title: Downregulation of the novel tumor suppressor DIRAS1 predicts poor prognosis in esophageal squamous cell carcinoma.
abstract: Loss of chromosome 19p is one of the most frequent allelic imbalances in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes within this region. In this study, we investigated a role in ESCCs for a candidate tumor suppressor gene located at 19p13.3, the Ras-like small GTPase DIRAS1. Downregulation of DIRAS1 occurred in approximately 50% of primary ESCCs where it was associated significantly with advanced clinical stage, lymph node metastasis, and poor overall survival. LOH and promoter methylation analyses suggested that loss of DIRAS1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of DIRAS1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation. Mechanistic investigations suggested that DIRAS1 acted through extracellular signal-regulated kinase (ERK1/2; MAPK3/1) and p38 mitogen-activated protein kinase (MAPK; MAPK14) signaling to trigger BAD Ser112 dephosphorylation and matrix metalloproteinase (MMP)2/9 transcriptional inactivation to promote apoptosis and inhibit metastasis, respectively. Taken together, our results revealed that DIRAS1 has a pivotal function in ESCC pathogenesis, with possible use as a biomarker and intervention point for new therapeutic strategies.
authors: State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors: Ying-Hui
authors: YH
authors: Zhu
authors: Li
authors: L
authors: Fu
authors: Leilei
authors: L
authors: Chen
authors: Yan-Ru
authors: YR
authors: Qin
authors: Haibo
authors: H
authors: Liu
authors: Fajun
authors: F
authors: Xie
authors: Tingting
authors: T
authors: Zeng
authors: Sui-Sui
authors: SS
authors: Dong
authors: Jiangchao
authors: J
authors: Li
authors: Yan
authors: Y
authors: Li
authors: Yongdong
authors: Y
authors: Dai
authors: Dan
authors: D
authors: Xie
authors: Xin-Yuan
authors: XY
authors: Guan
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality* / Q000556:secondary; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C468772:DIRAS1 protein, human; D020558:GTP Phosphohydrolases