NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma

Lin, Shupeng; Zhou, Shengde; Jiang, Shaojie; Liu, Xiaolong; Wang, Yifan; Zheng, Xue-Yong; Zhou, Hai‐Meng; Li, Xuhui; Cai, Xiujun

doi:10.3892/or.2016.4896

Cited by 33 publications

(42 citation statements)

References 49 publications

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“…Aberrant activation of Wnt/β-catenin signaling pathway plays an important role in sustaining cancer cell stemness [46]. Consistently, Lin et al reported that the overexpression of NEK2 could enhance self-renewal properties in HCC by activating the Wnt/β-catenin pathway [27]. Moreover, a study by Lai et al suggested that the overexpression of NEK2 could induce cell cycle progression and promote proliferation via the activation of Wnt/β-catenin signaling pathway [25].…”

Section: Discussionmentioning

confidence: 55%

“…Some studies have suggested that NEK2 is overexpressed in HCC tissues compared with adjacent normal tissues and is associated with poor survival [24][25][26][27][28][29][30][31]. In addition, there is evidence showing that elevated NEK2 expression could enhance stem-like properties, drug resistance, and the progression of HCC [27,28]. However, a study by Fu et al reported that HCC patients with high NEK2 expression had better survival [32].…”

Section: Introductionmentioning

confidence: 89%

“…Moreover, a study by Lai et al suggested that the overexpression of NEK2 could induce cell cycle progression and promote proliferation via the activation of Wnt/β-catenin signaling pathway [25]. ABCG2, a member of ABC transporter family, is a vital element of multi-drug resistance system in cancer [47] and Lin et al demonstrated that NEK2 plays a crucial role in chemotherapeutic resistance by regulating the expression of ABCG2 in HCC cells [27]. Similarly, a study by Wu et al demonstrated that NKE2 overexpression can induce the resistance of hepatoma J7 or Hep3B cells to chemotherapy via upregulation of ABCC10 and the expression of Twist [29].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to our cohort study, 9 of the previous studies were conducted in China [25,32,[39][40][41][42][43][44][45], and 1 in Japan [30]. The case numbers in each study ranged between [30,32,39,42,45], and 5 referring to liver cirrhosis [32,41,42,44,45]. The NOS scores of the studies included ranged from 5 to 7, indicating that the quality of these studies was moderate to high.…”

Section: Study Search and Study Characteristics In Meta-analysismentioning

confidence: 99%

“…Among the eligible studies, 4 referred to the correlation between NEK2 expression and DFS/RFS, including 3 previously published studies [24,27,30] and our cohort study. Because of the similarity between DFS and RFS, we merged them for a pooled analysis.…”

Section: Meta-analysis Of Nek2 Expression and Dfs/rfs In Hcc Patientsmentioning

confidence: 99%

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The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

Cheng

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Numerous studies have shown that NIMA-related kinase 2 (NEK2) expression in hepatocellular carcinoma (HCC) tissue is associated with survival and clinicopathological features; however, the evidence remains inconclusive. Thus, we aimed to further explore the prognostic and clinicopathological significance of NEK2 expression in HCC using a two-part study consisting of a retrospective cohort study and a meta-analysis. Methods: In the cohort study, NEK2 expression in 206 HCC samples and adjacent normal liver tissues was detected by immunohistochemistry (IHC). Patients were divided into a high NEK2 expression group and a low NEK2 expression group by the median value of the immunohistochemical scores. The Kaplan–Meier method with the log-rank test was used to analyze survival outcomes in the two groups, and multivariate analysis based on Cox proportional hazard regression models was applied to identify independent prognostic factors. In the meta-analysis, eligible studies were searched in PubMed, EMBASE, Web of Science, and CNKI databases. STATA version 12.0 (Stata Corporation, College Station, TX) was used for statistical analyses. Results: The IHC results of our cohort study showed higher NEK2 expression in HCC tissues compared with adjacent normal liver tissues. Multivariate analysis revealed that high NEK2 expression was an independent risk factor for poor overall survival (OS) [hazard ratio (HR) = 1.763; 95% CI, 1.060–2.935; P = 0.029] and disease-free survival (DFS) [hazard ratio (HR) = 1.687; 95% CI, 1.102–2.584; P = 0.016] in HCC patients. A total of 11 studies with 1,698 patients were enrolled in the meta-analysis, consisting of 10 studies from the database search and our cohort study. The pooled results revealed that high NEK2 expression correlated closely with poor OS among HCC patients (HR = 1.47; 95% CI, 1.21–1.80; P < 0.01), and DFS/recurrence-free survival (RFS) (HR = 1.92; 95% CI, 1.41–2.63; P < 0.01). Additionally, our meta-analysis also showed that the proportion of HCC patients with high NEK2 expression was greater in the group with larger tumors (> 5 cm) than in the group with smaller tumors (≤ 5 cm) [odds ratio (OR) = 2.02; 95% CI, 1.13–3.64; P < 0.01). Conclusion: Our study demonstrated that high NEK2 expression is a risk factor for poor survival in HCC patients. More prospective, homogeneous, and multiethnic studies are required to validate our findings.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Study Search and Study Characteristics In Meta-analysismentioning

