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Silencing of CDCA5 Inhibits Cancer Progression and Serves As a Prognostic Biomarker for Hepatocellular Carcinoma

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Silencing of CDCA5 Inhibits Cancer Progression and Serves As a Prognostic Biomarker for Hepatocellular Carcinoma ONCOLOGY REPORTS 40: 1875-1884, 2018 Silencing of CDCA5 inhibits cancer progression and serves as a prognostic biomarker for hepatocellular carcinoma JIANLIN WANG1*, CONGCONG XIA1*, MENG PU2*, BIN DAI1, XISHENG YANG1, RUNZE SHANG1, ZHEN YANG1, RUOHAN ZHANG1, KAISHAN TAO1 and KEFENG DOU1 1Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032; 2Department of Hepatobiliary Surgery, The Air Force General Hospital of The People's Liberation Army, Beijing 100142, P.R. China Received March 12, 2018; Accepted July 9, 2018 DOI: 10.3892/or.2018.6579 Abstract. Cell division cycle associated 5 (CDCA5) has been impeded HCC growth in vivo. Further study indicated that associated with the progression of several types of cancers. CDCA5 depletion decreased the levels of ERK1/2 and AKT However, its possible role and mechanism in hepatocellular phosphorylation in vitro and in vivo. Taken together, these carcinoma (HCC) remain unknown. In the present study, results indicate that CDCA5 may act as a novel prognostic immunohistochemical staining and real-time PCR were used biomarker and therapeutic target for HCC. to assess CDCA5 protein and mRNA levels in clinical samples. Statistical analysis was performed to explore the clinical Introduction correlation between CDCA5 protein expression and clinico- pathological features and overall survival in HCC patients. Hepatocellular carcinoma (HCC) is the sixth most aggressive Cell counting and colony formation assays were employed to human malignancy and the third leading cause of cancer-related analyse the effect of CDCA5 on cell proliferation, and flow mortality worldwide (1). In addition to genetic and epigen- cytometry was used to study the role of CDCA5 in cell cycle etic alterations, positive HBV and HCV infection, aflatoxin progression and apoptosis. Moreover, subcutaneous xenograft exposure, smoking, obesity and diabetes are considered the tumour models were implemented to predict the efficacy of main risk factors associated with the incidence of HCC (2,3). targeting CDCA5 in HCC in vivo. We found that CDCA5 Although some progress has been achieved in regards to expression was significantly higher in HCC tumour tissues, clinical treatments, the overall survival (OS) of patients with was associated with clinicopathological characteristics, and HCC remains poor (4). Hence, a greater understanding of the predicted poor overall survival in HCC patients. Silencing of molecular mechanisms underlying HCC tumourigenesis may CDCA5 with small interfering RNA (siRNA) inhibited cell provide new insights into functional pathogenic and thera- proliferation and induced G2/M cell cycle arrest in vitro. The peutic strategies. xenograft growth assay revealed that CDCA5 downregulation Human cell division cycle associated 5 (CDCA5), also known as sororin and encoded by CDCA5, was identified from a gene expression meta-analysis screen of cell cycle-associated (CDCA) transcripts (5,6). CDCA5 is a key regulator of sister Correspondence to: Professor Kefeng Dou or Professor chromatid cohesion and separation, is involved in the generation Kaishan Tao, Department of Hepatobiliary Surgery, Xijing Hospital, and maintenance of sister chromatid cohesion and regulates the The Fourth Military Medical University, Xi'an, Shaanxi 710032, removal of cohesin from chromatin (6,7). CDCA5 is required P. R. Ch i na for sister chromatid cohesion during S and G2 phases, degraded E-mail: [email protected] through anaphase-promoting complex (APC)-dependent ubiq- E-mail: [email protected] uitination during G1 phase, and phosphorylated and dissociated from chromatids during prophase/prometaphase (8-10). In * Contributed equally addition, CDCA5 was found to be significantly upregulated in human tumour tissues, including lung cancer, oral squamous cell Abbreviations: HCC, hepatocellular carcinoma; CDCA5, cell carcinoma, urothelial cancers, gastric cancer and HCC (11-16), division cycle associated 5; ERK, extracellular signal-regulated kinase; qRT-PCR, quantitative real-time polymerase chain reaction; and silencing of CDCA5 in lung cancer and oral squamous cell IHC, immunohistochemistry; p-AKTS, AKT (ser473); p-AKTT, carcinoma was found to result in decreased cell growth in vivo AKT (Thr308); ANLTs, adjacent non-tumour liver tissues and in vitro (11,14). However, knowledge of the biological and clinical significance of CDCA5 in HCC remains minimal, Key words: CDCA5, proliferation, cell cycle, ERK/AKT pathway, which prompted us to explore the functional roles of CDCA5 in hepatocellular carcinoma HCC pathogenesis. In the present study, we examined CDCA5 expression in