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Increased Fibrillarin Expression Is Associated with Tumor Progression and an Unfavorable Prognosis in Hepatocellular Carcinoma

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Increased Fibrillarin Expression Is Associated with Tumor Progression and an Unfavorable Prognosis in Hepatocellular Carcinoma ONCOLOGY LETTERS 21: 92, 2021 Increased fibrillarin expression is associated with tumor progression and an unfavorable prognosis in hepatocellular carcinoma JING ZHANG1, GANG YANG2, QIANG LI2 and FEI XIE3 Departments of 1Gastroenterology and 2Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000; 3Department of Hepatobiliary Surgery, The First People's Hospital of Neijiang, Neijiang, Sichuan 641000, P.R. China Received June 8, 2020; Accepted November 2, 2020 DOI: 10.3892/ol.2020.12353 Abstract. Hepatocellular carcinoma (HCC) is the sixth shorter overall survival time and disease‑free survival time in most common cancer and third most common cause of patients with HCC. Bioinformatics analysis demonstrated that cancer‑associated mortality worldwide. Hepatectomy and FBL may be regulated by methylation modification. In addition, liver transplantation are the main treatments for early HCC. analyses of functional annotations using the Gene Ontology Immunotherapy and targeted therapy for advanced HCC have database indicated that FBL‑related genes were predominantly become increasingly popular; however, their clinical benefits enriched in DNA repair and proliferation‑related cell‑signaling are limited. Thus, identification of novel therapeutic targets pathways. Notably, high FBL expression signified larger tumor for advanced HCC remains essential. Fibrillarin (FBL) is an diameter, advanced tumor stage and a poor prognosis. Taken essential nucleolar protein that catalyzes the 2'‑O‑methylation together, the results of the present study suggest that FBL may of ribosomal RNAs. Recently, experimental data have suggested be a potential target for HCC treatment. that FBL can influence breast‑cancer progression. However, the association between FBL expression and HCC remains known. Introduction In the present study, the UALCAN database was used to assess FBL mRNA expression in HCC. Immunohistochemistry Hepatocellular carcinoma (HCC) is a common malignant analysis was performed to detect FBL protein expression in cancer in humans, and the fourth leading cause of cancer‑asso‑ 139 patients with HCC. In addition, bioinformatic analysis was ciated morality worldwide (1,2). Globally, from 2004 to 2017, performed using the UALCAN, the Database for Annotation, the incidence of hepatocellular carcinoma was 1/100,000 (3), Visualization and Integrated Discovery, cBioportal and with a low overall 5‑year survival rate of 18% (4). In addition TargetScan databases. Data were analyzed using Kaplan‑Meier to liver resection and liver transplantation, targeted therapy, curves and the log‑rank test, and a Cox proportional hazards immunotherapy and transarterial chemoembolization are regression model. The results demonstrated that FBL expres‑ used to treat advanced HCC (5‑7). However, patients with sion was significantly higher in tumor tissues compared with HCC suffer from a high prevalence of mortality and recur‑ para‑tumor tissues. Furthermore, high FBL expression was rence (5,7‑11). Thus, identification of novel effective targets for significantly associated with tumor diameter and advanced the treatment of advanced HCC remains essential. TNM stage in HCC. High FBL expression also predicted a Ribosomes take part in the synthesis of proteins, as the site of mRNA translation (12). Recently, increasing evidence has demonstrated that ribosomes can regulate cancer progression and drug reactions by ‘alternative translation’, which enables tumor cells to adapt to their environment in order to prolif‑ Correspondence to: Dr Fei Xie, Department of Hepatobiliary erate (13‑16). Methylation of ribosomal (r)RNA is the primary Surgery, The First People's Hospital of Neijiang, 31 Tuozhong Lane, method to control protein synthesis (17‑19). Jiaotong Road, Neijiang, Sichuan 641000, P.R. China E‑mail: [email protected] The nucleolar protein, fibrillarin (FBL) catalyzes the 2'‑O‑methylation (2'‑O‑Me) of rRNAs to manage translation Abbreviations: FBL, fibrillarin; HCC, hepatocellular carcinoma; of mRNAs (20,21), which enables changes in the combination IHC, immunohistochemical; TMAs, tissue microarrays; M, median; of rRNAs and specific mRNAs (22‑24). FBL can promote AFP, α‑fetoprotein cancer‑cell proliferation by regulating mRNA translation and controlling the methylation of rRNAs, which has been Key words: hepatocellular carcinoma, fibrillarin, prognosis, demonstrated in breast cancer and cancer of the prostate methylation, ribosomal gland (20,25,26). Marcel et al (20) reported that p53 acts as a safeguard of protein synthesis by regulating FBL expression to inhibit tumor 2 ZHANG et al: