Open Access

High expression of citron kinase predicts poor prognosis of prostate cancer

  • Authors:
    • Junnan Liu
    • Jianguo Dou
    • Wujiao Wang
    • Hengchuan Liu
    • Yunlang Qin
    • Qixin Yang
    • Wencheng Jiang
    • Yong Liang
    • Yuejiang Liu
    • Jiang He
    • Li Mai
    • Ying Li
    • Delin Wang
  • View Affiliations

  • Published online on: January 7, 2020     https://doi.org/10.3892/ol.2020.11254
  • Pages: 1815-1823
  • Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Citron kinase (CIT) is a Rho‑effector protein kinase that is associated with several types of cancer. However, the role of CIT in prostate cancer (PCa) is unclear. The current study utilized microarray data obtained from The Cancer Genome Atlas, which was analyzed via Biometric Research Program array tools. Additionally, reverse transcription‑quantitative (RT‑q)PCR was performed to compare the mRNA expression of CIT in PCa tissue and in benign prostatic hyperplasia. The protein expression of CIT was detected in a consecutive cohort via immunochemistry and CIT was screened as a potential oncogene in PCa. The results of RT‑qPCR demonstrated that the mRNA expression of CIT was increased in PCa tissues. Furthermore, immunochemistry revealed that CIT protein expression was positively associated with age at diagnosis, Gleason grade, serum PSA, clinical T stage, risk group, lymph node invasion and metastasis. When compared with the low expression group, patients with a high CIT expression exhibited shorter survival rates, cancer specific mortalities (CSM) and biochemical recurrence (BCR). In addition, multivariate analysis revealed that CIT was a potential predictor of CSM and BCR. The results revealed that CIT is overexpressed during the malignant progression of PCa and may be a predictor of a poor patient prognosis.

Introduction

Prostate cancer (PCa) is one of the most common cancers worldwide (1), with an incidence rate that has increased in China in recent years (2). Prostate specific antigen (PSA) screening is a primary method for the surveillance of PCa. However, PSA exhibits a low specificity, which leads to the incorrect diagnoses and treatment of patients with PCa (3). Therefore, the discovery and identification of new biomarkers are essential for monitoring patients with PCa.

Citron-kinase (CIT) comprises an amino-terminal serine/threonine kinase domain, which is highly conserved between insects and mammals (4). It has been revealed that CIT is critical for cytokinesis (5,6). CIT is also involved in the cleavage of the furrow and midbody, which is essential to cellular abscission (79). Furthermore, CIT phosphorylates the regulatory light chain of myosin II at the Ser 19/Thr 18 positions, consequently activating myosin II, which is the primary motor protein and responsible for cytokinesis (10).

In the current study, increased expression of CIT was identified as an oncogene by bioinformatic analysis. This result was verified by reverse transcription-quantitative (RT-q)PCR and immunochemistry. The aim of the current study was to assess the role of CIT in PCa and to determine the possibility of using CIT in the diagnosis and therapy of patients with PCa.

Materials and methods

Dataset gene expression analysis

mRNA expression profiles and associated PCa clinical datasets (PRAD_2015_02_24) from The Cancer Genome Atlas (TCGA) were downloaded from the University of California Santa Cruz cancer genome browser (https://xena.ucsc.edu/welcome-to-ucsc-xena/). The profile contained 52 cases of normal tissue and 499 cases of primary PCa tissue. Microarray data were normalized and compared using Biometric Research Program (BRB) array tools developed by Dr Richard Simon and Dr Yingdong Zhao (http://linus.nci.nih.gov/BRB-ArrayTools) (11). Differentially expressed genes (DEGs) were filtered by comparing cancer and normal tissue, Gleason grades ≥7 and Gleason grades <7, PSA ≥10 ng/ml and PSA <10 ng/ml, Ta-2 and T3-4, regional lymph node metastasis (N1) and no regional lymph nodes metastasis (N0), and metastasis to distant organs (M1) and no distant metastasis (M0). DEGs were defined as a fold-change (FC) >1 and P<0.01. Volcano plots were established to visualize the genes that were screened.

Patients and tissues

To determine the expression of CIT mRNA in patients with PCa, fresh PCa tissue (n=35) and benign prostatic hyperplasia tissue (BPH; n=20) were collected from the First Affiliated Hospital of Chongqing Medical University (Chongqing, China). All samples were confirmed by pathological examination and subsequently stored in liquid nitrogen (−196°C) for mRNA analysis. Patient characteristics are shown in Table I.

Table I.

Characteristics of prostate cancer patients.

