Abstract:Objective: To analyze characteristics of dual specificity phosphatases (DUSPs) gene family expression in hepatocellular carcinoma (HCC) and their correlation with severity of clinical prognosis and immune cells infiltration. Methods: Characteristics of DUSPs mRNA expression and its correlation with severity of clinical prognosis and immune cell infiltration were analyzed in public database: Oncomine、GEPIA、Kaplan-Meier plotter,TCGA,TIMER. 19 paired HCC tissues were collected from our hospital to analyze DUSPs protein expression characteristics and their correlation with the pathological grade and clinical stage. Gene enrichment analysis (GSEA) was used to predict the possible mechanism of DUSPs involved in HCC progression. Results: Public database analysis results showed that compared with adjacent tissues, DUSP12 mRNA was highly expressed in HCC tumour tissues (P<0.05), and high expression of DUSP12 mRNA was associated with decreased overall survival rate (P< 0.001), increased pathological grade (P<0.001), increased elevated immune cells infiltration (P<0.001) and elevated expression of immune checkpoint related molecules (P<0.001). Immunohistochemical staining results of paired HCC postoperative tumour and adjacent tissues collected in our hospital showed that compared with adjacent tissues, DUSP12 protein was highly expressed in HCC tumour tissues (P<0.001), and further increased with the increase of pathological grade (P<0.05) and clinical stage (P<0.05). GSEA predicted that DUSP12 was involved in HCC progression by regulating cell cycle, RNA splicing, bile acid synthesis and retinol metabolism. Conclusion: DUSP12 expression is significantly up-regulated in HCC tumour tissues, and HCC patients with high expression of DUSP12 have decreased overall survival rate, increased pathological grade, elevated immune cell infiltration and expression of immune checkpoint related molecules. DUSP12 can be used as an important biomarker to predict the pathological grade and prognosis of HCC patients.
[1] Chen HF,Chuang HC,Tan TH.Regulation of dual-specificity phosphatase (DUSP) ubiquitination and protein stability[J].Int Mol Sci,2019,20 (11):2668. [2] Nunes-Xavier CE,Martin-Perez J,Elson A,et al.Protein tyrosine phosphatases as novel targets in breast cancer therapy[J].Biochim Biophys Acta,2013,1836 (2):211~226. [3] Rhodes DR,Yu J,Shanker K,et al.ONCOMINE:a cancer microarray database and integrated data-mining platform[J].Neoplasia,2004,6 (1):1~6. [4] Gyorffy B,Lanczky A,Eklund AC,et al.An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients[J].Breast Cancer Res Treat,2010,123 (3):725~731. [5] Gyorffy B,Lanczky A,Szallasi Z.Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients[J].Endocr Relat Cancer,2012,19 (2):197~208. [6] Tomczak K,Czerwinska P,Wiznerowicz M.The cancer genome atlas (TCGA):an immeasurable source of knowledge[J].Contemp Oncol (Pozn),2015,19(1A):A68~77. [7] 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~e110. [8] Gerber JM,Gucwa JL,Esopi D,et al.Genome-wide comparison of the transcriptomes of highly enriched normal and chronic myeloid leukemia stem and progenitor cell populations[J].Oncotarget,2013,4 (5):715~728. [9] Huang Z,Wu LM,Zhang JL,et al.Dual specificity phosphatase 12 regulates hepatic lipid metabolism through inhibition of the lipogenesis and apoptosis signal-regulating kinase 1 pathways[J].Hepatology,2019,70 (4):1099~1118. [10] Kim EK,Choi EJ.Compromised MAPK signaling in human diseases:an update[J].Arch Toxicol,2015,89 (6):867~882. [11] Subbannayya Y,Pinto SM,Bosl K,et al.Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling[J].Int Mol Sci,2019,20 (9):2086.