clinical HCC samples and demonstrated that aberrant CDCA5 1876 WANG et al: KNOCKDOWN OF CDCA5 INHIBITS HCC CELL PROLIFERATION expression in HCC tissues is correlated with multiple malignant produced by Shanghai GeneChem. MHCC97-H cells were clinicopathological characteristics and is an independent prog- plated in 6-well plates and incubated overnight. The culture nostic factor for the OS of individuals with HCC. Both in vitro medium was replaced with transduction-enhancing solution and in vivo assays showed that silencing of CDCA5 inhibited containing lentivirus at 20 MOI and 50 µg/ml polybrene. After HCC cell growth. The molecular mechanism underlying 12 h, the medium was replaced with complete medium. these effects involved inactivation of the ERK/AKT signaling pathway. These findings reveal that targeting CDCA5 is likely RNA extraction and qRT‑PCR. Total RNA was isolated a promising strategy for HCC treatment. using RNAiso Plus reagent (Takara Biotechnology Co., Ltd., Dalian, China) from the HCC cell lines or frozen tissue Materials and methods samples according to the manufacturer's protocol. Reverse transcription was conducted with PrimeScript™ Master Mix Cell lines and tissue samples. The HCC cell lines MHCC97-H (Takara Biotechnology) at 37˚C for 15 min. Gene mRNA and Huh7 were obtained from the Cell Bank of the Chinese levels were determined using SYBR Premix EX TaqTM II Academy of Sciences (Shanghai, China). All cell lines were (Takara Biotechnology) on a Bio-Rad IQ™5 detection system maintained in Dulbecco's Modified Eagle's medium (DMEM) (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The PCR supplemented with 10% fetal bovine serum (FBS), 100 U/ml conditions were as follows: Pre‑denaturation at 95˚C for penicillin and 100 µg/ml streptomycin and then incubated 30 sec; 40 cycles of denaturation (95˚C for 5 sec), annealing at 37˚C in a humidified atmosphere containing 5% CO2. (60˚C for 30 sec). β-actin was used as a quantitative control to Additionally, 30 HCC samples and matched adjacent normal normalize the mRNA expression levels of the target genes. All tissues from HCC patients were obtained at Xijing Hospital experiments were performed according to the manufacturer's (Xi'an, China) between December 2014 and November instructions. The data were analysed with the comparative Ct 2015. The mean ages of these patients were 53.8 years, and (2-∆∆Cq) method. The primer was designed and synthesized by the percentage of male was 76.7%. The study protocol was Shanghai Genechem Co., Ltd., for CDCA5 (forward primer, approved by the Ethics Committee of Xijing Hospital, and all GAC GCC AGA GAC TTG GAA ATG and reverse primer, GGA participants provided written informed consent. CCT CGG TGA GTT TGG AG); β-actin (forward primer, CAT GTA CGT TGC TAT CCA GGC and reverse primer, CTC CTT Immunohistochemistry. A commercially available tissue AAT GTC ACG CAC GAT). microarray (TMA) was purchased from Shanghai Outdo Biotech Co., Ltd. (Shanghai, China). CDCA5 protein expres- Western blotting. Protein samples were prepared according sion in 98 paired paraffin-embedded tumour tissues and to normal procedures with fresh lysis buffer (Beyotime adjacent normal tissues was detected using an immunoperoxi- Institute of Biotechnology, Haimen, China) containing dase method. In brief, after deparaffinization, antigen retrieval protease and phosphatase inhibitor cocktails (Sigma-Aldrich; was performed in a sodium citrate solution (pH 6.0). After Merck KGaA, Darmstadt, Germany). Total protein extracts the sections were blocked with normal goat serum, they were were separated by 10% sodium dodecyl sulfate-polyacryl- incubated with rabbit anti-CDCA5 (1:100; cat. no. ab192237; amide gel electrophoresis (SDS-PAGE), transferred to PVDF Abcam) overnight at 4˚C. Subsequently, the sections membranes (Millipore, Billerica, MA, USA), and sequentially were washed and incubated with horseradish peroxidase incubated with primary antibodies targeting CDCA5 (1:1,000; (HRP)-conjugated anti-rabbit IgG at room temperature for 1 h. cat. no. ab192237; Abcam), ERK1/2 (1:1,000; 4695; Cell Finally, 3,3'‑diaminobenzidine tetrahydrochloride substrate Signaling Technology, Inc., Danvers, MA, USA), p-ERK1/2 (DAB; ZSGB-BIO, Beijing, China) was used as a substrate (1:1,000; cat. no. 4370; Cell Signaling Technology, Inc.), AKT, to visualize the bound antibody, and the sections were lightly p-AKT (Thr308), p-AKT (Ser473) (1:1,000; cat. no. 9916T; Cell counterstained with haematoxylin, dehydrated and mounted. Signaling Technology, Inc.) and β-actin (1:1,000; cat. no. 3700; Cell Signaling Technology, Inc.) overnight at 4°C. Afterward, siRNA and plasmid transfection. The following siRNAs the membranes were incubated with horseradish peroxidase targeting CDCA5 were purchased from ShanghaGenePharma (HRP)-conjugated secondary antibodies (1:3,000; ProteinTech Co., Ltd., (Shanghai,
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