Table I.

Characteristics of prostate cancer patients.

ItemsN (%)
Sample type
  Aggressive PCa131 (48.34)
  Primary PCa140 (51.66)
Origin
  The First Affiliated Hospital of Chongqing Medical University156 (57.56)
  The Zigong No. 4 People's Hospital53 (19.56)
  The Zigong No. 1 People's Hospital62 (22.88)
Age, years
  <7025 (9.23)
  70–79148 (54.61)
  ≥8098 (36.16)
Gleason score
  <788 (32.47)
  789 (32.84)
  ≥894 (34.69)
PSA level
  <434 (12.55)
  4-9.935 (12.92)
  10-19.941 (15.13)
  ≥20161 (59.40)
pT stage
  ≤T2150 (55.35)
  T375 (27.68)
  T446 (16.97)
pN stage
  N0255 (94.10)
  N116 (5.90)
pM stage
  M0254 (93.73)
  M117 (6.27)
Therapy
  ADT88 (32.47)
  PR183 (67.53)
BCR after ADT
  No15 (17.05)
  Yes68 (77.27)
  Loss5 (5.68)
CSM after RP
  No137 (74.86)
  Yes35 (19.13)
  Loss or death for other cause11 (6.01)

[i] PSA, prostate-specific antigen; BCR, biochemical recurrence; ADT, androgen deprivation therapy; RP, radical prostatectomy; CSM, cancer-specific morality; PCa, prostate cancer.

Formalin fixed paraffin embedded BPH (n=39) and PCa (n=271) samples were retrieved from the Pathology Department of the First Affiliated Hospital of Chongqing Medical University, Zigong Fourth People's Hospital and Zigong First People's Hospital from 2005 to 2017. None of the patients recruited into the present study received chemotherapy, radiation therapy androgen deprivation (ADT) or radical prostatectomy (RP) prior to enrollment. The use of tissue was approved by the Ethics committee of the First Affiliated Hospital of Chongqing Medical University (approval no. 2018-69), Zigong Fourth People's Hospital (approval no. 2018-32) and Zigong First People's Hospital (approval no. 2018-47).

Patients were sub-divided into a high-risk group (HR-group) when one of the following criteria was met: i) Gleason grades ≥8; ii) T2c-T4 tumor or iii) PSA level ≥20 ng/ml (12). Patients that exhibited local invasion and metastasis were considered to have aggressive PCa (13). The Gleason score was evaluated according to the guidelines conducted by World Health Organization and the International Society of Urological Pathology (14,15). Moreover, patients with PCa were stratified into three grades including low, middle and high grade, which determined by a Gleason sum <5, between 5 to 7, and >7, respectively (16).

Patients who received RP were followed-up by a telephone call and patients who received ADT were monitored via continuous serum PSA surveillance (in 6-month intervals). The follow-up time of patients receiving ADT was 14.6±8.2 months with 54.2% patients being followed-up for more than one year. The follow-up time of patients receiving RP was 25±20.3 months, with 66.3% patients being followed-up for more than one year. Due to the different therapies administered and the follow-up methods used, follow-up outcomes were stratified to cancer-specific mortality (CSM) for patients receiving RP and biochemical recurrence (BCR) for patients receiving ADT. BCR was defined when patients exhibited a PSA level ≥0.2 ng/ml on at least two consecutive postoperative occasions, as described previously (17).

Immunohistochemistry

Tissues from the patients were fixed in 10% buffered formalin at room temperature for 2 days, and then were transferred to 70% ethanol overnight. The infiltrated tissues were embedded into paraffin blocks. A single 3-µm section was cut from each block. Immunochemistry and the assessment of immunoreactivity were performed as described previously (18). The sections were incubated with primary antibody (1:50; cat. no. YT0931; ImmunoWay Biotechnology Company) at 4°C overnight. CIT immunoreactivity was scored by multiplying the staining intensity by the percentage of area stained. Intensity was scored as follows: 0 (no staining), 1 (weak staining), 2 (moderate staining) and 3 (strong staining). The percentage of area stained was defined as follows: 0 (no staining), 1 (1–25% of cells stained), 2 (26–50% of cells stained), 3 (51–75% of cells stained), 4 (>75% of cells stained). A high expression of CIT (H-CIT) was defined as 6–12, whereas a low expression of CIT (L-CIT) was defined as 0–5 (18). CIT immunohistochemical staining was scored under a light microscope independently by two experienced pathologists (LY and ZT) who were blinded to patient clinical information.