confidence: 99%

Section: Meta-analysis Of Nek2 Expression and Dfs/rfs In Hcc Patientsmentioning

confidence: 99%

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The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

Cheng

Chen

et al. 2018

Cell Physiol Biochem

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Hepatoma cell functions modulated by NEK2 are associated with liver cancer progression

Lin

Lee

et al. 2017

Intl Journal of Cancer

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NEK2 (NIMA-related expressed kinase 2) is a serine/threonine centrosomal kinase that acts as a critical regulator of centrosome structure and function. Aberrant NEK2 activities lead to failure in regulating centrosome duplication. NEK2 overexpression promotes tumorigenesis and is associated with poor prognosis in several cancers. Increased NEK2 expression during the late pathological stage has been detected in the Oncomine liver dataset and hepatocellular carcinoma (HCC) specimens. Elevated NEK2 protein is associated with poor overall survival in patients with HCC. However, the precise roles and mechanisms of NEK2 in liver cancer progression remain largely unknown. An earlier functional study revealed that NEK2 mediates drug resistance (cisplatin or lipo-doxorubicin) via expression of an ABCC10 transporter. Active angiogenesis and metastasis underlie the rapid recurrence and poor survival of HCC. Results from the current study showed that NEK2 mediates tumor growth, metastasis and angiogenesis in vivo. NEK2-mediated drug resistance was blocked by a specific PI3K or AKT inhibitor. Moreover, NEK2 mediated liver cancer cell migration via pAKT/NF-κB signaling and matrix metalloproteinase (MMP) activation. Angiogenesis was induced via the same signaling pathway and IL-8 stimulation. Our findings collectively indicate that NEK2 modulates hepatoma cell functions, including growth, drug resistance, metastasis and angiogenesis via downstream genes activation.

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Comprehensive kinomic study via a chemical proteomic approach reveals kinome reprogramming in hepatocellular carcinoma tissues

Wang

Yang

et al. 2022

Proteomics

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Kinases are attractive therapeutic targets since they are commonly altered in cancers. Here, to identify kinases of potential therapeutic interest in HCC, a quantitative kinomic study of tumour and adjacent non‐tumour liver tissues was performed using a chemical proteomics approach. In total, 124 kinases were found differentially expressed and they were distributed over all nine kinase groups. Exploration of The Cancer Genome Atlas (TCGA) data showed that the dysregulation of 45 kinases was correlated with poor prognosis in HCC patients. We then tested 11 inhibitors targeting 12 crucial protein kinases alone or in combination for their ability to inhibit cell growth in Hep3B and PLC/PRF/5 cell lines. Six inhibitors significantly reduced viability in both cell lines. Combination inhibition of polo‐like kinase 1 (PLK1) and casein kinase 1 epsilon (CSNK1E) significantly induced growth arrest in both cell lines synergistically. In summary, our analysis presents the most complete view of kinome reprogramming in HCC and provides novel insight into crucial kinases in HCC and potential therapeutic targets for HCC treatment. Moreover, the identification of hundreds of differentially expressed kinases forms a rich resource for novel drug targets or diagnostic biomarker discovery. Data are available via ProteomeXchange (identifier PXD023806).

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NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma

Cited by 33 publications

References 49 publications

The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

The Prognostic Significance of NEK2 in Hepatocellular Carcinoma: Evidence from a Meta-Analysis and Retrospective Cohort Study

Hepatoma cell functions modulated by NEK2 are associated with liver cancer progression

Comprehensive kinomic study via a chemical proteomic approach reveals kinome reprogramming in hepatocellular carcinoma tissues

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