Analysis of CCN4 expression and its clinical significance in hepatocellular carcinoma based on bioinformatics

doi:10.3877/cma.j.issn.2095-3232.2023.06.020

Abstract

Abstract:

Objective

To investigate the expression level and clinical significance of cellular communication network factor 4 (CCN4) gene in hepatocellular carcinoma (HCC) based on bioinformatics.

Methods

The expression level of CCN4 protein in HCC tissues and its relationship with clinicopathological parameters were analyzed by TCGA database. The correlation between the expression of CCN4 protein and tumor purity and immune cell infiltration was analyzed by TIMER database. Kaplan-Meier Plotter database was used to analyze the relationship between the expression of CCN4 protein and clinical prognosis in HCC. Protein-protein interaction (PPI) network was constructed by using STRING database, and the correlation between proteins was assessed. The relationship between CCN4 expression and clinicopathological parameters was analyzed by Chi-square test. Correlation analysis was conducted by Spearman's rank correlation.

Results

Clinical information and corresponding RNA sequencing data of 371 patients were obtained from TCGA HCC dataset. Data analysis showed that the expression of CCN4 protein in HCC patients was correlated with race, T stage and pathological G grade (χ²=9.055, 14.012, 17.163; P<0.05). Kaplan-Meier Plot demonstrated that HCC patients with high expression of CCN4 obtained shorter overall survival (HR=1.50, 95%CI: 1.05-2.14, P<0.05). TIMER database analysis showed that the expression level of CCN4 in HCC was negatively correlated with tumor purity (r_s=-0.397, P<0.05), whereas positively correlated with the infiltration levels of B cells, CD8⁺T cells, CD4⁺T cells, macrophages, neutrophils, dendritic cells and M2 macrophages (r_s=0.306, 0.279, 0.460, 0.490, 0.465, 0.404, 0.532; P<0.05). PPI network analysis indicated that decorin was the main protein interacting with CCN4 (score=0.953).

Conclusions

The expression level of CCN4 protein is associated with race, T stage and pathological G grade, which can be used as a biomarker for poor prognosis of HCC. The underlying mechanism may be related to the infiltration of immune cells, the polarization of M2 macrophages and the formation of stromal fibers.

Key words: Carcinoma, hepatocellular, CCN4 gene, WISP1 gene, Biomarker, Bioinformatics

An Chen, Juan Feng, Zhenyu Yang, Xilin Du, Qiangshan Bai, Jikai Yin, Li Zang, Jianguo Lu. Analysis of CCN4 expression and its clinical significance in hepatocellular carcinoma based on bioinformatics[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2023, 12(06): 702-707.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhgzwkssxdzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-3232.2023.06.020