RT-qPCR

The isolation of total RNA and RT-qPCR were performed as described previously (19). All samples were amplified in triplicate. To calculate the expression of CIT mRNA in samples, GAPDH was used as reference gene. The following primers were used in RT-qPCR: CIT forward, 5′-ACCATAGCTGAGTTACAGGAGC-3′ and reverse, 5′-GTCCCCGGTTGCTTTCTCT-3′; GAPDH forward, 5′-TGGAAGGACTCATGACCACA-3′ and reverse, 5′-TTCAGCTCAGGGATGACCTT-3′.

Statistical analyses

Statistical analyses were performed using SPSS 20.0 software (IBM Corp.) and Prism 5.0 software (GraphPad Software, Inc.). Comparison between groups was made by unpaired t-tests or Kruskal-Wallis test. The association between CIT expression and the clinicopathological parameters of patients with PCa was analyzed using a χ2 test. Follow-up outcomes were stratified to CSM for patients that received RP or BCR for patients that received ADT. The Kaplan-Meier method and a log-rank test were established to plot survival curves. Univariate and multivariate Cox regression analysis by backward selection were used to evaluate the prognostic significance of CIT for predicting BCR and CSM. The experiments were repeated 3 times and the data were presented as mean ± standard error. P<0.05 was considered to indicate a statistically significant difference.

Results

CIT is screened as an oncogene in PCa

A total of 3,279 DEGs were filtered from the TCGA profile when comparing normal prostate gland tissue with PCa tissue. A further screening was performed by dividing groups according to Gleason grades, serum PSA levels and tumor, node and metastasis (TNM) stages (Fig. 1). A total of 30 DEGs were identified to be significant in all of these comparisons (Table II). Significantly high expression of CIT mRNA was exhibited in PCa samples (FC=2.180; P<0.001) and in patients with Gleason grades ≥7 (FC=1.637; P<0.001), serum PSA levels ≥10 ng/ml (FC=1.649; P=0.002), T3-T4 (FC=1.606; P<0.001), positive lymph node invasion (LNI; FC=1.474; P<0.001) and distant metastasis (FC=1.765; P=0.009). The results indicate that CIT may be a potential PCa-associated oncogene.

Table II.

The differential expression of citron kinase mRNA in the Cancer Genome Atlas mRNA expression profiles (PRAD_2015_02_24).

Table II.

The differential expression of citron kinase mRNA in the Cancer Genome Atlas mRNA expression profiles (PRAD_2015_02_24).

Tumor vs. normalGleason ≥7 vs. Gleason <7PSA ≥10 vs. PSA <10T3-4 vs. Ta-2N1 vs. N0M1 vs. M0






Gene nameFCPFCPFCPFCPFCPFCP
CIT2.18<0.0011.64<0.0011.65<0.0011.61<0.0011.47<0.0011.770.010
STAC1.55<0.001−1.78<0.001−2.63<0.001−1.45<0.001−1.85<0.001−3.72<0.001
HELLS1.35<0.0011.41<0.0011.66<0.0011.43<0.0011.42<0.0011.750.010
RIC3−1.40<0.001−1.38<0.001−1.560.010−1.38<0.001−1.42<0.001−2.21<0.001
C8orf46−1.54<0.001−1.300.010−1.590.010−1.29<0.001−1.32<0.001−1.870.010
PTN−1.89<0.001−1.75<0.001−2.040.010−1.73<0.001−1.89<0.001−2.650.010
NTF3−2.00<0.001−1.260.010−1.49<0.001−1.17<0.001−1.24<0.001−1.73<0.001
PAGE4−2.19<0.001−2.22<0.001−2.78<0.001−2.05<0.001−2.65<0.001−5.16<0.001
BMPER−2.25<0.001−1.91<0.001−2.67<0.001−1.46<0.001−1.84<0.001−3.01<0.001
RSPO2−2.27<0.001−1.85<0.001−2.28<0.001−1.73<0.001−1.94<0.001−3.11<0.001
FXYD1−2.31<0.001−1.58<0.001−1.970.010−1.36<0.001−1.75<0.001−2.550.010
RNF112−2.41<0.001−1.74<0.001−2.21<0.001−1.68<0.001−1.87<0.001−3.00<0.001
PROK1−2.42<0.001−2.13<0.001−2.40<0.001−2.01<0.001−2.40<0.001−3.73<0.001
C20orf200−2.55<0.001−1.67<0.001−1.83<0.001−1.55<0.001−1.68<0.001−2.32<0.001
ANO4−2.82<0.001−1.72<0.001−2.23<0.001−1.79<0.001−1.99<0.001−2.64<0.001
GSTM5−2.96<0.001−1.53<0.001−2.01<0.001−1.44<0.001−1.75<0.001−2.270.010
B3GALT2−3.08<0.001−1.69<0.001−2.01<0.001−1.48<0.001−1.95<0.001−2.40<0.001
ADRA1D−3.19<0.001−2.05<0.001−1.980.010−1.63<0.001−1.97<0.001−2.86<0.001
NDP−3.30<0.001−1.72<0.001−2.04<0.001−1.48<0.001−1.71<0.001−2.58<0.001
HIF3A−3.55<0.001−1.78<0.001−2.42<0.001−1.67<0.001−2.06<0.001−2.91<0.001
SMOC1−4.19<0.001−1.72<0.001−2.30<0.001−2.03<0.001−2.48<0.001−3.21<0.001
LDB3−4.28<0.001−1.80<0.001−2.060.010−1.64<0.001−2.00<0.001−3.00<0.001
LOC572558−4.35<0.001−2.29<0.001−2.46<0.001−2.15<0.001−2.57<0.001−3.98<0.001
PPARGC1A−4.42<0.001−1.60<0.001−2.08<0.001−1.60<0.001−1.98<0.001−2.430.010
HRNBP3−4.54<0.001−2.17<0.001−2.48<0.001−2.11<0.001−2.72<0.001−5.42<0.001
SRD5A2−4.57<0.001−1.98<0.001−2.170.010−2.18<0.001−2.74<0.001−5.26<0.001
COL4A6−4.95<0.001−1.84<0.001−2.010.010−1.78<0.001−1.98<0.001−3.32<0.001
LGR6−6.41<0.001−1.78<0.001−2.44<0.001−1.59<0.001−2.02<0.001−3.45<0.001