FIBRILLARIN: A NOVEL BIOMARKER FOR HEPATOCELLULAR CARCINOMA occurrence. In addition, reversible acetylation of FBL regu‑ IHC analysis. Fresh tissue samples were fixed in 4% formalin lates methylation of nucleolar H2AQ104, thereby reinforcing for 24 h at room temperature, washed five times with PBS oscillation of Pol‑I transcription during the cell cycle (27). (3 min each) and subsequently dehydrated with ethanol. Shubina et al (21) demonstrated the potential roles of FBL Tissue samples were embedded in paraffin and cut into in the regulation of cell proliferation, cancer progression and 4‑µm‑thick sections (diameter of 2 mm) to produce TMAs. aging. Taken together, these results suggest that FBL may func‑ TMAs were deparaffinized in xylene and rehydrated in tion as an oncogene. However, the function of FBL in HCC and a descending ethanol series (100, 95 and 85%) at room the effect of FBL expression on HCC cells remain unknown. temperature. TMAs were incubated with 0.3% H2O2 to To investigate the expression difference of FBL in tumor inhibit endogenous peroxidase activity, and antigen‑retrieval tissues and para‑tumor tissues of HCC, immunohistochemistry was subsequently performed with ethylenediamine (IHC) and bioinformatics analyses demonstrated that FBL tetraacetic acid antigen‑retrieval solution (Beyotime Institute expression was upregulated in patients with HCC. Furthermore, of Biotechnology; P0085), using a microwave for 15 min. high FBL expression signified an advanced tumor stage and a TMAs were blocked with 10% goat serum (Beijing Solarbio poor prognosis. Using publicly available RNA‑sequencing data, Science & Technology Co., Ltd.; SL038) for 30 min at room it was demonstrated that the methylated modification of FBL temperature, and incubated with anti‑FBL (1:100; Abcam; was frequent in HCC. Taken together, the results of the present cat. no. ab166630) overnight at 4˚C. Following the primary study suggest that FBL may regulate the biological behavior of incubation, TMAs were incubated with a secondary antibody tumor cells by DNA damage/repair, cell‑cell adhesion, the cell for 1 h at 37˚C (1:1; Dako; Agilent Technologies, Inc; cat. cycle, as well as signaling pathways involving fibroblast growth no. K5007). The REAL™ EnVision™ immunohistochem‑ factor receptors, epidermal growth factor receptors and nuclear istry kit include the secondary antibody, and the secondary factor‑κB (NF‑κB)‑inducing kinase/NF‑κB. antibody from the manufacturer has come out of the working fluid concentration. The TAMs were color rendered using Materials and methods the REAL™ EnVision™ immunohistochemistry kit (Dako; Agilent Technologies, Inc; cat. no. K5007), according to Ethical approval of the study protocol. The present study was the manufacturer's instructions. To score the expression approved by the Ethics Committee of the Affiliated Hospital of of FBL in the TMAs, the TMAs were imaged using an North Sichuan Medical College (Nanchong, China; approval automatic immunohistochemical section scanning system no. 2020ER(A)024; May 29, 2019). Written informed consent (Pannorramic SCAN, Hungary). was provided by patients, their authorized agents or their close relatives prior to the study start for use of their tissue samples IHC scoring. Color intensity was divided into four classifica‑ and clinical details. tions of staining, as follows: None, score=0; weak, score=1; moderate, score=2 and intense, score=3. The proportion of Study cohort. A total of 139 patients with HCC from the positive cells was ranked into five levels, as follows: <5%, Affiliated Hospital of North Sichuan Medical College formed score=0; 5‑25%, score=1; 26‑50%, score=2; 51‑74%, score=3 the study cohort, between June 2014 and December 2016. The and ≥75%, score=4. Multiplication of the staining score with present study included 114 men and 25 women with HCC, with the score for the percentage of positive cells provided the an average age of 54.22 years (age range, 36‑73 years). HCC final score. The cut‑off point for high FBL expression was was confirmed via histological analysis. A total of 139 HCC based on the median IHC score ‑6 (29). Thus, a score <6 was tissues and 81 paired para‑tumor tissues were selected from classified as low FBL protein expression, while a score ≥6 patients who had not undergone radiotherapy or chemotherapy was classified as high FBL protein expression. Each score prior to surgery. In addition, patients with distant metastasis, was independently evaluated by two experienced pathologists Child‑Pugh (28) liver function of grade C or other types of from the Department of Pathology, The First People's Hospital cancer were excluded from the present study. The cancer of Neijiang (Neijiang, China). In the case of ambiguity, a third tissues and corresponding adjacent tissues were applied to experienced pathologist from the Department of Pathology, produce tissue microarrays (TMAs).
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