The Functional Role And Underlying Molecular Mechanism Of LncRNA HNF1A-AS1 In The Metastatic Progression Of Colon Cancer

Background A newly identified long non-coding RNA HNF1A-AS1(HNF1A antisense RNA 1),which transcribed from the opposite strand of HNF1 A gene transcription is a 2455-nucleotide single-exon transcript with no protein-coding capacity located at chromosomal band 12q24.31.A previous report demonstrated that lnc RNA HNF1A-AS1 was detectable and highly expressed in human gastrointestinal track including esophagus,small intestine and colon by expression profiling of HNF1A-AS1 across 20 normal human tissues.Dysregulation of lnc RNA HNF1A-antisense 1(HNF1A-AS1)has been reported in many types of human cancers,and studies on lnc RNA HNF1A-AS1 function in cancers revealed that lnc RNA HNF1A-AS1 could act as either oncogene or tumor suppressor.Nevertheless,the functional involvement of lnc RNA HNF1A-AS1 in colon cancer remains unknown.The current study aimed to investigate the clinical relevance of lnc RNA HNF1A-AS1 and its activities in colon cancer.Methods lncRNA HNF1A-AS1 expression was evaluated in 98 paired clinical colon cancer samples by quantitative real-time PCR(q RT-PCR).A series of in vitro and in vivo cell biology assays were performed to explore the effects of lnc RNA HNF1A-AS1 in regulating cell proliferation,migration,invasion and apoptosis.Insights of the mechanism of competing endogenous RNAs(ce RNAs)were elucidated by fluorescent in situ hybridization(FISH),bioinformatics analysis,luciferase assays and RNA binding protein immunoprecipitation(RIP)in colon cancer cells.Results lncRNA HNF1A-AS1 was frequently upregulated in colon cancer tissues(66/98,67.3%),where it was associated with advanced stage(p=0.007),vascular invasion(p=0.001),distant metastasis(p=0.012)and lymph node metastas is(p<0.001).The Kaplan–Meier plot showed upregulation of lnc RNA HNF1A-AS1 predicted both shorter overall survival and disease free survival.Moreover,lnc RNA HNF1A-AS1 silencing decreased colon cancer cell proliferation and invas ion and increased apoptosis in vitro;lnc RNA HNF1A-AS1 s ilencing also inhibited tumor growth and metastasis in vivo.lnc RNA HNF1A-AS1 functioned as a competing endogenous RNA(ce RNA)by directly targeting and down-regulating mi RNA-34 a,consequently with repression of mi R-34a/SIRT1/p53 feedback loop and activation of a set of canonical Wnt genes.Conclusions In this study,we reported that lnc RNA HNF1A-AS1 was frequently upregulated in colon cancer tissues and associated with poor prognosis.Upregulated HNF1A-AS1 promoted colon cancer cell viability,migration and invasion both in vitro and in vivo.lnc RNA HNF1A-AS1 silencing impaired tumor growth and metastasis in xenograft model assay.Moreover,lnc RNA HNF1A-AS1 functioned as an oncogene in metastas is of colon cancer in part through serving as a competing endogenous RNA to modulate mi RNA-34 a expression,subsequently with repression of mi R-34a/SIRT1/p53 feedback loop and activation of canonical Wnt signaling pathway.Our results demonstrated that lnc RNA HNF1A-AS1 mediated the metastatic progression of colon cancer in part through mi R-34a/p53 signaling axis,and established its candidacy as a new prognostic biomarker and a potential novel therapeutic target.