[i] FC, fold-change; P, P-value; PSA, prostate specific antigen.

Expression of CIT is increased in PCa

The expression of CIT mRNA was increased in PCa when compared with BPH (Fig. 2A). The immunoreactivity of CIT is presented in Fig. 2B. None and low staining were detected in BPH and low-grade PCa, whereas moderate and strong staining was detected in middle- and high-grade PCa. The staining scores of CIT were significantly increased in primary and aggressive PCa, compared with BPH (P<0.001; Fig. 2C). Additionally, compared with the non-HR-group, CIT expression was significantly increased in the HR-group (P<0.001; Fig. 2D). As presented in Table III, the percentage of patients with H-CIT was significantly associated with Gleason grades (P=0.001), serum PSA levels (P=0.001), T stages (P<0.001), lymph node invasion (P=0.032) and metastasis (P=0.021). These results were consistent with those of the aforementioned bioinformatic analysis.

Table III.

Correlation between CIT and clinical parameters of prostate cancer patients.

Table III.

Correlation between CIT and clinical parameters of prostate cancer patients.

ParametersNo. (%)Low CIT expressionHigh CIT expressionP-value
Gleason scores 0.001
  <78852 (59.09)36 (40.91)
  ≥718369 (37.70)114 (62.30)
Serum PSA (ng/ml) 0.001
  <106943 (62.32)26 (37.68)
  ≥1020278 (38.61)124 (61.39)
pT stage <0.001
  Ta-T215087 (58.00)63 (42.00)
  T3-T412134 (28.10)87 (71.90)
LNI 0.032
  N0255118 (46.46)137 (53.94)
  N1163 (18.75)13 (81.25)
Metastasis 0.021
  M0254118 (46.46)136 (53.54)
  M1173 (17.65)14 (82.35)

[i] PCa, prostate cancer; BPH, benign prostatic hyperplasia; PSA, prostate-specific antigen; LNI, lymph node invasion; CIT, citron kinase.

CIT is a risk factor for poor outcomes in patients with PCa

In IHC, the protein level of CIT expression was significantly upregulated in BCR patients (P<0.001; Fig. 3A) and the recurrence time of patients with H-CIT was significantly decreased compared with L-CIT (P=0.013; Fig. 3B). Further multivariate analysis demonstrated that the independent value of H-CIT [hazard ratio (HR)=1.090–4.231; P=0.027] and LNI (HR=1.002–4.294; P=0.049) was significant for BCR prediction (Table IV).

Table IV.

Univariate and Multivariate Cox regression analysis for BCR.

Table IV.

Univariate and Multivariate Cox regression analysis for BCR.