https://zhgzwkssxdzzz.cma-cmc.com.cn/EN/Y2023/V12/I06/702

Figures/Tables 3

References 29

[1]	杨振宇, 杜锡林, 雷世雄, 等. 肝切除联合微波固化治疗BCLC-B期肝细胞癌的生存预后分析[J]. 中华普通外科杂志, 2017, 32(5):381-385.
[2]	Yeger H, Perbal B. CCN family of proteins: critical modulators of the tumor cell microenvironment[J]. J Cell Commun Signal, 2016, 10(3):229-240.
[3]	Nishida T, Kubota S, Aoyama E, et al. CCN family protein 2 (CCN2) promotes the early differentiation, but inhibits the terminal differentiation of skeletal myoblasts[J]. J Biochem, 2015, 157(2):91-100.
[4]	Li J, Ye L, Owen S, et al. Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (review) [J]. Int J Mol Med, 2015, 36(6):1451-1463.
[5]	Weiskirchen R. CCN proteins in normal and injured liver[J]. Front Biosci, 2011, 16(5):1939-1361.
[6]	Zarogoulidis P, Tsakiridis K, Karapantzou C, et al. Use of proteins as biomarkers and their role in carcinogenesis[J]. J Cancer, 2015, 6(1):9-18.
[7]	Tsai HC, Tzeng HE, Huang CY, et al. WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma[J]. Cell Death Dis, 2017, 8(4):e2750.
[8]	Klenotic PA, Zhang C, Lin Z. Emerging roles of CCN proteins in vascular development and pathology[J]. J Cell Commun Signal, 2016, 10(3):251-257.
[9]	Gaudreau PO, Clairefond S, Class CA, et al. WISP1 is associated to advanced disease, EMT and an inflamed tumor microenvironment in multiple solid tumors[J]. Oncoimmunology, 2019,8(5):e1581545.
[10]	Vasaikar SV, Straub P, Wang J, et al. LinkedOmics: analyzing multi-omics data within and across 32 cancer types[J]. Nucleic Acids Res, 2018, 46(D1):D956-963.
[11]	Li T, Fan J, Wang B, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells[J]. Cancer Res, 2017, 77(21):e108-110.
[12]	Tang Z, Kang B, Li C, et al. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis[J]. Nucleic Acids Res, 2019, 47(W1):W556-560.
[13]	Nagy á, Lánczky A, Menyhárt O, et al. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets[J]. Sci Rep, 2018, 8(1):9227.
[14]	Szklarczyk DFA, Wyder S. String v10: proteinprotein interaction networks, integrated over the tree oflife[J]. Nucleic Acids Res, 2015, 43(Database issue):D447-452.
[15]	Gilbert DC, Serup-Hansen E, Linnemann D, et al. Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer[J]. Br J Cancer, 2016, 114(2):134-137.
[16]	Jia Q, Dong Q, Qin L. CCN: core regulatory proteins in the microenvironment that affect the metastasis of hepatocellular carcinoma[J]. Oncotarget, 2016, 7(2):1203-1214.
[17]	Deng W, Fernandez A, McLaughlin SL, et al. WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition[J]. J Biol Chem, 2019, 294(14):5261-5280.
[18]	Soon LL, Yie TA, Shvarts A, et al. Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation[J]. J Biol Chem, 2003, 278(13):11465-11470.
[19]	Jia S, Qu T, Feng M, et al. Association of Wnt1-inducible signaling pathway protein-1 with the proliferation, migration and invasion in gastric cancer cells[J]. Tumour Biol, 2017, 39(6):1010428317699755.
[20]	Davies SR, Watkins G, Mansel RE, et al. Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer[J]. Ann Surg Oncol, 2007, 14(6):1909-1918.
[21]	Tao W, Chu C, Zhou W, et al. Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma[J]. Nat Commun, 2020, 11(1):3015.
[22]	Liu L, Hu J, Yang L, et al. Association of WISP1/CCN4 with risk of overweight and gestational diabetes mellitus in Chinese pregnant women[J]. Dis Markers, 2020:4934206.
[23]	Ono M, Masaki A, Maeda A, et al. CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα[J]. Matrix Biol, 2018(68/69):533-546.
[24]	Chen CT, Lee HL, Chiou HL, et al. Impacts of WNT1-inducible signaling pathway protein 1 polymorphism on hepatocellular carcinoma development[J]. PLoS One, 2018, 13(6):e0198967.
[25]	Yan J, Lei J, Chen L, et al. Human leukocyte antigen F locus adjacent transcript 10 overexpression disturbs WISP1 protein and mRNA expression to promote hepatocellular carcinoma progression[J]. Hepatology, 2018, 68(6):2268-2284.
[26]	Liao X, Bu Y, Xu Z, et al. WISP1 predicts clinical prognosis and is associated with tumor purity, immunocyte infiltration, and macrophage M2 polarization in pan-cancer[J]. Front Genet, 2020(11):502.
[27]	Kim H, Son S, Shin I. Role of the CCN protein family in cancer[J]. BMB Rep, 2018, 51(10):486-492.
[28]	Baghy K, Reszegi A, Tátrai P, et al. Decorin in the tumor microenvironment[J]. Adv Exp Med Biol, 2020(1272):17-38.
[29]	Wang M, Li Z, Zhang M, et al. Decorin knockdown affects the gene expression profile of adhesion, growth and extracellular matrix metabolism in C-28/I2 chondrocytes[J]. PLoS One, 2020, 15(4):e0232321.

Please choose a citation manager

Content to export