The Function And Mechanistic Study Of Snora121 In The Metastasis Of Esophageal Squamous Cell Carcinoma

Esophageal cancer(EC)is one of the most aggressive malignant tumors in the world with the sixth leading cause of the cancer mortality globally according to the world health organization(WHO).EC is mainly consisted of two subtypes,esophageal adenocarcinoma(EAC)and esophageal squamous cell carcinoma(ESCC),the latter is the most common histologic type in China.Most ESCC patient were diagnosed at a late stage,loss the opportunity for operation excision.It remains urgent to identify tumor markers for early detection,prognosis prediction and personalized therapies purpose in ESCCSmall nucleolar RNA(snoRNA)is a class of small non-coding RNAs with a length of 60-300 nts encoded by introns.The main function of snoRNAs is related to 2’-0-ribose methylation and pseudouridylation modification by antisense complementary with rRNA.Besides,a part of snoRNAs is participated in the splicing progress and post-transcripted modification for pre-rRNA.In recent years,the family of snoRNAs are identified and play an important role in tumorigenesis.In this study,we found the expression of snora121 was novely up-regulated in ESCC compared with adjacent tissues for transcriptome sequencing in 24-paired tissues.Firstly,we identified snora121 was up-regulated in ESCC tissues.Snora121 promoted the invasion and migration in ESCC cell lines and had no effect on cell proliferation and colony formation.Meanwhile,the result was confirmed in vivo.In order to clarify the mechanism of snora121,DDX21 was identified to interact with snora121 by combining RNA Pull-down assay with mass spectrometry,and the result was proved by RNA-immunoprecipitation(RIP).The expression and localization of DDX21 was not affected by snora121.However,snora121 could elevate the expression of JUN N-Terminal Kinase(JNK)and c-jun,and interaction existed in DDX21,JNK and c-jun.The interaction between DDX21 and JNK is enhanced when snora121 is overexpressed.Therefore,we suggested that snora121 affected the progression of invasion ang migration in ESCC via affecting the DDX21/JNK/c-jun complex formation.Esophageal squamous cell carcinoma(ESCC)is one of the most common malignant tumors in China with an overall 5-year survival less than 20%.Most ESCC patient were diagnosed at a late stage,loss the opportunity for operation excision.It remains urgent to identify tumor markers for early detection,prognosis prediction and personalized therapies purpose in ESCC.Interferon-stimulated gene 15(ISG15)encodes a 15 KDa protein responsible for post-translational modification(PTMs)of multiple protein targets involved in cellular responses.However,the molecular functions of ISG15 in the progression of ESCC remains unclear.In this work,we found ISG15 was aberrantly expressed ESCC tissues and cell lines.Enhanced protein level of ISG15 promoted cellular malignant phenotypes including proliferation,migration,invasion and tumor formation in vivo.Consistently,depletion of ISG15 attenuated the cellular malignant phenotype in ESCC cell lines.Furthermore,gene-expression profiles suggested the differentially expressed ISG15 could affected the expression of a panel of genes enrichment in the cell adherens junction such as c-MET,Fyn and β-catenin.Notably,as a secreted protein,the concentration of ISG15 was higher in ESCC plasma than healthy individuals,acting as a potential diagnostic marker.Taken together,our work suggested a tumor promotion role of ISG15 in ESCC via c-MET/Fyn/β-catenin pathway.