UnivariateMultivariate


VariablesHazard ratio (95% CI)P-valueHazard ratio (95% CI)P-value
CIT (low vs. high)2.231 (1.137–4.377)0.0202.147 (1.090–4.231)0.027
Gleason score (<8 vs. ≥8)2.309 (1.148–4.644)0.0191.561 (0.663–3.676)0.404
Serum PSA level (<10 vs. ≥10 ng/ml)2.634 (1.124–6.171)0.0262.238 (0.949–5.277)0.066
T stage (Ta-2 vs. T3-4)1.021 (0.614–1.699)0.9351.034 (0.601–1.782)0.903
LNI (N0 vs. N1)2.181 (1.060–4.489)0.0342.074 (1.002–4.294)0.049
Metastasis (M0 vs. M1)1.225 (0.623–2.409)0.5560.515 (0.237–1.118)0.094

[i] CIT, citron kinase; PSA, prostate-specific antigen; BCR, biochemical recurrence; LNI, lymph node invasion.

The results also revealed that the expression of CIT was increased in CSM patients (Fig. 3C). The Kaplan-Meier survival curve revealed that patients with H-CIT exhibited shorter survival times compared with patients with L-CIT (P<0.001; Fig. 3D). Multivariate analysis also revealed that the independent risk factors of CSM were CIT (HR=2.408–12.802; P=0.000), Gleason grades (HR=1.148–5.068; P=0.020) and T stages (HR=1.815–8.085; P<0.001; Table V).

Table V.

Univariate and multivariate Cox regression analysis for cancer-specific morality.

Table V.

Univariate and multivariate Cox regression analysis for cancer-specific morality.

UnivariateMultivariate


VariablesHazard ratio (95% CI)P-valueHazard ratio (95% CI)P-value
CIT (low vs. high)5.316 (2.314–12.213)<0.0015.553 (2.408–12.802)<0.001
Gleason score (<8 vs. ≥8)1.764 (0.875–3.556)0.1082.412 (1.148–5.068)0.020
Serum PSA, ng/ml (<10 vs. ≥10)1.452 (0.628–3.355)0.3830.869 (0.341–2.173)0.751
T stage (Ta-2 vs. T3-4)2.977 (1.504–5.895)0.0023.831 (1.815–8.085)0.000
LNI (N0 vs. N1)4.584 (1.570–13.384)0.0050.684 (0.181–2.586)0.576
Metastasis (M0 vs. N0)3.032 (1.570–13.384)0.1341.134 (0.288–5.645)0.878

[i] CIT, citron kinase; PSA, prostate-specific antigen; LNI, lymph node invasion; CI, confidence interval.

Discussion

A previous study of CIT in PCa demonstrated that the loss of CIT inhibited the proliferation of LNCaP and C4-2B cells (20), however the limited number of cell types available and lack of investigation in a clinical setting restricted the study. The current study screened CIT as a potential oncogene in PCa. CIT was highly expressed in PCa samples and was associated with Gleason scores, serum PSA levels, T stage and risk groups. Furthermore, patients with a high CIT expression were more likely to exhibit an increased BCR and CSM compared with those with a low CIT expression. Additionally, the high expression of CIT was determined to be a risk factor for BCR and CSM in patients with PCa.

Cytokinesis is the final stage of cell division, in which two daughter cells are separated (21). Resolving the midbody during the final stage of abscission serves an important role in cytokinesis (5). Failure to complete cytokinesis may lead to tetraploidy and the presence of multiple centrosomes, which has been proposed to promote tumorigenesis (22). Pihan et al (23) observed that centrosomes were structurally and numerically abnormal in the majority of patients with PCa. Furthermore, bladder cancer samples frequently contain a number of centrosomes that are significantly increased as a result of cytokinesis failure (24). CIT is specifically required during the late stages of cytokinesis for the organization and function of the midbody (7,25). The overexpression of CIT kinase-active mutants causes the dysregulation of cytokinesis, which results in the production of multinucleate cells (26). Therefore, the disrupted function of CIT may contribute to cytokinesis failure, leading to the progression of cancer. Madhavan et al (27) revealed that the activation of the CIT/kinesin family member kinesin like protein KIF14 (KIF14) axis, where CIT localizes to the central spindle via the kinesin-3 motor, KIF14, is involved in the carcinogenesis of retinoblastoma.

