a patient stratification strategy by dissecting previously unknown multiple TP53-mutated patient groups.

Ad5/35E1aPSESE4: A novel approach to marking circulating prostate tumor cells with a replication competent adenovirus controlled by PSA/PSMA transcription regulatory elements.

Circulating tumor cells serve as useful biomarkers with which to identify disease status associated with survival, metastasis and drug sensitivity. Here, we established a novel application for detecting PSA/PSMA-positive prostate cancer cells circulating in peripheral blood employing an adenovirus called Ad5/35E1aPSESE4. Ad5/35E1aPSESE4 utilized PSES, a chimeric enhancer derived from PSA/PSMA promoters that is highly active with and without androgen. A fluorescence signal mediated by GFP expression upon Ad5/35E1aPSESE4 infection was selectively amplified in PSA/PSMA-positive prostate cancer cells in vitro and ex vivo. Furthermore, for the in vivo model, blood drawn from TRAMP was tested for CTCs with Ad5/35E1aPSESE4 infection and was positive for CTCs at week 16. Validation was performed on patient blood at various clinical stages and found out 1-100 CTCs expressing GFP upon Ad5/35E1aPSESE4 infection. Interestingly, CTC from one patient was confirmed to be sensitive to docetaxel chemotherapeutic reagent and to abundantly express metastasis-related genes like MMP9, Cofilin1, and FCER1G through RNA-seq. Our study established that the usage of Ad5/35E1aPSESE4 is effective in marking PSA/PSMA-positive prostate cancer cells in patient blood to improve the efficacy of utilizing CTCs as a biomarker.

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.

Network Comparison of Inflammation in Colorectal Cancer and Alzheimer's Disease.

Recently, a large clinical study revealed an inverse correlation of individual risk of cancer versus Alzheimer's disease (AD). However, no explanation exists for this anticorrelation at the molecular level; however, inflammation is crucial to the pathogenesis of both diseases, necessitating a need to understand differing signaling usage during inflammatory responses distinct to both diseases. Using a subpathway analysis approach, we identified numerous well-known and previously unknown pathways enriched in datasets from both diseases. Here, we present the quantitative importance of the inflammatory response in the two disease pathologies and summarize signal transduction pathways common to both diseases that are affected by inflammation.

A pathway-based approach for identifying biomarkers of tumor progression to trastuzumab-resistant breast cancer.

Although trastuzumab is a successful targeted therapy for breast cancer patients with tumors expressing HER2 (ERBB2), many patients eventually progress to drug resistance. Here, we identified subpathways differentially expressed between trastuzumab-resistant vs. -sensitive breast cancer cells, in conjunction with additional transcriptomic preclinical and clinical gene datasets, to rigorously identify overexpressed, resistance-associated genes. From this approach, we identified 32 genes reproducibly upregulated in trastuzumab resistance. 25 genes were upregulated in drug-resistant JIMT-1 cells, which also downregulated HER2 protein by >80% in the presence of trastuzumab. 24 genes were downregulated in trastuzumab-sensitive SKBR3 cells. Trastuzumab sensitivity was restored by siRNA knockdown of these genes in the resistant cells, and overexpression of 5 of the 25 genes was found in at least one of five refractory HER2 + breast cancer. In summary, our rigorous computational approach, followed by experimental validation, significantly implicate ATF4, CHEK2, ENAH, ICOSLG, and RAD51 as potential biomarkers of trastuzumab resistance. These results provide further proof-of-concept of our methodology for successfully identifying potential biomarkers and druggable signal pathways involved in tumor progression to drug resistance.

A nanowire-based label-free immunosensor: direct incorporation of a PSA antibody in electropolymerized polypyrrole.

We have suggested a novel method for the preparation of a label-free electrochemical immunosensor for the detection of prostate-specific antigen (PSA) as target marker for prostate cancer. Direct incorporation of PSA antibody (anti-PSA) into polypyrrole (Ppy) electropolymerized on a three-dimensional Au nanowire array has resulted in enhanced molecular interactions, ultimately leading to improved sensing performance. The electrochemical performance of the nanowire-based immunosensor array were characterized by (1) differential pulse voltammetry (DPV) to evaluate the specific recognition of PSA, (2) impedance and cyclic voltammetry to observe surface resistance and electroactivity, and (3) scanning electron microscopy (SEM) to demonstrate the three-dimensional architecture. The vertically-aligned geometric organization of Ppy provides a novel platform to improve the anti-PSA loading capacity. Overall, enhanced electrochemical performance of the proposed immunosensor has been demonstrated by its linear response over PSA concentrations ranging from 10 fg mL(-1) to 10 ng mL(-1) and a detection limit of 0.3 fg mL(-1), indicating that the strategy proposed here has great potential for clinical applications.

Mg2+ effect on argonaute and RNA duplex by molecular dynamics and bioinformatics implications.

RNA interference (RNAi), mediated by small non-coding RNAs (e.g., miRNAs, siRNAs), influences diverse cellular functions. Highly complementary miRNA-target RNA (or siRNA-target RNA) duplexes are recognized by an Argonaute family protein (Ago2), and recent observations indicate that the concentration of Mg2+ ions influences miRNA targeting of specific mRNAs, thereby modulating miRNA-mRNA networks. In the present report, we studied the thermodynamic effects of differential [Mg2+] on slicing (RNA silencing cycle) through molecular dynamics simulation analysis, and its subsequent statistical analysis. Those analyses revealed different structural conformations of the RNA duplex in Ago2, depending on Mg2+ concentration. We also demonstrate that cation effects on Ago2 structural flexibility are critical to its catalytic/functional activity, with low [Mg2+] favoring greater Ago2 flexibility (e.g., greater entropy) and less miRNA/mRNA duplex stability, thus favoring slicing. The latter finding was supported by a negative correlation between expression of an Mg2+ influx channel, TRPM7, and one miRNA's (miR-378) ability to downregulate its mRNA target, TMEM245. These results imply that thermodynamics could be applied to siRNA-based therapeutic strategies, using highly complementary binding targets, because Ago2 is also involved in RNAi slicing by exogenous siRNAs. However, the efficacy of a siRNA-based approach will differ, to some extent, based on the Mg2+ concentration even within the same disease type; therefore, different siRNA-based approaches might be considered for patient-to-patient needs.

The condensin component NCAPG2 regulates microtubule-kinetochore attachment through recruitment of Polo-like kinase 1 to kinetochores.

The early event of microtubule-kinetochore attachment is a critical stage for precise chromosome segregation. Here we report that NCAPG2, which is a component of the condensin II complex, mediates chromosome segregation through microtubule-kinetochore attachment by recruiting PLK1 to prometaphase kinetochores. NCAPG2 colocalizes with PLK1 at prometaphase kinetochores and directly interacts with the polo-box domain (PBD) of PLK1 via its highly conserved C-terminal region. In both humans and Caenorhabditis elegans, when NCAPG2 is depleted, the attachment of the spindle to the kinetochore is loosened and misoriented. This is caused by the disruption of PLK1 localization to the kinetochore and by the decreased phosphorylation of its kinetochore substrate, BubR1. In addition, the crystal structure of the PBD of PLK1, in complex with the C-terminal region of NCAPG2, (1007)VLS-pT-L(1011), exhibits structural conservation of PBD-phosphopeptides, suggesting that the regulation of NCAPG2 function is phosphorylation-dependent. These findings suggest that NCAPG2 plays an important role in regulating proper chromosome segregation through a functional interaction with PLK1 during mitosis.