Various kinases have been demonstrated to be intimately involved in processes and to contribute to tumor cell proliferation and survival (28). Certain kinases are considered to be oncogenic due to their transforming capacity, including BRAF in colon carcinoma and ALK in neuroblastoma (29,30). In addition, Rho-associated protein kinase serves an essential role in the metastasis and proliferation of breast cancer and hepatocellular carcinoma (31,32). The knockdown of CIT directly inhibits the proliferation of breast cancer and hepatocellular carcinoma cells (33,34). Since a previous study determined that CIT is an essential kinase that targets Rho-associated kinases (including ROCK and ROK) (27), it seems likely that CIT serves an important role in these cancers by interacting with Rho signaling. Previous studies have also revealed that Rho signaling factors are involved in the invasion of PCa cells (35,36), such that CIT may also participate in the regulation of Rho signaling, which serves a key role in the progression of PCa.

Currently, the main clinical signatures of patients with PCa include TNM stage PSA levels and Gleason scores (37). The results of the current study revealed that a high expression of CIT was positively associated to a high T stage, serum PSA level and Gleason score. Furthermore, CIT was determined to be an independent predictor of BCR and CSM. These data indicated that CIT may serve as a potential marker of PCa and may compensate for these clinical signatures. Currently, ADT is one of the primary methods of treatment for patients with PCa (38). However, certain patients that receive ADT will still advance to castration-resistant PCa and suffer from a poor prognosis (39). Although recent studies have determined that the glucocorticoid receptor can be targeted to improve anti-androgen therapy (40,41), new targets in the process of castration resistance should be explored. In the current study, patients with a high CIT expression exhibited shorter PSA recurrence time, which implies that CIT may serve a role in androgen-resistant PCa.

However, the number of PCa samples was limited in the current study and the mechanism of CIT in PCa also needs to be further elucidated. More patient samples should therefore be utilized in further study and the interaction between CIT and the Rho pathway should be determined in PCa cell lines.

In conclusion, the results of the current long-term retrospective study indicated that CIT is an independent indicator of CSM and BCR. CIT may therefore be a potential biomarker of PCa in the future. Although further study is required to assess the function and mechanism of CIT in PCa, it may still serve as a biomarker to improve the survival of patients with PCa.

Acknowledgements

The authors would like to thank Professor Fangzhou Song (Department of Biochemistry & Molecular Biology, Molecular Medicine & Cancer Research Center, Chongqing Medical University, Chongqing, PR China) and Professor Xiaoni Zhong (Department of Health Statistics and Information Management, School of Public Health and Management, Chongqing Medical University, Chongqing, China.) for helpful suggestions. Thanks to Dr. Yutao Zhang (Department of Pathology, Zigong First People's Hospital) and Dr. Yu Li (Department of Pathology, the First Affiliated Hospital of Chongqing Medical University) for the supports of pathological information and immunohistochemical assessment.

Funding

Funding was received from: National Natural Science Foundation of China (grant no. 30972999); Nature Science Foundation of Chongqing (grant no. Cstc2016shms-ztzx0054 and cstc2015jcyjBX0045); the Science and technology planning project of Yuzhong District (grant no. 20150111); the Health and Family Planning Commission Foundation of Chongqing Municipal (grant no. Cstc2012gg-yyjs10043); the Health Bureau of Chongqing (grant no. 20132082) and the Chongqing Education Commission (grant no. CYS16125).

Availability of data and materials

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

Authors' contributions

JD and JL analyzed the data and made major contributions to writing the manuscript. YQ, YJL and YL performed the experiments and wrote the initial draft of the manuscript. JH, WW, LM and HL analyzed the data and contributed to revising the article. DW and QY contributed to the design of the study and provided final approval of the manuscript. WJ and YLia contributed to the design of the study and assisted with writing the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The Ethics committee of the First Affiliated Hospital of Chongqing Medical University, Zigong Fourth People's Hospital and Zigong First People's Hospital approved the use of these samples for the educational purposes of this research. The consent from patients or patients' families was obtained verbally.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

PCa

prostate cancer

BPH

benign prostatic hyperplasia

CIT

citron kinase

ADT

androgen deprivation therapy

PR

prostatectomy

PSA

prostate specific antigen

CSM

cancer specific morality

BCR

biochemical recurrence

References

1 

Siegel RL, Miller KD and Jemal A: Cancer Statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Pokorny MR, de Rooij M, Duncan E, Schröder FH, Parkinson R, Barentsz JO and Thompson LC: Prospective study of diagnostic accuracy comparing prostate cancer detection by trans rectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. Eur Urol. 66:22–29. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Zhang W, Vazquez L, Apperson M and Kennedy MB: Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. J Neurosci. 19:96–108. 1999. View Article : Google Scholar : PubMed/NCBI

5 

Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT and Pellman D: Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature. 437:1043–1047. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Ganem NJ, Storchova Z and Pellman D: Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev. 17:157–162. 2007. View Article : Google Scholar : PubMed/NCBI

7 

McKenzie C, Bassi ZI, Debski J, Gottardo M, Callaini G, Dadlez M and D'Avino PP: Cross-regulation between aurora B and citron kinase controls midbody architecture in cytokinesis. Open Biol. 6:1600192016. View Article : Google Scholar : PubMed/NCBI

8 

D'Avino PP and Capalbo L: Regulation of midbody formation and function by mitotic kinases. Semin Cell Dev Biol. 53:57–63. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Gai M, Camera P, Dema A, Bianchi F, Berto G, Scarpa E, Germena G and Di Cunto F: Citron kinase controls abscission through RhoA and anillin. Mol Biol Cell. 22:3768–3778. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Yamashiro S, Totsukawa G, Yamakita Y, Sasaki Y, Madaule P, Ishizaki T, Narumiya S and Matsumura F: Citron kinase, a Rho-dependent kinase, induces di-phosphorylation of regulatory light chain of myosin II. Mol Biol Cell. 14:1745–1756. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Zhao Y and Simon R: BRB-ArrayTools data archive for human cancer gene expression: A unique and efficient data sharing resource. Cancer Inform. 6:9–15. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, Fossati N, Gross T, Henry AM, Joniau S, et al: EAU-ESTRO-SIOG guidelines on prostate cancer Part 1: Screening, diagnosis, and local treatment with curative intent. Eur Urol. 71:618–629. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Yu L, Toriseva M, Tuomala M, Seikkula H, Elo T, Tuomela J, Kallajoki M, Mirtti T, Taimen P, Boström PJ, et al: Increased expression of fibroblast growth factor 13 in prostate cancer is associated with shortened time to biochemical recurrence after radical prostatectomy. Int J Cancer. 139:140–152. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Eble JN, Sauter G, Epstein JE and Sesterhenn IA: World Health Organization Classification of Tumours. Pathology and genetics of the urinary system and male genital organs. IARC Press; Lyon: 2004. pp. 159–215. 2004

15 

Epstein JI, Allsbrook WC Jr, Amin MB and Egevad LL; ISUP Grading Committee, : The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma. Am J Surg Pathol. 29:1228–1242. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Goktas S, Yilmaz MI, Caglar K, Sonmez A, Kilic S and Bedir S: Prostate cancer and adiponectin. Urology. 65:1168–1172. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Liu J, Xiao M, Li J, Wang D, He Y, He J, Gao F, Mai L, Li Y, Liang Y, et al: Activation of UPR signaling pathway is associated with the malignant progression and poor prognosis in prostate cancer. Prostate. 77:274–281. 2017. View Article : Google Scholar : PubMed/NCBI

18 

Roudier MP, Winters BR, Coleman I, Lam HM, Zhang X, Coleman R, Chéry L, True LD, Higano CS, Montgomery B, et al: Characterizing the molecular features of ERG-Positive tumors in primary and castration resistant prostate cancer. Prostate. 76:810–822. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Sheng X, Li WB, Wang DL, Chen KH, Cao JJ, Luo Z, He J, Li MC, Liu WJ and Yu C: YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells. Mol Med Rep. 12:4867–4876. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Whitworth H, Bhadel S, Ivey M, Conaway M, Spencer A, Hernan R, Holemon H and Gioeli D: Identification of kinases regulating prostate cancer cell growth using an RNAi phenotypic screen. PLoS One. 7:e389502012. View Article : Google Scholar : PubMed/NCBI

21 

Glotzer M: The molecular requirements for cytokinesis. Science. 307:1735–1739. 2005. View Article : Google Scholar : PubMed/NCBI

22 

Boveri T: Concerning the origin of malignant tumors by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci. 121:1–84. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L and Doxsey SJ: Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res. 61:2212–2219. 2001.PubMed/NCBI

24 

Yamamoto Y, Eguchi S, Junpei A, Nagao K, Sakano S, Furuya T, Oga A, Kawauchi S, Sasaki K and Matsuyama H: Intercellular centrosome number is correlated with the copy number of chromosomes in bladder cancer. Cancer Genet Cytogenet. 191:38–42. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Bassi ZI, Audusseau M, Riparbelli MG, Callaini G and D'Avino PP: Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proc Natl Acad Sci USA. 110:9782–9787. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Madaule P, Eda M, Watanabe N, Fujisawa K, Matsuoka T, Bito H, Ishizaki T and Narumiya S: Role of citron kinase as a target of the small GTPase Rho in cytokinesis. Nature. 394:491–494. 1998. View Article : Google Scholar : PubMed/NCBI

27 

Madhavan J, Mitra M, Mallikarjuna K, Pranav O, Srinivasan R, Nagpal A, Venkatesan P and Kumaramanickavel G: KIF14 and E2F3 mRNA expression in human retinoblastoma and its phenotype association. Mol Vis. 15:235–240. 2009.PubMed/NCBI

28 

Zhang J, Yang PL and Gray NS: Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 9:28–39. 2009. View Article : Google Scholar : PubMed/NCBI

29 

Garnett MJ and Marais R: Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 6:313–319. 2004. View Article : Google Scholar : PubMed/NCBI

30 

Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, et al: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 455:930–935. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Grise F, Bidaud A and Moreau V: Rho GTPases in hepatocellular carcinoma. Biochim Biophys Acta. 1795:137–151. 2009.PubMed/NCBI

32 

Tang Y, Olufemi L, Wang MT and Nie D: Role of Rho GTPases in breast cancer. Front Biosci. 13:759–776. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Fu Y, Huang J, Wang KS, Zhang X and Han ZG: RNA interference targeting CITRON can significantly inhibit the proliferation of hepatocellular carcinoma cells. Mol Biol Rep. 38:693–702. 2011. View Article : Google Scholar : PubMed/NCBI

34 

McKenzie C and D'Avino PP: Investigating cytokinesis failure as a strategy in cancer therapy. Oncotarget. 7:87323–87341. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE and Somlyo AP: Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem Biophys Res Commun. 269:652–659. 2000. View Article : Google Scholar : PubMed/NCBI

36 

Wu Y, He L, Zhang L, Chen J, Yi Z, Zhang J, Liu M and Pang X: Anacardic acid (6-pentadecylsalicylic acid) inhibits tumor angiogenesis by targeting Src/FAK/Rho GTPases signaling pathway. J Pharmacol Exp Ther. 339:403–411. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Porten SP, Whitson JM, Cowan JE, Cooperberg MR, Shinohara K, Perez N, Greene KL, Meng MV and Carroll PR: Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. J Clin Oncol. 29:2795–800. 2011. View Article : Google Scholar : PubMed/NCBI

38 

Sharifi N, Gulley JL and Dahut WL: Androgen deprivation therapy for prostate cancer. JAMA. 294:238–244. 2005. View Article : Google Scholar : PubMed/NCBI

39 

Kirby M, Hirst C and Crawford ED: Characterising the castration-resistant prostate cancer population: A systematic review. Int J Clin Pract. 65:1180–1192. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Puhr M, Hoefer J, Eigentler A, Ploner C, Handle F, Schaefer G, Kroon J, Leo A, Heidegger I, Eder I, et al: The Glucocorticoid receptor is a key player for prostate cancer cell survival and a target for improved Antiandrogen therapy. Clin Cancer Res. 24:927–938. 2018. View Article : Google Scholar : PubMed/NCBI

41 

Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, Shah N, Cai L, Efstathiou E, Logothetis C, et al: Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 155:1309–1322. 2013. View Article : Google Scholar : PubMed/NCBI

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March-2020
Volume 19 Issue 3

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Copy and paste a formatted citation
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Spandidos Publications style
Liu J, Dou J, Wang W, Liu H, Qin Y, Yang Q, Jiang W, Liang Y, Liu Y, He J, He J, et al: High expression of citron kinase predicts poor prognosis of prostate cancer. Oncol Lett 19: 1815-1823, 2020
APA
Liu, J., Dou, J., Wang, W., Liu, H., Qin, Y., Yang, Q. ... Wang, D. (2020). High expression of citron kinase predicts poor prognosis of prostate cancer. Oncology Letters, 19, 1815-1823. https://doi.org/10.3892/ol.2020.11254
MLA
Liu, J., Dou, J., Wang, W., Liu, H., Qin, Y., Yang, Q., Jiang, W., Liang, Y., Liu, Y., He, J., Mai, L., Li, Y., Wang, D."High expression of citron kinase predicts poor prognosis of prostate cancer". Oncology Letters 19.3 (2020): 1815-1823.
Chicago
Liu, J., Dou, J., Wang, W., Liu, H., Qin, Y., Yang, Q., Jiang, W., Liang, Y., Liu, Y., He, J., Mai, L., Li, Y., Wang, D."High expression of citron kinase predicts poor prognosis of prostate cancer". Oncology Letters 19, no. 3 (2020): 1815-1823. https://doi.org/10.3892/ol.2020.11254